cholecystokinin and Pain

Opioid peptides and receptors are broadly expressed throughout peripheral and central nervous systems and have been the subject of intense long-term investigations. Such studies indicate that some endogenous neuropeptides, called anti-opioids, participate in a homeostatic system that tends to reduce the effects of endogenous and exogenous opioids. Anti-opioid properties have been attributed to various peptides, including melanocyte inhibiting factor (MIF)-related peptides, cholecystokinin (CCK), nociceptin/orphanin FQ (N/OFQ), and neuropeptide FF (NPFF). These peptides counteract some of the acute effects of opioids, and therefore, they are involved in the development of opioid tolerance and addiction. In this work, the anti-opioid profile of endogenous peptides was described, mainly taking into account their inhibitory influence on opioid-induced effects. However, the anti-opioid peptides demonstrated complex properties and could show opioid-like as well as anti-opioid effects. The aim of this review is to detail the phenomenon of crosstalk taking place between opioid and anti-opioid systems at the in vivo pharmacological level and to propose a cellular and molecular basis for these interactions. A better knowledge of these mechanisms has potential therapeutic interest for the control of opioid functions, notably for alleviating pain and/or for the treatment of opioid abuse.

Topics: Analgesics, Opioid; Cholecystokinin; Drug Tolerance; Humans; Narcotic Antagonists; Nociceptin; Oligopeptides; Opioid Peptides; Pain; Receptors, Opioid; Substance-Related Disorders

Pain is a hallmark of almost all bodily ailments and can be modulated by agents, including analgesics and anesthetics that suppress pain signals in the central nervous system. Defects in the modulatory systems, including the endogenous pain-inhibitory pathways, are a major factor in the initiation and chronicity of pain. Thus, pain modulation is particularly applicable to the practice of medicine. This review summarizes the existing literature on pain modulation. Here, we critically reviewed the literature from PubMed on pain modulation published primarily within the past 5 years in high impact journals. Specifically, we have discussed important anatomical landmarks of pain modulation and outlined the endogenous networks and underlying mechanisms of clinically relevant pain modulatory methods. The Gate Control Theory is briefly presented with discussion on the capacity of pain modulation to cause both hyper- and hypoalgesia. An emphasis has been given to highlight key areas in pain research that, because of unanswered questions or therapeutic potential, merit additional scientific scrutiny. The information presented in this paper would be helpful in developing novel therapies, metrics, and interventions for improved patient management.

Topics: Adrenergic Neurons; Amygdala; Analgesics; Analgesics, Opioid; Anesthetics; Animals; Autonomic Nervous System; Cholecystokinin; Galanin; gamma-Aminobutyric Acid; Humans; Hyperalgesia; Mice; Pain; Pain Management; Placebos; Rats; Receptors, Cannabinoid; Serotonin; Signal Transduction; Treatment Outcome

The accurate assessment of pain is needed to control cancer pain and its treatment. Pain itself is subjective experience and is difficult to estimate quantitatively. Until now, there is no precise method to quantitate the cancer pain objectively. First, we show the tools to assess cancer pain by patient's description, including visual analogue scales, verval rating scales and numerical rating scales and so on. These scales have been used to evaluate the intensity of clinical pain, however they cannot assess the quality of cancer pain and only McGill Pain Questionnaire (MPQ) has specificity for the qualitative and quantitative properties of clinical pain. Molecular biological approach has been advanced in the neuroscience field to find the candidate of neuropathic pain. In this article, we would like to show the results of the proteomics research for neuropathic pain. We also tried to discuss about the biomarker and its possibility whether it can reflect cancer pain and effect of cancer treatment.

Topics: Animals; beta-Endorphin; Biomarkers; Cholecystokinin; Cytokines; Humans; Neoplasms; Oxidative Stress; Pain; Pain Measurement

The nocebo effect is a phenomenon that is opposite to the placebo effect, whereby expectation of a negative outcome may lead to the worsening of a symptom. Thus far, its study has been limited by ethical constraints, particularly in patients, as a nocebo procedure is per se stressful and anxiogenic. It basically consists in delivering verbal suggestions of negative outcomes so that the subject expects clinical worsening. Although some natural nocebo situations do exist, such as the impact of negative diagnoses upon the patient and the patient's distrust in a therapy, the neurobiological mechanisms have been understood in the experimental setting under strictly controlled conditions. As for the placebo counterpart, the study of pain has been fruitful in recent years to understand both the neuroanatomical and the neurochemical bases of the nocebo effect. Recent experimental evidence indicates that negative verbal suggestions induce anticipatory anxiety about the impending pain increase, and this verbally-induced anxiety triggers the activation of cholecystokinin (CCK) which, in turn, facilitates pain transmission. CCK-antagonists have been found to block this anxiety-induced hyperalgesia, thus opening up the possibility of new therapeutic strategies whenever pain has an important anxiety component. Other conditions, such as Parkinson's disease, although less studied, have been found to be affected by nocebo suggestions as well. All these findings underscore the important role of cognition in the therapeutic outcome, and suggest that nocebo and nocebo-related effects might represent a point of vulnerability both in the course of a disease and in the response to a therapy.

Topics: Animals; Brain; Cholecystokinin; Cognition; Emotions; Fear; Humans; Hyperalgesia; Magnetic Resonance Imaging; Pain; Parkinson Disease

Chronic pancreatitis represents a condition that is challenging for clinicians secondary to the difficulty in making an accurate diagnosis and the less than satisfactory means of managing chronic pain. This review emphasises the various manifestations that patients with chronic pancreatitis may have and describes recent advances in medical and surgical therapy. It is probable that many patients with chronic abdominal pain are suffering from chronic pancreatitis that is not appreciated. As the pathophysiology of this disorder is better understood it is probable that the treatment will be more successful.

Topics: Cholangiopancreatography, Endoscopic Retrograde; Cholecystokinin; Clinical Enzyme Tests; Diagnosis, Differential; Endoscopy, Digestive System; Female; Humans; Islets of Langerhans Transplantation; Malabsorption Syndromes; Male; Nerve Block; Oxidative Stress; Pain; Pain Management; Pancreas; Pancreatitis, Chronic

It is well documented that stressful life experiences contribute to the etiology of human mood disorders. Cholecystokinin (CCK) is a neuropeptide found in high concentrations throughout the central nervous system, where it is involved in numerous physiological functions. A role for CCK in the induction and persistence of anxiety and major depression appears to be conspicuous. While increased CCK has been associated with motivational loss, anxiety and panic attacks, an increase in mesocorticolimbic opioid availability has been associated with coping and mood elevation. The close neuroanatomical distribution of CCK with opioid peptides in the limbic system suggests that there may be an opioid-CCK link in the modulation and expression of anxiety or stressor-related behaviors. In effect, while CCK induces relatively protracted behavioral disturbances in both animal and human subjects following stressor applications, opioid receptor activation may change the course of psychopathology. The antagonistic interaction of CCK and opioid peptides is evident in psychological disturbances as well as stress-induced analgesia. There appears to be an intricate balance between the memory-enhancing and anxiety-provoking effects of CCK on one hand, and the amnesic and anxiolytic effects of opioid peptides on the other hand. Potential anxiogenic and mnemonic influences of site-specific mesocorticolimbic CCK and opioid peptide availability, the relative contributions of specific CCK and opioid receptors, as well as the time course underlying neuronal substrates of long-term behavioral disturbances as a result of stressor manipulations, are discussed.

Topics: Animals; Cholecystokinin; Cognition; Emotions; Endorphins; Humans; Pain; Receptors, Cholecystokinin

Cholecystokinin, originally thought to be confined only to the gastrointestinal tract, is now known to be co-localised in both the gastrointestinal tract and central nervous system. In animal models levels are increased after neural injury and with opioid administration. This peptide acts as an anti-opioid, and as levels increase, the extent of opioid derived antinociception decreases. Co-administration of a CCK antagonist along with an opioid is associated with an improved level of antinociception. Furthermore CCK antagonists may prevent antinociceptive tolerance with opioids and even reverse established tolerance. Human studies have now confirmed the pro-analgesic effect of some CCK antagonists. Human investigation of the effect of CCK antagonists on analgesic tolerance has yet to be performed. This review examines the available evidence that suggests a role for CCK antagonists in human pain management.

Topics: Analgesics; Animals; Cholecystokinin; Clinical Trials as Topic; Drug Tolerance; Dynorphins; Enkephalins; Humans; Narcotics; Pain; Time Factors

Opioid analgesics are frequently used for the long-term management of chronic pain states, including cancer pain. The prolonged use of opioids is associated with a requirement for increasing doses to manage pain at a consistent level, reflecting the phenomenon of analgesic tolerance. It is now becoming clearer that patients receiving long-term opioid therapy can develop unexpected abnormal pain. Such paradoxical opioid-induced pain, as well as tolerance to the antinociceptive actions of opioids, has been reliably measured in animals during the period of continuous opioid delivery. Several recent studies have demonstrated that such pain may be secondary to neuroplastic changes that result, in part, from an activation of descending pain facilitation mechanisms arising from the rostral ventromedial medulla (RVM). One mechanism which may mediate such pain facilitation is through the increased activity of CCK in the RVM. Secondary consequences from descending facilitation may be produced. For example, opioid-induced upregulation of spinal dynorphin levels seem to depend on intact descending pathways from the RVM reflecting spinal neuroplasticity secondary to changes at supraspinal levels. Increased expression of spinal dynorphin reflects a trophic action of sustained opioid exposure which promotes an increased pain state. Spinal dynorphin may promote pain, in part, by enhancing the evoked release of excitatory transmitters from primary afferents. In this regard, opioids also produce trophic actions by increasing CGRP expression in the dorsal root ganglia. Increased pain elicited by opioids is a critical factor in the behavioral manifestation of opioid tolerance as manipulations which block abnormal pain also block antinociceptive tolerance. Manipulations that have blocked enhanced pain and antinociceptive tolerance include reversible and permanent ablation of descending facilitation from the RVM. Thus, opioids elicit systems-level adaptations resulting in pain due to descending facilitation, upregulation of spinal dynorphin and enhanced release of excitatory transmitters from primary afferents. Adaptive changes produced by sustained opioid exposure including trophic effects to enhance pain transmitters suggest the need for careful evaluation of the consequences of long-term opioid administration to patients.

Topics: Analgesics, Opioid; Animals; Cholecystokinin; Drug Tolerance; Humans; Medulla Oblongata; Pain; Pain Measurement

Patients with suspected functional biliary pain often undergo cholecystectomy if a decreased gall-bladder ejection fraction (GBEF <35%) is demonstrated by cholecystokinin cholescintigraphy. However, the validity of GBEF in predicting which patients will have symptomatic relief following cholecystectomy is unclear.. To determine whether patients with suspected functional biliary pain with decreased GBEF have a better symptomatic outcome after cholecystectomy than those with normal GBEF.. Systematic review and meta-analysis of the published literature through MEDLINE and EMBASE databases.. We included nine studies with a total of 974 patients with suspected functional biliary pain; 362 patients underwent cholecystectomy. Most studies assessed outcome by direct patient interview. Mean ages across the studies ranged from 35 to 47 years; 78% of all patients were female. Mean duration of follow-up after surgery ranged from 1 to 2.5 years. After cholecystectomy, 94% of the patients with reduced GBEF had a positive outcome compared to 85% among those with normal GBEF. The pooled Mantel-Haenszel odds ratio for positive outcome was 1.37 (95% confidence interval 0.56-3.34), P=0.56.. These data do not support the use of GBEF to select patients with suspected functional biliary pain for cholecystectomy. Prospective randomized trials are required if this practice is to be evidence-based.

Topics: Cholecystectomy; Cholecystokinin; Gallbladder; Gallbladder Diseases; Gallbladder Emptying; Humans; Pain; Radionuclide Imaging; Radiopharmaceuticals; Technetium Tc 99m Disofenin; Treatment Outcome

Biliary pain is commonly reported in household surveys with the presumed cause being gallstones. When gallstones are absent or other abnormalities as a potential cause of similar pain do not exist, a different approach is necessary. Although trans-abdominal ultrasound can detect stones down to 3-5 mm, the advent of endoscopic ultrasound provides an even better definition for microlithiasis of < 3 mm. Duodenal aspiration of bile can further detect cholesterol microlithiasis or bilirubin granules, another potential source of biliary-type pain and perhaps even pancreatitis. Only in this way can acalculous gallbladder disease be clearly defined. The percentage of cholecystokinin-stimulated gallbladder emptying has been reputed to be the most sensitive diagnostic test for 'biliary dyskinesia', but abnormality of gallbladder emptying can be due to a smooth muscle defect of the gallbladder itself or heightened tone in the sphincter of Oddi. The value of surgical intervention has not been clearly established. The advent of laparoscopic cholecystectomy, however, has increased the number of patients with acalculous biliary disease who undergo surgery. Surgery is best done using impaired gallbladder emptying as the criterion for operation with improved outcome. Often, following cholecystectomy, biliary pain does not resolve the so-called 'post cholecystectomy syndrome'. Absence of the gallbladder as a pressure reservoir leaves the sphincter of Oddi as the prime determinant of bile duct pressure. Sphincter of Oddi dysfunction also exists in patients with an intact biliary tract and may become evident following cholecystectomy. Biliary manometry has clarified who might benefit from sphincterotomy. Choledochoscintigraphy is a non-invasive preliminary test. Advent of visceral hypersensitivity and better definition of this entity has shown, that in some of these patients with type III sphincter of Oddi, dysfunction appears to reside in duodenal hyperalgesia. It is clear that improved criteria are required to perform gallbladder emptying and better techniques to detect visceral hypersensitivity. Nonetheless, functional biliary pain in the absence of gallstone disease is a definite entity and a challenge for clinicians.

Topics: Acalculous Cholecystitis; Bile Ducts; Biliary Dyskinesia; Cholecystectomy, Laparoscopic; Cholecystokinin; Gallbladder Emptying; Humans; Pain; Postcholecystectomy Syndrome; Sphincter of Oddi

It is well established that cholecystokinin (CCK) reduces the antinociceptive effect of opioids. The level of CCK and CCK receptors, as well as CKK release, exhibits considerable plasticity after nerve injury and inflammation, conditions known to be associated with chronic pain. Such altered CCK release coupled in some situation with changes in CCK receptor levels may underlie the clinical phenomenon of varying opioid sensitivity in different clinical pain conditions. In particular, neuropathic pain after injury to the peripheral and central nervous system does not respond well to opioids, which is likely to be caused by increased activity in the endogenous CCK system. CCK receptor antagonists may thus be useful as analgesics in combination with opioids to treat neuropathic pain.

Topics: Analgesia; Animals; beta-Endorphin; Cholecystokinin; Chronic Disease; Humans; Inflammation; Morphine; Pain; Rats; Receptors, Cholecystokinin; Spinal Cord Injuries

Neuropeptides present in primary afferents and the dorsal horn of the spinal cord have an important role in the mediation of nociceptive input under normal conditions. Under pathological conditions, such as chronic inflammation or following peripheral nerve injury, the production of peptides and peptide receptors is dramatically altered, leading to a number of functional consequences. In this review, the role of two neuropeptides that undergo such altered expression under pathological conditions, cholecystokinin (CKK) and galanin, is reviewed.

Topics: Animals; Cholecystokinin; Galanin; Humans; Inflammation; Mononeuropathies; Neuropeptides; Pain; Polyneuropathies

According to the concept of negative feedback regulation of pancreatic enzyme secretion by proteases, treatment with pancreatic extracts has been proposed to lower pain in chronic pancreatitis by decreasing pancreatic duct pressure. The author, however, has demonstrated in healthy volunteers that intraduodenal application of porcine pancreatic extracts does not inhibit but rather stimulates pancreatic enzyme secretion. This is probably because of the high-protein content of porcine pancreatic extracts that may overwhelm a potential inhibitory effect of proteases. In a prospective placebo-controlled, double-blind multicenter study to investigate the effect of acid-protected porcine pancreatic extracts on pain in 43 patients with chronic pancreatitis, pain improved in most patients regardless of whether they started with placebo or verum. There was no significant difference between both treatment arms. In a meta-analysis, which included the author's study, six randomized, double-blind, placebo-controlled studies were evaluated. Statistical analysis demonstrated no benefit of the application of porcine pancreatic extracts to relieve pain in chronic pancreatitis. The author concluded that pancreatic extracts neither inhibit pancreatic enzyme secretion nor are they efficient in lowering pain in chronic pancreatitis.

Topics: Animals; Cholecystokinin; Chronic Disease; Feedback; Humans; Pain; Pancreatic Extracts; Pancreatitis

Until recently, basic science studies, both behavioural and electrophysiological, have concentrated on the antinociceptive actions of opioids primarily gauged against acute nociceptive responses. However, of more relevance to clinical situations are the actions of opioids in more persistent/prolonged pain states. This review sets out to examine the central actions of opioids against nociception of inflammatory origins. The first section deals with the response of the endogenous opioid system to the development of an inflammatory state and the second examines the ability of exogenous opioids to modulate inflammatory nociception. There are complex changes in the roles of endogenous opioids, in particular dynorphin, at the spinal level after inflammation although the physiological consequences remain unclear. With regard to exogenous opioids, the effectiveness of spinal morphine is rapidly enhanced after inflammation, likely to be due to changes in the interaction between the peptide cholecystokinin and the mu opioid receptor. The ability of inflammatory processes to alter both endogenous opioids and morphine analgesia at the spinal level illustrates the considerable degree of plasticity observed in opioid function.

Topics: Analgesia; Animals; Carrageenan; Cholecystokinin; Disease Models, Animal; Inflammation; Injections, Spinal; Narcotics; Opioid Peptides; Pain; Receptors, Adrenergic, alpha-2; Receptors, Opioid; Spinal Cord; Synaptic Transmission

Nociception is of vital importance for the organism, while its inhibition by endogenous opioid systems is usually a sign of surrender. Therefore, it must be assumed that endogenous analgesic systems are balanced, and in fact, under normal conditions, overwhelmed, by teleologically far more important anti-analgesic systems. The two main anti-analgesic systems--i.e., the melanotropinergic and the cholecystokininergic--are here reviewed for their role, not only in nociception, but in a wide variety of vital functions (endocrine, gastrointestinal, ingestive, reproductive, cardiovascular, immune, etc.). Available data strongly suggest that these systems (particularly the melanotropinergic one) play a key role in the overall homeostasis of the body. Moreover, modulation of endogenous anti-analgesic systems may disclose a new, unforeseen approach to the treatment of pain.

Topics: Analgesia; Cholecystokinin; Humans; Melanocyte-Stimulating Hormones; Pain; Receptors, Cholecystokinin; Receptors, Pituitary Hormone

CCK was first identified and characterized in the digestive tract where it is known to be a factor involved in the control of gut motility. Later, CCK and CCK receptors were identified in regions of the central nervous system that are associated with the control of emotion, motivation and sensory processing. The recent discovery and development of CCK-receptor antagonists having selective affinity for either CCKA or CCKB receptors has led to a better understanding of the functional role of CCK and its binding sites in the brain and periphery. Some of these compounds are being examined in man for their therapeutic usefulness in mental as well as in digestive disorders. This review will highlight the results from both basic and clinical investigations that have examined the effects of selective CCK receptor ligands. The focus will be on the central nervous system pharmacology of CCK antagonists and the involvement of CCK in gastrointestinal and colonic motility.

Topics: Animals; Anxiety Disorders; Brain; Central Nervous System; Cholecystokinin; Gastrointestinal Motility; Humans; Memory; Pain; Receptors, Cholecystokinin

Potent and selective CCK-B agonists with good bioavailability have been designed by modifying the natural CCK-8 peptide. Thus, BC 264 [Boc-Tyr(SO3H)-gNle-mGly-Trp-Me(Nle)-Asp-PheNH2] is a highly potent (0.15 nM) and selective agonist for CCK-B receptors which cross the blood brain barrier. Following i.v. injection of [3H]pBC 264 in mouse, the ligand was found in its intact form in brain tissue. Analgesic studies and in vivo binding experiments have shown that the CCKergic system could modify the release of endogenous enkephalins, whereas mu and delta opioid receptor activation modulates the release of endogenous CCK. Behavioural studies performed after local injection of CCK-8 or BC 264 into the postero-median part of the nucleus accumbens have shown the involvement of CCK-A receptors in motivation and/or emotional states of rats. In the anterior part, CCK-B receptor stimulation could be involved in attention and memory processes. BC 264 systemically administered in mice increased fear and/or "anxiety" in the black and white box test. In the elevated plus maze, BC 264 increased the emotional responses of the "anxious" rat and decreased these responses in "non anxious" animals. These results suggest that endogenous CCK could play a critical role in mood modulation through CCK-A/CCK-B receptor stimulation. Dysfunctioning of the CCK-A/CCK-B pathways could be implicated in anxiety and panic attacks.

Topics: Animals; Behavior, Animal; Biological Availability; Brain; Cholecystokinin; Disease Models, Animal; Emotions; Mice; Nucleus Accumbens; Pain; Rats; Receptors, Cholecystokinin

Recent research on the site of action of morphine, its distribution following systemic administration and activity in a model of neuropathic pain is reviewed. Neuropeptides and pain is discussed in relation to tachykinins and their antagonists, cholecystokinin (CCK) and its antagonists and somatostatin.

Topics: Animals; Cholecystokinin; Endorphins; Humans; Neuralgia; Nociceptors; Pain; Receptors, Adrenergic, alpha; Receptors, Opioid; Sensory Thresholds; Somatostatin; Tachykinins

Vascular headaches are among the most prevalent yet poorly understood problems in clinical neurology. Headaches may develop in association with hypertension, seizures, stroke or without a recognizable pathophysiology such as during migraine and cluster headaches. Cephalic blood vessels (pial and dural vessels) are implicated as the most important source for all headaches and are innervated by sensory fibers which arise from ganglia innervating the forehead, scalp and neck. Sensory fibers contain vasoactive neuropeptides which become released from peripheral (perivascular) and central terminations to mediate vasodilation and pain, respectively. The presence of vascular headache implies activation of this final common pain pathway which we have termed the trigeminovascular system. The presence of vascular headache implies activation of this final common pain pathway which we have termed the trigeminovascular system. The existence of such a system a) clarifies certain pain patterns which develop following stimulation of cephalic blood vessels, b) suggests a mechanism to explain the referral of pain to the forehead, c) provides a mechanism to explain the action of certain antimigraine drugs, d) suggests a local mechanism which enhances blood flow under certain pathological conditions. Hence, this review will update existing knowledge about the trigeminovascular system and its role in headache pathophysiology.

Topics: Animals; Calcitonin Gene-Related Peptide; Cerebrovascular Circulation; Cholecystokinin; Circle of Willis; Dura Mater; Guinea Pigs; Humans; Migraine Disorders; Neuropeptides; Pain; Peptide Fragments; Rats; Subarachnoid Hemorrhage; Tachykinins; Trigeminal Ganglion; Trigeminal Nerve; Vascular Headaches

The octapeptide form of CCK predominates in the central nervous system (CNS) of mammalian species, including man. Many of the physiological roles of CCK in the CNS are unknown, but it is believed to be involved in nociception. CCK is distributed throughout cortical grey matter, periaqueductal grey matter, ventromedial thalamus and spinal dorsal horn, all of which are areas known to be associated with pain modulation. CCK receptor subtypes have been identified and may be classified according to their affinity for the sulphated and desulphated forms of CCK-8 and the recently described selective antagonist. MK-329. CCK-A receptors have high affinity for sulphated CCK-8 and for MK-329 but low affinity for desulphated CCK-8 and CCK-4 whilst CCK-B sites bind MK-329 with low affinity and discriminate poorly between sulphated and desulphated CCK-8. CCK-A receptors are found predominantly in peripheral tissues but they also exist in discrete regions of the primate CNS, including the spinal cord. CCK-B receptors are found ubiquitously throughout other regions of the neuraxis. The results of studies on the effects of CCK-8 and the decapeptide analogue caerulein on pain thresholds are conflicting. Some workers suggest that large doses of CCK-8 and caerulein induce naloxone-reversible analgesia in certain pain models. However, it appears likely that analgesia induced by large doses of CCK and caerulein in animals may be a pharmacological rather than a physiological phenomenon. Accordingly, others have found that small (and most probably, physiological) doses of CCK-8 attenuate the analgesic effects of morphine, and of endogenous opioids. Thus, it has been proposed that CCK may act as an endogenous opiate antagonist. Studies in rats with the selective CCK antagonist MK-329 have helped clarify the interaction between CCK and morphine-induced analgesia. Treatment with MK-329 enhances morphine analgesia and chronic treatment with MK-329 prevents the development of tolerance to morphine analgesia. However, the antagonist does not prevent naloxone-precipitated withdrawal symptoms in morphine-dependent rats. In man, caerulein prevents pain associated with gall-bladder contraction, probably by relaxation of the sphincter of Oddi. Caerulein has also been shown to reduce renal colic and the pain of intermittent claudication. Preliminary clinical studies with the weak, non-selective, CCK antagonist proglumide, indicate an enhancement of morphine analgesia. As yet, no studies hav

Topics: Analgesia; Animals; Ceruletide; Cholecystokinin; Humans; Pain; Receptors, Cholecystokinin

Topics: Analgesia; Animals; Cholecystokinin; Endorphins; Humans; Neuropeptides; Neurotensin; Pain; Substance P

1. CCK-peptides are distributed throughout the whole brain with the exception of the cerebellum. 2. There is strong evidence that they act as neuromodulators on the noradrenergic, opioid and mainly dopaminergic system. 3. CCK reduces food-intake. However, tolerance occurs, when chronically given. Thus, potential benefits in the treatment of obesity seem unlikely. 4. CCK increases threshold and tolerance to electrically and thermally induced cutaneous pain. CCK yields relief of pain in colic and ischaemic pain. 5. To date, results about CCK-content in CSF and post-mortem-brain in various psychiatric and neurological diseases related to the dopaminergic system are equivocal. 6. Treatment studies do not provide evidence for beneficial effects of CCK-peptides in schizophrenia.

Topics: Animals; Brain; Cholecystokinin; Dopamine; Endorphins; Humans; Mental Disorders; Nervous System Diseases; Norepinephrine; Pain

Topics: Animals; Cholecystokinin; Chronic Disease; Chymotrypsin; Enzyme Therapy; Exocrine Pancreatic Insufficiency; Feedback; Female; Humans; Male; Pain; Pancreas; Pancreatitis; Rats; Trypsin

Topics: Analgesia; Animals; Cholecystokinin; Endorphins; Narcotics; Pain; Proglumide; Rats; Receptors, Opioid

Topics: Animals; Cholecystokinin; Mice; Pain; Pain Measurement; Rats; Sincalide

The authors highlight the potential importance of neuropeptides as clinical tools in the study and treatment of pain. Although many questions remain unanswered, it is encouraging that several clinical and experimental advances have shed new light on the neuropharmacology of nociception and have prompted new hope for more effective treatments of such diverse problems as chronic intractable pain, migraine, and drug dependency. Within the next few years, it is anticipated that further work in this area will lead to better basic and clinical understanding of these important clinical problems.

Topics: Animals; Bombesin; Bradykinin; Calcitonin; Central Nervous System; Cholecystokinin; Endorphins; Neurons, Afferent; Neuropeptides; Neurotensin; Pain; Somatostatin; Substance P; Vasopressins

Since the mid-1970s, evidence has accumulated that cholecystokinin (CCK) has a role as a neuromodulator or neurotransmitter in the central nervous system as well as in the periphery. CCK has been shown to have a variety of effects on gastrointestinal functions and is one of the main candidates for a role as a peripheral negative feedback signal to stop feeding behavior. CCK produces satiety not only in animals but also in man: it reduces appetite and activation arising from the preparation of a meal and inhibits intake of liquid and solid food in both lean and obese subjects. The closely related peptide caerulein has similar effects. The site of action of peripherally administered CCK seems to be on an abdominal organ innervated by gastric vagal branches and relayed to the brain by afferent vagal fibres, since selective gastric vagotomy blocks the satiety effect, but pharmacological antagonism of vagal motor effects or lesions of the ventromedial hypothalamus do not. CCK also may have a role in the regulation of pain perception. In mice, CCK and caerulein were shown to produce a decrement in response to noxious stimulation after peripheral and central administration. In man, caerulein was demonstrated to relieve pain originating from biliary and renal colic as well as from cancer and ischemia. A series of studies in healthy man revealed that caerulein also alleviates experimentally induced cutaneous pain. Data from animal studies suggest that CCK-like peptides not only are able to produce analgesic effects on their own, but also are involved in the modulation of opioid systems mediating analgesia. Further study of these effects of CCK should elucidate the regulatory connections between the life-sustaining functions of feeding and pain sensation.

Topics: Analgesics; Animals; Appetite Depressants; Central Nervous System; Ceruletide; Cholecystokinin; Digestive System; Dogs; Endorphins; Feeding Behavior; Female; Gastrointestinal Motility; Haplorhini; Humans; Hunger; Male; Mice; Neural Pathways; Obesity; Pain; Rats; Satiety Response; Sincalide; Vagus Nerve

Cholecystokinin is localized in two distinct systems, the gastrointestinal and the central nervous systems. At both locations, cholecystokinin (CCK) is synthesized, stored, and released, and high affinity binding sites for CCK have been identified. The blood-brain barrier is thought to completely block passage of CCK from the gut to the brain compartment, although CCK can pass from the cerebrospinal fluid out into the blood. A variety of behavioral actions of CCK have been described. Evidence that the actions of CCK on feeding and behavioral sedation are mediated through the peripheral site is reviewed. Recent studies demonstrating behavioral effects of CCK administered in nanogram doses directly into brain nuclei are reviewed. Caveats against administration of microgram doses of CCK into the cerebral ventricles are raised, emphasizing the interpretational difficulties inherent in this approach.

Topics: Animals; Behavior, Animal; Brain; Brain Mapping; Chickens; Cholecystokinin; Cricetinae; Digestive System Physiological Phenomena; Dopamine; Eating; Haplorhini; Humans; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mesocricetus; Mice; Narcotic Antagonists; Nucleus Accumbens; Pain; Rats; Receptors, Cell Surface; Receptors, Cholecystokinin; Sheep; Spinal Cord

Topics: Animals; Body Temperature Regulation; Cholecystokinin; Digestive System Physiological Phenomena; Endorphins; Female; Growth; Lactation; Neurotensin; Pain; Peptides; Pregnancy; Reproduction; Sincalide; Somatostatin; Substance P; Vasoactive Intestinal Peptide

Neuropeptides are sufficiently stable to allow valid radioimmunoassay of peptide concentrations in post-mortem human nervous tissue and in human cerebrospinal fluid. Studies have now documented abnormalities of peptide concentrations in degenerative diseases of the brain. Somatostatin concentration is reduced in the hippocampus and neocortex of patients dying with Alzheimer's type dementia. In Huntington's disease, there are reduced concentrations of substance P, met-enkephalin and cholecystokinin in the basal ganglia; in contrast the concentrations of somatostatin and TRH are increased. Immunocytochemical and experimental lesion studies are underway in an attempt to localize the peptide-containing cells affected by these disorders; and the potential role of alterations in neuropeptide function in the pathogenesis, clinical manifestations and therapy of these illnesses is of great interest. Although alterations of CSF peptide concentrations have been reported in a variety of human diseases, interpretation of these results requires knowledge of the origin and disposition of CSF peptides. Future research into the pathology of peptidergic systems will depend on the development of specific peptide antagonists to probe dynamic aspects of peptide function and on the application of the tools of molecular biology, such as specific mRNA assays, to human material.

Topics: Alzheimer Disease; Animals; Brain; Cholecystokinin; Choline O-Acetyltransferase; Endorphins; Epilepsy; Forecasting; Histocytochemistry; Humans; Huntington Disease; Migraine Disorders; Nerve Tissue Proteins; Nervous System Diseases; Pain; Parkinson Disease; Radioimmunoassay; Somatostatin; Substance P; Thyrotropin-Releasing Hormone; Tissue Distribution; Vasopressins

Topics: Animals; Axonal Transport; Axons; Capsaicin; Cholecystokinin; Edema; Fatty Acids, Unsaturated; Ganglia, Spinal; Nerve Degeneration; Nerve Fibers; Neurons, Afferent; Pain; Rats; Reflex; Sensation; Substance P

Topics: Animals; Cats; Cholecystokinin; Colon; Colonic Diseases, Functional; Dietary Fiber; Digestive System Diseases; Dogs; Electrophysiology; Emotions; Food; Gastrointestinal Hormones; Gastrointestinal Motility; Humans; In Vitro Techniques; Manometry; Muscle Contraction; Neostigmine; Neurotransmitter Agents; Pain; Parasympatholytics; Physical Stimulation; Pressure; Synaptic Transmission

Topics: Analgesia; Angiotensin II; Bombesin; Bradykinin; Cholecystokinin; Endorphins; Humans; Nerve Tissue Proteins; Neurotensin; Oligopeptides; Pain; Somatostatin; Substance P; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide; Vasopressins

To date about thirty peptides--low-molecular-weight, single-chain amino acid compounds--are known to be distributed widely in the central nervous system within selective neuron pathways. These findings, combined with a large body of neuropharmacological, behavioral, and electrophysiological data, open new horizons in neurobiology, force a reexamination of old and accepted hypotheses, and hold important implications for the clinician. There is evidence that substance P and the opioid peptides play a major role in the pain pathway, particularly at the level of the spinal cord. Available evidence also implicates vasoactive intestinal polypeptide in the control of cerebral circulation, cholecystokinin in the regulation of appetite, and vasopressin and adrenocorticotropic hormone in memory. Many questions, however, remain. For most peptides there is little information on mechanisms of biosynthesis, release, interaction with receptors, and termination of biological effect. Another important question is the interaction of peptides with other neurotransmitters. The evidence that both "classic" neurotransmitters and peptides can be found in the same neuronal necessitates reformulation of Dale's "one neuron, one neurotransmitter" hypothesis. It may be that a single cell, while containing different classes of neurotransmitter, will contain only one member of any particular class. It is not too early to speculate on the role of the numerous and diverse peptides in neuronal tissue and on the implications of peptide abnormalities in a variety of neurological diseases. The answers to these and other questions pose a fascinating challenge to neurobiologist and clinician alike.

Topics: Adrenocorticotropic Hormone; Animals; Appetite; Brain; Brain Chemistry; Brain Mapping; Cerebrovascular Circulation; Cholecystokinin; Enkephalins; Humans; Memory; Mesencephalon; Mice; Neural Pathways; Pain; Peptides; Rats; Spinal Cord; Substance P; Vasoactive Intestinal Peptide; Vasopressins

Topics: Abdomen; Biopsy; Carcinoma, Intraductal, Noninfiltrating; Celiac Disease; Cholecystokinin; Diabetes Mellitus; Hepatomegaly; Humans; Jaundice; Laparotomy; Mental Disorders; Pain; Palliative Care; Pancreatectomy; Pancreatic Neoplasms; Prednisolone; Prognosis; Radioisotopes; Radionuclide Imaging; Secretin; Selenium

This study was undertaken to test the effect of sequential administration of an opioid and intravenous cholecystokinin (CCK) on gallbladder ejection fraction.. Forty-nine patients who had received an opioid underwent quantitative cholescintigraphy with octapeptide of CCK (CCK-8). Gallbladder ejection fraction and CCK-8-induced paradoxical filling were calculated.. In the basal state, more of the hepatic bile entered the gallbladder (67%) than the small intestine (33%). After CCK-8 infusion, gallbladder ejection fraction was low in 37 (76%) of 49 patients and normal in 12 (24%). All 5 types of opioids lowered ejection fraction. CCK-induced paradoxical filling of the gallbladder was noted in 7 patients, but only one showed paradoxical filling of greater than 20% and none had a normal gallbladder ejection fraction. The lowering effect of opioids on gallbladder ejection fraction may last as long as 18 h after intake.. CCK-8 produced a normal gallbladder ejection fraction in 24% of patients who had received an opioid and thus could exclude both acute and chronic cholecystitis during a single hepatobiliary study.

Topics: Artifacts; Cholecystitis; Cholecystokinin; Drug Administration Schedule; Drug Combinations; Female; Gallbladder; Gallbladder Emptying; Humans; Male; Middle Aged; Narcotics; Pain; Radionuclide Imaging

Nutritional support and pain control by medication are often used concomitantly, but interactions are hardly investigated. A randomised, double-blind, cross-over study in ten right-handed volunteers was performed evaluating the influence of cholecystokinin (CCK)-excretion on the perception of pain in a standardised model. CCK-excretion was induced by a liquid formula diet with either long- or medium-chain triglycerides (LCT, MCT). Plasma samples were drawn over a 60 min period in 15-min intervals and CCK and somatostatin (SMS) were measured by radioimmunoassay (RIA). Gastric emptying was evaluated by C-13-breath testing. Transcutaneous electrical stimulation at a high current density (5 Hz, 70.1+/-5.8 mA) was used to provoke acute pain and stable areas of secondary mechanical hyperalgesia and pinprick allodynia for 2 h. Ongoing pain ratings as well as extension of pinprick-hyperalgesia and allodynia were compared between both liquid formula diets. In a second series of experiments, alfentanil (4.1+/-0.5 mg) was administered for 90 min using target-controlled infusions and measurements were performed as stated above. Oral administration of LCT as well as MCT may lead to different CCK blood levels, but we found no evidence for CCK-induced effects on pain sensation, touch-evoked allodynia, secondary hyperalgesia or morphine-induced anti-nociception in humans. In our studies, liquid formula diets did not influence acute pain perception or the efficacy of opioids in a human model of pain.

Topics: Acute Disease; Adult; Analgesics, Opioid; Analysis of Variance; Cholecystokinin; Cross-Over Studies; Dietary Fats; Double-Blind Method; Food, Formulated; Humans; Hyperalgesia; Male; Pain; Pain Measurement

The analgesic efficacy of morphine is sometimes only partial in patients with chronic benign pain. Among the possible factors contributing to this limitation are increased levels of cholecystokinin (CCK). We performed this prospective, placebo-controlled, double-blind, cross-over study to examine the effect of proglumide, a nonspecific CCK agonist, on analgesia in patients taking morphine on a chronic basis. Forty patients with intractable pain who were taking sustained-release morphine were recruited, and we obtained results from 36 of these patients. Median visual analog scale scores before the study were 8 and 7 after the addition of placebo for 2 wk (P = 0.16), and 6 after proglumide for 2 wk (P = 0.002). Mobility was unchanged by proglumide or placebo. Of the 36 patients, 13 elected to continue receiving proglumide after the study. We conclude that proglumide enhances the analgesia produced by morphine in some, but not all, patients with chronic benign pain.. The pain-killing effect of morphine is incomplete in some patients. Increasing doses may be needed to maintain the initial effect. The peptide cholecystokinin may be partially responsible for this. In this study, we demonstrated that the cholecystokinin antagonist proglumide increases the analgesic effect of morphine in some patients with chronic benign pain.

Topics: Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Cholecystokinin; Chronic Disease; Cross-Over Studies; Double-Blind Method; Drug Synergism; Female; Humans; Male; Middle Aged; Morphine; Pain; Pain Measurement; Proglumide

Cholecystokinin (CCK) and related peptides are supposed to be potent analgesic neuropeptides. Studies in rodents suggest a dose-dependent biphasic effect. The present study aimed to examine the pain modulating effect of different doses (0.5 microgram and 5 micrograms) of ceruletide (CRL), infused i.v. for 30 min. Pain thresholds were obtained for ischemic, mechanical, and thermal pain. In addition, pain tolerance was measured for mechanical pain. According to a placebo-controlled double-blind within-subject design 25 healthy men attended three experimental sessions each. Pain perception was measured as a baseline and twice after the infusion. The effect of both doses of CRL to enhance the pain threshold for thermal stimuli is in line with former studies. However, perception of heat stimuli above or below the threshold was not substantially affected by CRL treatment. Algesic properties of CRL are also indicated, because the tolerance for mechanical pain decreased after administration of the high dose of CRL. Perception of ischemic pain was not obviously influenced by any of the treatments. The role of CRL in human pain modulation seems to vary, depending on the type of experimental pain.

Topics: Adult; Affect; Analgesics, Non-Narcotic; Blood Pressure; Ceruletide; Cholecystokinin; Double-Blind Method; Hot Temperature; Humans; Hydrocortisone; Ischemia; Male; Pain; Pain Measurement; Pain Threshold; Pressure; Reaction Time

Over a 6-year period 264 cholecystokinin (CCK) provocation tests have been performed in 174 patients with undiagnosed right upper quadrant pain. All were carried out by one person (T.W.J.L.) as part of a prospective placebo-controlled crossover study. Following infusion of CCK but not saline, 103 patients developed pain (CCK + ve). These patients were offered cholecystectomy and 90 accepted. Seventy patients developed no pain during either infusion (CCK - ve), and one patient experienced pain with both CCK and saline infusions. Of the 90 patients who underwent cholecystectomy, 81 (90 per cent) have been followed up for a mean of 35 months (range 12 months to 5 1/2 years), 67 per cent have had complete resolution of symptoms and a further 24 per cent have had a marked improvement in symptoms. Only 9 per cent of patients did not benefit from cholecystectomy. This compares well with patients undergoing cholecystectomy for uncomplicated calculous gallbladder disease, 88 per cent of whom, in our study, were improved by surgery. Patients with a positive CCK test have an excellent chance of symptomatic improvement following cholecystectomy.

Topics: Biliary Tract Diseases; Cholecystectomy; Cholecystokinin; Female; Follow-Up Studies; Humans; Long-Term Care; Male; Pain; Postoperative Care

A prospective double blind placebo controlled study was conducted on 41 patients with a clinical diagnosis of acalculous biliary pain (ABP) and 10 healthy volunteers. Cholecystokinin (CCK) ( Kabivitrum , Uxbridge ) was given intravenously (1 Ivy Dog Unit/kg) over 5 min in a randomized crossover study using normal saline as a placebo infusion. All referred patients had undergone at least one normal oral cholecystogram, abdominal ultrasound and upper gastrointestinal endoscopy before infusions. Twenty-six patients developed pain in response to the CCK infusion and not the placebo, and the pain did not differ from their spontaneous pre-infusion pain as measured by the McGill Pain Questionnaire and a Visual Analogue Pain Scale. Fourteen patients developed no pain with either infusion, and one developed pain with both placebo and CCK. All patients whose pain was reproduced (CCK-positive) underwent cholecystectomy and peroperative cholangiography. Operative findings were normal in all of the CCK-positive group except one in whom a small common bile duct stone was found. Histopathology of resected gallbladders was abnormal in 24 out of 26 cases, but all patients operated on remained pain-free at follow-up (mean 11 months, range 2-24 months). Repeat CCK infusion postoperatively failed to bring on pain in any of the postoperative group. The CCK infusion test is a simple, cheap, bedside or out-patient procedure which will identify true acalculous biliary pain which will respond well to cholecystectomy.

Topics: Biliary Tract Diseases; Cholecystectomy; Cholecystokinin; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Male; Middle Aged; Pain

Functional gallbladder disorder is most commonly defined by biliary colic and low ejection fraction (EF) on cholescintigraphy. Biliary hyperkinesia is a controversial type of functional gallbladder disorder, and its definition and the role of cholecystectomy in treating functional gallbladder disorder remains unclear.. We conducted a retrospective review of patients who underwent cholecystokinin-stimulated cholescintigraphy and cholecystectomy at 3 Mayo Clinic sites between 2007 and 2020. Eligible patients were 18 years or older, presented with symptoms of biliary disease, had an EF greater than 50%, underwent cholecystectomy, and had no evidence of acute cholecystitis or cholelithiasis on imaging. We used receiver operating characteristics curve analysis to identify the optimal cutoff value that predicted symptom resolution within 30 days of cholecystectomy.. A total of 2,929 cholecystokinin-stimulated cholescintigraphy scans were performed during the study period; the average EF was 67.5% and the median EF was 77%. Analyzing those with EFs greater than or equal to 50% yielded 1,596 patients with 141 (8.8%) going on to have cholecystectomy. No significant differences were found in age, sex, BMI, final pathology between patients with and without pain resolution. Using a cutoff EF of 81% was significantly associated with pain resolution after cholecystectomy (78.2% for EF greater than or equal to 81% vs 60.0% for EF less than 81%, p = 0.03). Chronic cholecystitis was found in 61.7% of the patients on final pathology.. We determined that an EF cutoff of 81% is a reasonable upper limit of normal gallbladder EF. Patients with biliary symptoms and an EF greater than 81% but no evidence of biliary disease on ultrasound or scintigraphy can be classified as having biliary hyperkinesia. Based on our findings, we recommend cholecystectomy for this patient population.

Topics: Biliary Dyskinesia; Cholecystectomy; Cholecystokinin; Gallbladder Diseases; Humans; Hyperkinesis; Pain; Retrospective Studies

Pain is associated with negative emotions such as anxiety, but the underlying neurocircuitry and modulators of the association of pain and anxiety remain unclear. The neuropeptide cholecystokinin (CCK) has both pronociceptive and anxiogenic properties, so we explored the role of CCK in anxiety and nociception in the central amygdala (CeA), a key area in control of emotions and descending pain pathways. Local infusion of CCK into the CeA of control rats increased anxiety, as measured in the light-dark box test, but had no effect on mechanical sensitivity. By contrast, intra-CeA CCK infusion 4 days after Complete Freund's Adjuvant (CFA) injection into the hindpaw resulted in analgesia, but also in loss of its anxiogenic capacity. Inflammatory conditions induced changes in the CeA CCK signaling system with an increase of CCK immunoreactivity and a decrease in CCK1, but not CCK2, receptor mRNA. In CFA rats, patch-clamp experiments revealed that CCK infusion increased CeA neuron excitability. It also partially blocked the discharge of wide dynamic range neurons in the dorsal spinal cord. These effects of CCK on CeA and spinal neurons in CFA rats were mimicked by the specific CCK2 receptor agonist, gastrin. This analgesic effect was likely mediated by identified CeA neurons projecting to the periaqueductal gray matter that express CCK receptors. Together, our data demonstrate that intra-CeA CCK infusion activated a descending CCK2 receptor-dependent pathway that inhibited spinal neuron discharge. Thus, persistent pain induces a functional switch to a newly identified analgesic capacity of CCK in the amygdala, indicating central emotion-related circuit controls pain transmission in spinal cord.

Topics: Amygdala; Animals; Cholecystokinin; Dark Adaptation; Disease Models, Animal; Exploratory Behavior; Freund's Adjuvant; Gastrins; Glutamate Decarboxylase; Inflammation; Male; Neurons; Nociception; Pain; Pain Threshold; Periaqueductal Gray; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Signal Transduction; Sincalide; Tetragastrin

A growing body of evidence is emerging for a phenomenon known as the nocebo effect. This is when a person is conditioned to expect a negative response, or to anticipate negative effects from an experience. These findings highlight the importantance of effective communication with patients and the influence that good anxiety and pain management control can have in improving treatment outcomes. The placebo effect has been widely researched, but new studies have shown that nocebo can have a greater effect than placebo The nocebo effect is prevalent in interactions between patients and healthcare workers. Research has demonstrated that if a patient deems a healthcare professional not to understand or believe them, this can cause distress, and the physiological effect can reduce the prognosis of treatment. It has also been demonstrated that patients who are anxious or expect pain during a procedure, feel more pain because of this negative expectation.

Topics: Analgesics; Anxiety; Attitude to Health; Cholecystokinin; Dental Anxiety; Humans; Neural Pathways; Nocebo Effect; Pain; Perception; Placebo Effect

Cholecystokinin (CCK) has been suggested to be both pro-nociceptive and "anti-opioid" by actions on pain-modulatory cells within the rostral ventromedial medulla (RVM). One consequence of activation of RVM CCK₂ receptors may be enhanced spinal nociceptive transmission; but how this might occur, especially in states of pathological pain, is unknown. Here, in vivo microdialysis was used to demonstrate that levels of RVM CCK increased by approximately 2-fold after ligation of L₅/L₆ spinal nerves (SNL). Microinjection of CCK into the RVM of naïve rats elicited hypersensitivity to tactile stimulation of the hindpaw. In addition, RVM CCK elicited a time-related increase in (prostaglandin-E₂) PGE₂ measured in cerebrospinal fluid from the lumbar spinal cord. The peak increase in spinal PGE₂ was approximately 5-fold and was observed at approximately 80 minutes post-RVM CCK, a time coincident with maximal RVM CCK-induced mechanical hypersensitivity. Spinal administration of naproxen, a nonselective COX-inhibitor, significantly attenuated RVM CCK-induced hindpaw tactile hypersensitivity. RVM-CCK also resulted in a 2-fold increase in spinal 5-hydroxyindoleacetic acid (5-HIAA), a 5-hydoxytryptophan (5-HT) metabolite, as compared with controls, and mechanical hypersensitivity that was attenuated by spinal application of ondansetron, a 5-HT₃ antagonist. The present studies suggest that chronic nerve injury can result in activation of descending facilitatory mechanisms that may promote hyperalgesia via ultimate release of PGE₂ and 5-HT in the spinal cord.

Topics: Animals; Cholecystokinin; Dinoprostone; Hyperalgesia; Male; Medulla Oblongata; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Nerves

The (99m) technetium labelled hepato imino diacetic acid (HIDA) scan is widely used in the investigation of patients with typical biliary pain but whose trans-abdominal ultrasound scan (US) is normal. Although the standard measure by which the HIDA scan is deemed positive is the presence of an ejection fraction (EF) of <35% following provocation with cholecystokinin (CCK), there still remains debate as to the usefulness of this measure. The aim of this study was to compare the roles of EF and symptom provocation following CCK infusion in relation to the outcome following laparoscopic cholecystectomy (LC). More specifically, we aimed to review the resolution of symptoms for our significant population of patients with normal HIDA scan EFs for whom surgery has traditionally been deemed inappropriate.. All patients undergoing LC for a presumed diagnosis of biliary dyskinesia were identified from a prospectively maintained database. Data were collected regarding pre-operative symptoms, EF and symptom provocation during the CCK HIDA scan, histological findings, early symptomatic outcome, and medium-term follow-up.. During the period from March 2006 to October 2009, 42 patients with biliary symptoms but a negative US were referred for assessment by a single surgeon. There were 31 women and 11 men with a mean age of 39.0 ± 12.6 years. All underwent a CCK HIDA scan of which 17 were positive with an EF <35% and the remaining 25 were negative. All patients reported recreation of symptoms following administration of CCK. All gallbladders were delivered intact for histological assessment and all but one showed evidence of chronic cholecystitis. At each postoperative visit, approximately 2 weeks following the procedure, all patients reported resolution of symptoms. After a mean of 18.7 ± 12.1 months symptom recurrence had been noted in only one of 42 (2.4%).. The CCK HIDA scan is a useful study in the investigation of acalcalous cholecystitis; however, we would suggest that recreation of symptoms following CCK provocation is superior to EF for the identification of underlying chronic cholecystitis. Indeed, a normal gallbladder ejection fraction does not necessarily rule out a biliary aetiology of symptoms for this patient population.

Topics: Adult; Biliary Dyskinesia; Cholecystectomy, Laparoscopic; Cholecystokinin; Female; Follow-Up Studies; Gallbladder; Humans; Imino Acids; Male; Middle Aged; Pain; Predictive Value of Tests; Radionuclide Imaging; Technetium; Treatment Outcome

This study investigates the potential correlation between acalculous biliary pain and mechanical stress during the bile-emptying phase. This study is built on the previously developed mathematical model used to estimate stress in the gallbladder wall during emptying [Li, W. G., X. Y. Luo, et al. Comput. Math. Methods Med. 9(1):27-45, 2008]. Although the total stress was correctly predicted using the previous model, the contribution from patient-specific active stress induced by the cholecystokinin (CCK) test was overlooked. In this article, we evaluate both the active and passive components of pressure in a gallbladder, which undergoes isotonic refilling, isometric contraction and emptying during the infusion of CCK. The pressure is estimated from in vivo ultrasonographical scan measurements of gallbladder emptying during CCK tests, assuming that the gallbladder is a thin ellipsoidal membrane. The passive stress is caused by the volume and shape changes during refilling at the gallbladder basal pressure, whereas the active stress arises from the pressure rise during the isometric gallbladder contraction after the CCK infusion. The effect on the stress estimates of the gallbladder to the liver is evaluated to be small by comparing numerical simulations of a gallbladder model with and without a rigid 'flat top' boundary. The model was applied to 51 subjects, and the peak total stress was found to have a strong correlation with the pain stimulated by CCK, as measured by the patient pain score questionnaires. Consistent with our previous study for a smaller sample, it is found that the success rate in predicting of CCK-induced pain is over 75%.

Topics: Acalculous Cholecystitis; Cholecystokinin; Computer Simulation; Gallbladder; Gallbladder Emptying; Humans; Isometric Contraction; Models, Biological; Muscle, Smooth; Pain; Stress, Mechanical

In the present study we determined whether spinal cholecystokinin (CCK) or the cholecystokinin receptor is involved in below-level neuropathic pain of spinal cord injury (SCI). The effect of the CCK(B) receptor antagonist, CI-988 on mechanical allodynia and the expression level of CCK and CCK(B) receptor were investigated. Spinal hemisection was done at the T13 level in rats under enflurane anesthesia. CI-988 was administered intraperitoneally and intrathecally and behavioral tests were conducted. After systemic injection, mechanical allodynia was reduced by higher doses of CI-988 (10 and 20mg/kg). Intrathecal CI-988 (100, 200 and 500 microg) dose-dependently increased the paw withdrawal threshold in both paws. Following spinal hemisection, CCK mRNA expression increased on the ipsilateral side at the spinal segments caudal to the injury and both sides of the spinal L4-5 segments without any significant changes in CCK(B) receptor mRNA levels. These results suggest that up-regulation of spinal CCK may contribute to maintenance of mechanical allodynia following SCI and that clinical application of CI-988 or similar drugs may be useful therapeutic agents for management of central neuropathic pain.

Topics: Animals; Cholecystokinin; Indoles; Male; Meglumine; Pain; Pain Measurement; Physical Stimulation; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; RNA, Messenger; Spinal Cord; Spinal Cord Injuries; Thorax

CCK is one of the strongest endogenous anti-opioid substances and suppresses morphine tolerance which results from long term use of morphine. This study explores the modulatory effect of CCK on pain formalin-induced.. The effect of formalin-induced pain on CCK immunoreactivity in rat sensory neurons was observed through immunohistochemistry technique.. After 1 h of subcutaneous injection of formalin in one paw of rats, the number of positive neurons of CCK immunoreactivity in spinal cord neurons was obviously increased and greater than that of non-injection side (P <0.01). The semi-quantitative optical density average values of CCK immunoreactivity neurons were 0.397 +/- 0.014 and 0.295 +/- 0.007 in injection side and non-injection side respectively, the difference was obvious (P < 0.01). After 3 h of subcutaneous injection of formalin in one paw of rats, the semi-quantitative optical density average values of CCK immunoreactivity neurons were 0.366 +/- 0.009 and 0.303 +/- 0.005 in injection side and noninjection side respectively, the difference was significant (P < 0.01).. Formalin-induced pain can significantly change semi-quantitative optical density average value of CCK immunoractivity in spinal cord neurons, this indicates CCK participates in modulation of pain.

Topics: Animals; Cholecystokinin; Female; Formaldehyde; Male; Neurons; Pain; Random Allocation; Rats; Rats, Wistar; Receptors, Cholecystokinin; Spinal Cord

The dorsal spinal cord synthesizes a variety of neuropeptides that modulate the transmission of nociceptive sensory information. Here, we used genetic fate mapping to show that Tlx3(+) spinal cord neurons and their derivatives represent a heterogeneous population of neurons, marked by partially overlapping expression of a set of neuropeptide genes, including those encoding the anti-opioid peptide cholecystokinin, pronociceptive Substance P (SP), Neurokinin B, and a late wave of somatostatin. Mutations of Tlx3 and Tlx1 result in a loss of expression of these peptide genes. Brn3a, a homeobox transcription factor, the expression of which is partly dependent on Tlx3, is required specifically for the early wave of SP expression. These studies suggest that Tlx1 and Tlx3 operate high in the regulatory hierarchy that coordinates specification of dorsal horn pain-modulatory peptidergic neurons.

Topics: Aging; Animals; Animals, Newborn; Cholecystokinin; Embryo, Mammalian; Gene Expression Regulation; Homeodomain Proteins; Mice; Mice, Transgenic; Mutation; Neurokinin B; Neurons; Neuropeptides; Pain; PAX2 Transcription Factor; Somatostatin; Spinal Cord; Substance P; Transcription Factor Brn-3A; Transcription, Genetic

We previously demonstrated that electroacupuncture (EA) stimulation both produced antinociception and attenuated intrathecal (i.t.) morphine analgesia, suggesting that EA is capable of inducing two opposing systems, that is, opioid and anti-opioid mechanisms. This study examined the involvement of cholecystokinin (CCK) in the anti-opioid effects following EA in the spinal cord. EA was applied to commonly used acupoints for antinociception, ST-36 located 5-mm lateral to the anterior tubercle of the tibia, and analgesia was assessed by the hind-paw pressure test in male Sprague-Dawley rats. I.t. administration of CCK (0.01 - 10 microg) attenuated i.t. morphine analgesia (10 microg) dose-dependently. The attenuation of morphine analgesia following EA was reversed by i.t. proglumide, a CCK-receptor antagonist (0.01 microg). CCK-like immunoreactivity was increased in lamina I and II in the dorsal horn, and expression of spinal CCK mRNA increased after EA. Moreover, i.t. pretreatment with the neurokinin-1 (NK1)-receptor antagonist L-703,606 (18 microg) reversed both EA- and CCK-induced attenuation of morphine analgesia. These results suggest that CCK-mediated neural systems in the spinal cord may be involved in the attenuation of morphine analgesia following EA and that substance P-induced activation of NK1 receptors may be responsible for the downstream neuronal transmission of the CCK-mediated neuronal system.

Topics: Acupuncture Points; Analgesia; Analgesics, Opioid; Animals; Cholecystokinin; Dose-Response Relationship, Drug; Electroacupuncture; Gene Expression; Hindlimb; Injections, Spinal; Male; Morphine; Pain; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Receptors, Neurokinin-1; RNA, Messenger; Spinal Cord; Substance P

Cholecystokinin (CCK) released in the CNS inhibits the analgesic action of exogenous opioids and may antagonize analgesia resulting from the activation of an endogenous pain inhibitory system. The aim of this study was to analyse the central action of PD 140.548 N-methyl-D-glucamine--a peptide antagonist of a specific peripheral type CCK receptor--on animal behaviour, catecholamines (CA) and cortisol concentration, as well as clinical symptoms of visceral pain induced by duodenal distension (DD). A 5 min distension of the duodenum wall, using a 10 cm long balloon filled with 40 and/or 80 ml of water (DD 40 and/or DD 80) at animal body temperature, produced a significant increase in plasma CA and cortisol levels, an increase in the heart rate, hyperventilation and other clinical symptoms (inhibition of rumen motility, bleating, teeth grinding, prostration, urination, defecation) that may be related to pain, proportionally to the degree of intestinal distension. Intracerebroventricular administration of PD 140.548 at the dose of 1 or/and 2 mg in toto 10 min before applying DD 40 completely blocked the increase in blood plasma cortisol, epinephrine (E), norepinephrine (NE) and dopamine (DA) concentration. It is suggested that the central inhibitory action of CCK antagonist on the cortisol and catecholamine release produced by visceral pain is due to the inhibition of peripheral CCK1 type receptors in the central centrifugal descending pain facilitatory system in sheep perhaps via the hypothalamic-pituitary-adrenal axis.

Topics: Animals; Autonomic Nervous System; Behavior, Animal; Catecholamines; Cholecystokinin; Duodenum; Hydrocortisone; Hypothalamo-Hypophyseal System; Meglumine; Pain; Pituitary-Adrenal System; Receptors, Cholecystokinin; Sheep

Opioid-induced hyperalgesia is characterized by hypersensitivity to innocuous or noxious stimuli during sustained opiate administration. Microinjection of lidocaine into the rostral ventromedial medulla (RVM), or dorsolateral funiculus (DLF) lesion, abolishes opioid-induced hyperalgesia, suggesting the importance of descending pain facilitation mechanisms. Here, we investigate the possibility that cholecystokinin (CCK), a pronociceptive peptide, may drive such descending facilitation from the RVM during continuous opioid administration. In opioid-naive rats, CCK in the RVM produced acute tactile and thermal hypersensitivity that was antagonized by the CCK2 receptor antagonist L365,260 or by DLF lesion. CCK in the RVM also acutely displaced the spinal morphine antinociceptive dose-response curve to the right. Continuous systemic morphine elicited sustained tactile and thermal hypersensitivity within 3 d. Such hypersensitivity was reversed in a time-dependent manner by L365,260 in the RVM, and blockade of CCK2 receptors in the RVM also blocked the rightward displacement of the spinal morphine antinociceptive dose-response curve. Microdialysis studies in rats receiving continuous morphine showed an approximately fivefold increase in the basal levels of CCK in the RVM when compared with controls. These data suggest that activation of CCK2 receptors in the RVM promotes mechanical and thermal hypersensitivity and antinociceptive tolerance to morphine. Enhanced, endogenous CCK activity in the RVM during sustained morphine exposure may diminish spinal morphine antinociceptive potency by activating descending pain facilitatory mechanisms to exacerbate spinal nociceptive sensitivity. Prevention of opioid-dose escalation in chronic pain states by CCK receptor antagonism represents a potentially important strategy to limit unintended enhanced clinical pain and analgesic tolerance

Topics: Analgesics, Opioid; Animals; Benzodiazepinones; Cholecystokinin; Drug Tolerance; Hot Temperature; Hyperalgesia; Male; Medulla Oblongata; Morphine; Neural Pathways; Pain; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Sensory Thresholds; Spinal Cord; Touch

Pain in patients with chronic pancreatitis is difficult to manage. We examined if an enteral formulation containing medium-chain triglycerides (MCT) and hydrolyzed peptides would (1) minimally stimulate the exocrine pancreas by blunting cholecystokinin release and (2) decrease pain in patients with chronic pancreatitis.. In the first part of the study, on separate days, 6 healthy controls consumed a standard enteral formulation, an enteral formulation containing MCT and hydrolyzed peptides, and a high-fat meal. Baseline and postprandial plasma cholecystokinin (CCK) concentrations were analyzed. Subsequently, 8 patients with chronic pancreatitis were enrolled and instructed to complete a visual analog pain assessment for a baseline period of 2 weeks followed by three cans per day of the enteral formulation containing MCT and hydrolyzed peptides for 10 weeks.. Mean CCK levels for our control subjects were 0.46 +/- 0.29 pM at baseline, 10.75 +/- 0.45 pM in response to the high-fat meal, and 7.9 +/- 1.25 pM in response to the standard enteral formulation. Of note, CCK levels were 1.43 +/- 0.72 pM in response to the enteral supplement containing MCT and hydrolyzed peptides. In patients with chronic pancreatitis, the average improvement in pain scores from baseline to the conclusion of the study was 61.8% (p = 0.01). This corresponded to a clinical improvement in 6 of the 8 patients.. A complete enteral supplement containing MCT and hydrolyzed peptides minimally increases plasma CCK levels. This therapy may be effective in reducing postprandial pain associated with chronic pancreatitis.

Topics: Adult; Aged; Case-Control Studies; Cholecystokinin; Chronic Disease; Enteral Nutrition; Humans; Hydrolysis; Middle Aged; Pain; Pancreatitis; Peptides; Postprandial Period; Triglycerides

Cholecystokinin (CCK) in the CNS antagonizes the opioid system and has been implicated post-spinal cord injury (SCI) pain. The current study found that excitotoxic SCI alters levels of CCK mRNA levels in the cortex, diencepahlon, and mesencephalon of rats. Animals that developed pain post-SCI had significantly higher levels than animals that did not develop pain. Upregulation of CCK mRNA in the cortex may be related to post-SCI pain in rats.

Topics: Animals; Behavior, Animal; Cerebral Cortex; Cholecystokinin; Diencephalon; Disease Models, Animal; Efferent Pathways; Grooming; Gyrus Cinguli; Mesencephalon; Neuronal Plasticity; Neurons; Opioid Peptides; Pain; Rats; RNA, Messenger; Spinal Cord Injuries; Up-Regulation

Although it is well established that adenosine exerts antinociceptive effects at the spinal level in various species including human, the mechanisms responsible for such effects are still a matter of debate. We presently investigated whether adenosine-induced antinociception might possibly be related to an inhibitory influence of this neuromodulator on the spinal release of neuropeptides implicated in the transfer and/or control of nociceptive signals. For this purpose, the K(+)-evoked overflow of substance P-, calcitonin gene-related peptide (CGRP)- and cholecystokinin-like materials was measured from slices of the dorsal half of the rat lumbar enlargement superfused with an artificial cerebrospinal fluid supplemented with increasing concentrations of various adenosine receptor ligands. The data showed that stimulation of adenosine A(1) and (possibly) A(3) receptors, but not A(2A) receptors, exerted an inhibitory influence on the spinal release of CGRP-like material. In contrast, none of the adenosine A(1), A(2A) and A(3) receptor agonists tested within relevant ranges of concentrations significantly affected the release of substance P- and cholecystokinin-like materials. These results support the idea that adenosine-induced antinociception at the spinal level might possibly be caused, at least partly, by the stimulation of inhibitory adenosine A(1) receptors located presynaptically on primary afferent fibres containing CGRP but not substance P.

Topics: Adenosine; Adenosine-5'-(N-ethylcarboxamide); Animals; Calcitonin Gene-Related Peptide; Cholecystokinin; Dose-Response Relationship, Drug; In Vitro Techniques; Male; Neuropeptides; Pain; Phenethylamines; Potassium; Purinergic P1 Receptor Agonists; Purinergic P1 Receptor Antagonists; Rats; Rats, Sprague-Dawley; Receptors, Purinergic P1; Spinal Cord; Substance P; Xanthines

We examined the tail-flick response to various heat intensities in diabetic and non-diabetic mice. Heat intensities were set to one of six values by adjusting the source of voltage for a 50-W projection bulb to 20, 25, 35, 50, 65 and 80 V. Tail-flick latencies at source voltages of 35 and 50 V in diabetic mice were significantly shorter than those in non-diabetic mice. However, tail-flick latencies at 25, 65 and 80 V in diabetic mice were not significantly altered. Although tail-flick latencies in non-diabetic mice were not affected by i.t. pre-treatment with CI-988, a selective cholecystokinin B (CCK(B)) receptor antagonist, those at 35 and 50 V in diabetic mice were significantly increased. In non-diabetic mice, i.t. pre-treatment with cholecystokinin octapeptide (CCK-8), at a dose of 0.3 ng, decreased tail-flick latencies at 35 and 50 V. Furthermore, the attenuation of tail-flick latencies induced by i.t. pre-treatment with CCK-8 in non-diabetic mice was reversed by i.t. pre-treatment with CI-988. Protein kinase C (PKC) activator phorbol-12, 13-dibutyrate (PDBu)-induced reduction in the tail-flick latencies at heat intensities of 35 and 50 V in non-diabetic mice was dose-dependently and significantly reversed by i.t. pre-treatment with CI-988. On the other hand, the CCK-8-induced thermal hyperalgesia and allodynia at heat intensities of 35 and 50 V in non-diabetic mice were inhibited when PKC activity was inhibited by i.t. pre-treatment with calphostin C. These results indicate that the thermal allodynia and hyperalgesia in diabetic mice may be due, at least in part, to the activation of CCK(B) receptors followed by the activation of PKC in the spinal cord.

Topics: Animals; Capsaicin; Cholecystokinin; Diabetes Mellitus, Experimental; Enzyme Activators; Hot Temperature; Hyperalgesia; Indoles; Injections, Spinal; Male; Meglumine; Mice; Mice, Inbred ICR; Nerve Fibers; Nociceptors; Pain; Protein Kinase C; Reaction Time; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Spinal Cord

Some opioid-resistant pain conditions can be alleviated by voltage-dependent Na(+) channel blockers such as lamotrigine. The mu-opioid-receptor agonist morphine can modulate cation entry into cells to affect overall cellular excitability, an effect which can in turn be endogenously antagonised by the neuropeptide cholecystokinin (CCK). However, lamotrigine may also modulate cellular excitability by non-specifically blocking voltage-dependent ion channels. We have looked for interactions of lamotrigine with the opioid/CCK pathway within the spinal dorsal horn, to rule out the possibility that lamotrigine may attenuate nociceptive responses via actions on this pathway. Both lamotrigine and the mu-opioid agonist DAMGO inhibited mustard oil-evoked cell firing by approximately 50% compared with control levels. Co-application of CCK8S reversed DAMGO-, but not lamotrigine-induced inhibition of cell firing and this reversal was prevented with the selective CCK(B) receptor antagonist PD 135158. Although lamotrigine inhibited both brush- and cold-evoked cell firing in neuropathic animals, lamotrigine inhibition of mustard oil-evoked cell firing in the same animals was not significantly greater than that observed in controls. These results suggest that the antinociceptive properties of lamotrigine within the spinal dorsal horn are unlikely to be mediated via interactions with the opioid/CCK pathway.

Topics: Action Potentials; Analgesics, Opioid; Animals; Anti-Anxiety Agents; Calcium Channel Blockers; Cholecystokinin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Indoles; Inflammation; Lamotrigine; Male; Meglumine; Mustard Plant; Neural Pathways; Nociceptors; Opioid Peptides; Pain; Peripheral Nervous System Diseases; Plant Extracts; Plant Oils; Posterior Horn Cells; Rats; Rats, Wistar; Sincalide; Triazines

We examined the role of cholecystokinin in the reduction of endomorphin-2-induced antinociception in diabetic mice. Endomorphin-1 (1-10 microg, i.c.v.) and endomorphin-2 (3-30 microg, i.c.v.) dose dependently inhibited the tail-flick response in non-diabetic and diabetic mice. There was no significant difference between the antinociceptive effect of endomorphin-1 in non-diabetic and diabetic mice. On the other hand, the antinociceptive effect of endomorphin-2 in diabetic mice was significantly less than that in non-diabetic mice. Cholecystokinin octapeptide (CCK-8) dose dependently reduced the antinociceptive effects of endomorphin-1 and endomorphin-2 in non-diabetic mice. However, in diabetic mice, CCK-8 significantly inhibited the antinociceptive effect of endomorphin-1, but not of endomorphin-2. In non-diabetic mice, CI-988 ((R-[R*,R*])-4-([3-1H-indol]-3-yl)-2-methyl-1-oxo-2-([(tricyclo(3.3.1.1)dec-2-yloxy)carbonyl] amino)propylamino-1-phenyl-ethylamino-4-oxybutanoic acid) had no significant effect on either endomorphin-1- or endomorphin-2-induced antinociception. In diabetic mice, while CI-988 had no significant effect on endomorphin-1-induced antinociception, it dose dependently enhanced the antinociceptive effect of endomorphin-2. The results indicated that the reduction of endomorphin-2-induced antinociception in diabetic mice might be due, at least in part, to the activation of CCK(2) receptors.

Topics: Analgesics; Animals; Behavior, Animal; Cholecystokinin; Diabetes Mellitus, Experimental; Dose-Response Relationship, Drug; Indoles; Injections, Intraventricular; Meglumine; Mice; Mice, Inbred ICR; Nociceptors; Oligopeptides; Pain; Pain Measurement; Sincalide

We compared the antinociceptive activity of a kappa-opioid agonist, U-50488H, in streptozotocin-induced diabetic mice with that in non-diabetic mice. Subcutaneously administered U-50488H (3 and 10 mg kg(-1)) showed a more potent antinociceptive effect, as evaluated by the tail-pressure method, in diabetic mice than in non-diabetic mice. Increased antinociceptive activity of U-50488H observed in diabetic mice was also observed in mice given U-50488H intrathecally (3 and 10 microg). However, there were no differences observed between diabetic and non-diabetic mice given U-50488H intracerebroventricularly (3 and 10 microg). Although the antinociceptive effect of U-50488H (3 mg kg(-1), s.c.) in non-diabetic mice was increased by treatment with PD135158 (100 ng, i.c.v.), a cholecystokininB (CCKB) antagonist, the antinociceptive activity of U-50488H which was enhanced in diabetic mice was not influenced by PD135158. Moreover, the increased antinociceptive activity of U-50488H (3 mg kg(-1), s.c.) in diabetic mice diminished when desulfated octapeptide of cholecystokinin (3-100 ng, i.c.v.), a CCKB agonist, was administered. These results suggested that diabetic mice were selectively hyper-responsive to spinal kappa-opioid receptor-mediated antinociception. The function of the analgesia inhibitory system in which cholecystokinin is used as a transmitter might be diminished in diabetic mice.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics; Analgesics, Non-Narcotic; Animals; Anti-Bacterial Agents; Cholecystokinin; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Mice; Pain; Streptozocin

Cholecystokinin (CCK) is a physiological antagonist of opioid-mediated antinociception and may be involved in some chronic pain states where opioids have reduced effect. We have previously shown in a rat model of central neuropathic pain after spinal cord injury that blockade of CCK-B receptors lead to marked pain relief. In the present study, we showed that spinally injured rats exhibiting chronic pain-like behaviors (aversive reaction to innocuous mechanical and cold stimulation) had significantly elevated level of CCK-like immunoreactivity in cerebrospinal fluid compared to normal rats or spinally injured rats which did not exhibit pain-like behaviors. The increased level of circulating CCK in the cerebrospinal fluid may thus contribute to the maintenance of chronic pain in these rats by reducing the endogenous inhibitory tone provided by opioid peptides and may be involved in the phenomenon of opioid insensitivity.

Topics: Animals; Behavior, Animal; Cholecystokinin; Female; Immunoglobulin G; Narcotics; Pain; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Spinal Cord Injuries

A common complaint among pain patients is that they lose their appetite. These accounts are anecdotal, however, and the neural mechanism underlying pain-induced loss of appetite remains unknown. In this study, we documented the occurrence of appetite loss in patients under migraine attack and investigated the neuronal substrate of pain-induced anorexia in our animal model of intracranial pain. We found that loss of appetite during the migraine attack in humans coincided strongly with the onset and duration of the head pain in 32/39 cases, and that brief noxious stimulation of the dura in conscious rats produced a transient suppression of food intake. Mapping of neuronal activation in the rat showed that noxious dural stimulation induced a 3- to 4-fold increase in the number of Fos-positive neurons in medullary dorsal horn areas that process nociceptive signals (laminae I, V) and in parabrachial and hypothalamic neurons positioned to suppress feeding behavior. In the parabrachial area, activated neurons were localized in the superior-lateral subnucleus, and 40% of them expressed the mRNA encoding the anorectic neuropeptide cholecystokinin. In the hypothalamus, activated Fos-positive neurons were found in the dorsomedial area of the ventromedial nucleus, and 76% of them expressed the mRNA for cholecystokinin type-B receptor. Based on these findings, we suggest that at least one of several groups of hypothalamic neurons that normally inhibit appetite in response to metabolic cues is positioned to mediate the suppression of food intake by pain signals.

Topics: Animals; Anorexia; Brain Stem; Cholecystokinin; Dura Mater; Eating; Electric Stimulation; Humans; In Situ Hybridization; Male; Migraine Disorders; Nerve Tissue Proteins; Neurons; Nociceptors; Pain; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; RNA, Messenger; Trigeminal Nuclei; Ventromedial Hypothalamic Nucleus

The present study assessed the effect of a single subcutaneous injection of resiniferatoxin (RTX), an ultrapotent capsaicin analogue, on the activity of spinal cholecystokinin (CCK) systems, by using electrophysiological and in situ hybridization techniques. Subcutaneous RTX at 0.3 mg/kg, but not vehicle, produced marked thermal hypoalgesia in rats on the hot plate and tail flick tests. Partial recovery from hypoalgesia occurred in some (<50%), but not all, RTX-treated rats after 2 weeks. The flexor reflex in response to activation of high threshold afferents was recorded 15-35 days after RTX- or vehicle-treatment. There was no obvious difference between RTX- and vehicle-treated rats in the baseline flexor reflex. Intravenous morphine at 1 mg/kg caused a depression of the flexor reflex in vehicle- and in RTX-treated rats. The reflex depressive effect of morphine was significantly briefer in RTX-treated, non-recovered rats than vehicle-treated rats. Furthermore, CI-988, a high affinity antagonist of CCKB receptors, caused a minor depression of the reflex in vehicle- and RTX-treated rats that had partially recovered, whereas the reflex depressive effect of CI-988 was significantly enhanced in RTX-treated, non-recovered rats. In situ hybridization showed that RTX treatment caused a marked and significant increase in the number of dorsal root ganglion (DRG) neurone profiles expressing CCKB receptor mRNA, whereas only a small increase was observed for CCKA receptor mRNA expressing neurone profiles. Significantly more DRG neurone profiles expressed CCKB receptor mRNA in RTX-treated, non-recovered rats compared to partially recovered rats. RTX-treatment did not influence the expression of CCK mRNA in DRGs. Since CCK functions as a physiological antagonist of morphine, it is suggested that RTX treatment enhances the activity of spinal CCK systems, leading to the reduced effect of morphine and increased effect of the CCKB receptor antagonist CI-988. This may mainly be due to upregulation of CCKB receptors in DRG neurones.

Topics: Animals; Cholecystokinin; Decerebrate State; Diterpenes; Ganglia, Spinal; Hormone Antagonists; Indoles; Injections, Subcutaneous; Male; Meglumine; Morphine; Neurons; Neurotoxins; Pain; Rats; Rats, Sprague-Dawley; Receptor, Cholecystokinin B; Receptors, Cholecystokinin; Reflex; RNA, Messenger; Spinal Cord; Time Factors; Transcription, Genetic

Complete or partial spinal section at T(8) has been shown to block tactile allodynia but not thermal hyperalgesia following L(5)/L(6) spinal nerve ligation (SNL), suggesting the supraspinal integration of allodynia in neuropathic pain. In the present study, the possibility of mediation of nerve injury-associated pain through tonic activity of descending nociceptive facilitation arising from the rostroventromedial medulla (RVM) was investigated. Specifically, the actions of brainstem cholecystokinin and the possible importance of sustained afferent input from injured nerve fibers were determined using pharmacological and physiological approaches in rats with SNL. Lidocaine given bilaterally into the RVM blocked tactile allodynia and thermal hyperalgesia in SNL rats and was inactive in sham-operated rats. Bilateral injection of L365,260 (CCK(B) receptor antagonist) into the RVM also reversed both tactile allodynia and thermal hyperalgesia. Microinjection of CCK-8 (s) into the RVM of naive rats produced a robust tactile allodynic effect and a more modest hyperalgesia. CCK immunoreactivity was not significantly different between SNL and sham-operated rats. The anti-nociceptive effect of morphine given into the ventrolateral periaqueductal gray region (PAG) was substantially reduced by SNL. The injection of L365,260 into the RVM or of bupivacaine at the site of nerve injury restored the potency and efficacy of PAG morphine in SNL rats. These results suggest that changes in supraspinal processing are likely to contribute to the observed poor efficacy of opioids in clinical states of neuropathic pain. These data also indicate that the activation of descending nociceptive facilitatory pathways is important in the maintenance of neuropathic pain, appears to be dependent on CCK release, and may be driven from sustained afferent input from injured nerves to brainstem sites. Collectively, these data support the hypothesis that abnormal tonic activity of descending facilitation mechanisms may underlie chronic pain from peripheral nerve injury.

Topics: Anesthetics, Local; Animals; Benzodiazepinones; Cholecystokinin; Hot Temperature; Hyperalgesia; Lidocaine; Ligation; Male; Medulla Oblongata; Pain; Pain Measurement; Periaqueductal Gray; Phenylurea Compounds; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Spinal Cord; Spinal Nerves

Topics: Abdominal Pain; Bile Acids and Salts; Cholecystokinin; Chronic Disease; Duodenum; Eating; Humans; Osmolar Concentration; Pain; Pancreatitis; Prospective Studies

There is abundant evidence that opioid receptors are present on peripheral terminals of primary afferent neurons. Experimental and clinical studies have shown that activation of these peripheral opioid receptors produces potent analgesia. In addition to peripheral opioid receptors, cholecystokinin receptors are present in sensory neurons. We examined the hypothesis that cholecystokinin receptors may be present on the same primary afferent neuron and that either exogenous or endogenous cholecystokinin may modulate peripheral antinociceptive effects of mu-opioid receptor agonists. Administration of cholecystokinin into inflamed paws, of the rat, but not intravenously attenuated peripheral antinociceptive effects induced by two mu-opioid receptor agonists, [D-Ala2,N-methyl-Phe4,Gly-ol5]-enkephalin and fentanyl. Only the desulphated form of cholecystokinin produced significant and dose-dependent attenuation. Cholecystokinin alone did not alter nociceptive baseline values in inflamed or non-inflamed paws. The anti-opioid effect of cholecystokinin was dose-dependently antagonized by the cholecystokininB receptor-selective antagonist L-365260, but not by the cholecystokininA receptor-selective antagonist L-364718. Local pretreatment with the protein kinase C specific inhibitor calphostin C abolished cholecystokinin's effect. Peripheral antinociceptive effects of [D-Ala2,N-methyl-Phe4,Gly-ol5]-enkephalin and fentanyl were not altered by intraplantar L-365260 alone. These results indicate that activation of peripheral cholecystokininB but not cholecystokininA receptors attenuates the local antinociceptive effects of mu-opioid receptor agonists in inflamed tissue. This anti-opioid effect may be mediated by protein kinase C in sensory nerve terminals. Endogenous cholecystokinin does not seem to influence the efficacy of peripheral opioids under both normal and inflammatory conditions.

Topics: Analgesics, Opioid; Animals; Cholecystokinin; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Enzyme Inhibitors; Fentanyl; Male; Naphthalenes; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Protein Kinase C; Rats; Rats, Wistar; Receptors, Cholecystokinin

Although there are numerous opioid-sensitive structures in the central nervous system, the contribution of each to the analgesic effect of systemically administered morphine is controversial. One such structure is the rostral ventromedial medulla. In the present study, we tested the hypothesis that the rostral ventromedial medulla is necessary for the full expression of systemic morphine-induced antinociception. Additionally, we examined whether the modulatory effect of the rostral ventromedial medulla on tail-flick latency is dependent on the behavioral state of the animal. In unrestrained rats, inactivation of the rostral ventromedial medulla with either lidocaine (0.5 microl of 4%) or muscimol (50 ng) had no effect on tail-flick latency. In contrast, in restrained rats, inactivation of the rostral ventromedial medulla with either lidocaine (0.5 microl of 4%) or muscimol (50 ng) significantly decreased tail-flick latency. In both conditions, microinjection of morphine (5 microg) into this region significantly increased tail-flick latency. Additionally, in unrestrained rats, muscimol (50 ng) and cholecystokinin tetrapeptide (0.5 ng) infusion into the rostral ventromedial medulla completely reversed systemic morphine-induced analgesia, while lidocaine (0.5 microl of 4%) and cholecystokinin octapeptide (0.25 ng) infusion partially reversed systemic morphine-induced analgesia. These findings demonstrate that the rostral ventromedial medulla does not tonically modulate tail-flick latency in unrestrained rats, but does modulate tail-flick latency when animals are stressed via restraint. These findings also strongly support the hypothesis that the rostral ventromedial medulla is necessary for the full analgesic effects of systemically administered morphine.

Topics: Analgesics, Opioid; Animals; Cholecystokinin; Male; Medulla Oblongata; Microinjections; Morphine; Pain; Pain Measurement; Rats; Rats, Sprague-Dawley; Reaction Time; Restraint, Physical; Stress, Physiological; Tail

The cholecystokinin provocation test (CCKPT) has been claimed to predict a better symptomatic result after cholecystectomy in patients with acalculous biliary pain.. To examine the predictive value of the CCKPT for symptom relief after cholecystectomy in both CCKPT positive and negative patients.. Fifty eight patients with acalculous biliary pain underwent CCKPT with serial ultrasound gall bladder volumetry. CCKPT positive patients were offered cholecystectomy; negative patients were reassessed and were offered a cholecystectomy if symptoms persisted. Six months after cholecystectomy, the CCKPT was repeated.. Of 32 CCKPT positive patients, 27 underwent cholecystectomy and of these, 18 (67%) became symptom-free. Postoperatively, 20 of 25 patients converted to CCKPT negative but five remained CCKPT positive and were symptomatic. Of the 26 CCKPT negative patients, nine became symptom-free without cholecystectomy; six of 14 (42.8%) patients undergoing cholecystectomy became asymptomatic and remained CCKPT negative. Cholecystectomy seemed to reduce symptoms in both groups, but there was no significant difference in the symptomatic outcome between preoperative CCKPT positive and negative patients.. In this study, cholecystokinin provocation testing did not predict symptomatic benefit from cholecystectomy and we suggest it should no longer be used in the evaluation of patients with acalculous biliary pain.

Topics: Adolescent; Adult; Algorithms; Cholecystectomy; Cholecystokinin; Female; Gallbladder Diseases; Gallbladder Emptying; Humans; Male; Middle Aged; Pain; Pain Measurement; Postoperative Period; Predictive Value of Tests; Prognosis

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved with the gamma-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic pain of peripheral and central origin often cannot be relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the up-regulation of endogenous antiopioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section, both CCK and CCK-R are up-regulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine, reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, up-regulation of CCK and CCK-R in the CNS may also underlie opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue.

Topics: Animals; Baclofen; Central Nervous System; Cholecystokinin; GABA Agonists; Hormone Antagonists; Indoles; Ischemia; Meglumine; Narcotics; Neural Inhibition; Pain; Pain Measurement; Peripheral Nervous System; Rats; Receptors, GABA; Spinal Cord; Spinal Cord Injuries

The effect of the cholecystokininB (CCKB) receptor-selective cholecystokinin octapeptide (CCK-8) analog SNF 9007 on forskolin-stimulated adenylyl cyclase activity in NG108-15 hybrid cells was measured. The activity of SNF 9007 was compared to the delta opioid agonists D-Pen2-D-Pen5-enkephalin (DPDPE, delta 1 receptor-selective) and Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2, (D-Ala2-deltorphin II, delta 2-receptor-selective) because SNF 9007 binds with moderate affinity to delta opioid receptors. SNF 9007 inhibited forskolin-stimulated adenylyl cyclase activity with efficacy similar to DPDPE. IC50 determinations showed that D-Ala2-deltorphin II was the most potent, followed by DPDPE, then SNF 9007 (IC50 values = 0.013, 0.21 and 4.8 microM, respectively). CCK-8 had no effect on adenylyl cyclase activity. The delta 1 receptor-selective antagonist 7-benzylidenenaltrexone hydrochloride (BNTX, 10 nM) had no effect on the activity of any of these agonists, but the delta 2 receptor-selective antagonist naltriben methanesulfonate (NTB, 10 nM) increased IC50 values of all the agonists. Combinations of BNTX and NTB (10 nM each) increased the D-Ala2-deltorphin II IC50 value 12-fold, the DPDPE IC50 value 18-fold and the SNF 9007 IC50 value 26-fold. The effect of the combined delta antagonists on SNF 9007 activity was different from the effect on DPDPE or D-Ala2-deltorphin II activity. These data suggest that the interaction of the CCK-8 analog SNF 9007 with opioid receptors in NG108-15 hybrid cells is different from the interaction of opioid peptides with these receptors.

Topics: Adenylyl Cyclase Inhibitors; Amino Acid Sequence; Analgesics; Cholecystokinin; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Enzyme Inhibitors; Glioma; Hybrid Cells; Molecular Sequence Data; Neuroblastoma; Oligopeptides; Pain; Peptide Fragments; Receptors, Opioid, delta

We have recently developed a rat model of chronic pain states after spinal cord injury. Thus, after severe, but incomplete, ischemic spinal cord injury, some rats chronically exhibited responses indicative of pain to innocuous mechanical stimuli (allodynia) in the rostral dermatomes involving the injured spinal segments. These responses have some characteristics in common with chronic central pain in patients with spinal cord injury. We now report that systemic CI988, a specific antagonist of the cholecystokinin (CCK) type B receptor, effectively relieved the allodynia-like symptom, an effect that was reversed by the opioid receptor antagonist naloxone. Furthermore, in rats which did not develop the allodynia-like symptom after spinal cord lesion, systemic naloxone induced typical allodynia. In contrast, naloxone failed to produce allodynia in normal animals. It is thus suggested that the abnormal sensory processing initiated by spinal cord ischemic lesion is under tonic opioidergic control and dysfunction of this control by the upregulated endogenous CCK system is responsible for the development of painful sensations in these rats.

Topics: Animals; Anti-Anxiety Agents; Behavior, Animal; Cholecystokinin; Chronic Disease; Diazepam; Endorphins; Female; Indoles; Meglumine; Naloxone; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; Spinal Cord Injuries; Vocalization, Animal

Previous studies have established that the antinociceptive effect of morphine was subjected to peptidergic modulation at spinal level. Intrathecal (i.t.) galanin (GAL) potentiated morphine-induced analgesia, whereas i.t. cholecystokinin (CCK) antagonized morphine's hypoalgesic effect. In the present study, we examined the possible interaction between GAL, CCK and clonidine, an alpha 2 adrenoceptor agonist and potent spinal antinociceptive agent, in the spinal nociceptive flexor reflex. I.t. clonidine dose-dependently depressed the flexor reflex similarly to i.t. morphine. However, unlike morphine, the reflex depressive effect of i.t. clonidine was neither potentiated by i.t. GAL nor blocked by i.t. CCK. The present results suggested that the analgesia elicited by activation of spinal alpha 2 adrenoceptors is not subjected to the modulatory effect of CCK and GAL and therefore may be mediated through different mechanisms than opioids.

Topics: Animals; Cholecystokinin; Clonidine; Drug Synergism; Female; Galanin; Injections, Spinal; Morphine; Pain; Peptides; Rats; Rats, Sprague-Dawley; Reflex

The effects of intracerebroventricular administration of the cholecystokinin (CCK) analogue, BDNL, and the selective CCK-B agonist, BC 264, were determined using the hot plate test in mice. BDNL (0.2 nmol and 0.5 nmol) increased the jump and the paw lick latencies. These effects were blocked by the CCK-A antagonist MK-329 (0.02 mg/kg), supporting the involvement of CCK-A receptors in CCK-induced analgesia. In contrast, the selective CCK-B agonist BC 264 produced, at one dose (2.5 nmol), a slight decrease in the lick latency that was only antagonized by the CCK-B antagonist. Naloxone, but not naltrindole, antagonized BDNL-induced analgesia. The results suggest that activation of CCK-A receptors by BDNL leads to antinociceptive responses indirectly mediated by stimulation of mu-opioid receptors by endogenous enkephalins.

Topics: Animals; Benzodiazepinones; Cerebral Ventricles; Cholecystokinin; Devazepide; Hot Temperature; Injections, Intraventricular; Male; Mice; Mice, Inbred Strains; Naloxone; Pain; Peptide Fragments; Phenylurea Compounds; Receptors, Cholecystokinin; Sincalide

1. Much evidence in the literature supports the idea that cholecystokinin (CCK) interacts with opioids in pain mechanisms. In this work, we have investigated the supraspinal interactions between enkephalins and CCK, using the hot plate test in mice. 2. Intracerebroventricular (i.c.v.) administration of BDNL (a mixed CCKA/CCKB agonist) induced dose-dependent antinociceptive responses on both paw lick and jump responses. In contrast, using the same test, the i.c.v. injection of BC 264 (a selective CCKB agonist) induced a hyperalgesic effect, which was restricted to paw licking and occurred only at a high dose of 2.5 nmol. 3. In addition, i.c.v. administration of BDNL potentiated the antinociceptive effects of the mixed inhibitor of enkephalin degrading enzymes, RB 101 and of the mu-agonist, DAMGO, while BC 264 reduced these effects. 4. Furthermore, at a dose where it interacts selectively with delta-opioid receptors, the opioid agonist BUBU reversed the hyperalgesic responses of BC 264 (2.5 nmol) but was unable to modify the effects induced by BDNL. 5. Taken together, these results suggest the existence of regulatory mechanisms between CCK and enkephalin systems in the control of pain. These regulatory loops could enhance the antinociceptive effects of morphine allowing the opiate doses used to be reduced and thus, possibly, the side-effects to be minimized.

Topics: Amino Acid Sequence; Analgesics; Animals; Cholecystokinin; Disulfides; Endorphins; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalins; Injections, Intraventricular; Male; Mice; Molecular Sequence Data; Oligopeptides; Pain; Pain Measurement; Peptide Fragments; Phenylalanine; Sincalide; Spinal Cord

We examined the distribution of mRNA for the peptide cholecystokinin (CCK) with in situ hybridization in adult rat lumbar dorsal root ganglia following unilateral section of the sciatic nerve, as well as the effect of systemic CI 988, a selective antagonist of the CCK type B receptor, applied alone or in combination with intrathecal (i.t.) morphine, on the self-mutilating behavior of rats (autotomy) after axotomy, a sign of neuropathic pain and/or dysesthesia. There was a dramatic increase in the number of neurons in dorsal root ganglia synthesizing the peptide cholecystokinin (CCK) after sciatic nerve section. Furthermore, the autotomy behavior of rats was significantly inhibited by chronic i.t. administration of morphine in conjunction with subcutaneous (s.c.) injection of CI 988. Neither i.t. morphine nor s.c. CI 988 alone produced a comparable effect on autotomy. Our results suggested that up-regulation of the mRNA for CCK in primary afferents after nerve injury may be related to the clinical phenomenon of opioid insensitivity. Thus, coadministration of CCK antagonists in combination with opioids may offer a new approach in treating neuropathic pain.

Topics: Animals; Cholecystokinin; Ganglia, Spinal; Indoles; Male; Meglumine; Morphine; Neurons, Afferent; Pain; Rats; Rats, Sprague-Dawley; Receptors, Cholecystokinin; RNA, Messenger; Sciatic Nerve; Self Mutilation

To further address the hypothesis that cholecystokinin (CCK) in the medullary dorsal horn (MDH) arises from intrinsic or higher-order neurons, CCK-8-specific radioimmunoassay (RIA) and immunohistochemical (IHC) experiments were carried out in adult rats after trigeminal tractotomy. RIA of punches from deafferented superficial layers of the MDH revealed no significant change in CCK levels vs. the control right side. In this same area, IHC revealed modest reductions in CCK, gastrin, and substance P staining. Calcitonin gene-related peptide (CGRP) staining was reduced substantially. Gastrin immunoreactive cell bodies, present normally in inner lamina II, were reduced in number. RIA and IHC methods were also used to assess MDH CCK concentrations in adult rats subjected to left infraorbital nerve section at birth. The left medulla contained significantly higher levels of CCK than the control right medulla (1.27 +/- 0.19 vs. 0.97 +/- 0.11 ng/mg protein). IHC revealed a dense band of CCK-like staining in laminae I and II ipsi- and contralateral to the lesion. Thus, neonatal deafferentation elevates medullary CCK. To determine if the neonatal lesion-induced increase in medullary CCK is due to primary afferent or higher-order reorganization, RIA and IHC experiments were run after infraorbital nerve section at birth and trigeminal tractotomy in adulthood. RIA revealed no significant change in CCK levels caudal to the tractotomy, although they were higher than control levels in 9 of 12 cases. IHC revealed modest reductions in CCK, substance P, and gastrin staining that resembled the reductions observed in tractotomy-alone cases. These data suggest that 1) most MDH CCK is of non-primary afferent origin, 2) gastrin immunoreactivity in layer II probably originates in CCK-containing cells intrinsic to layer II, the expression of which is dependent upon trigeminal primary afferent input, 3) neonatal V deafferentation induces increased CCK in the superficial MDH, reflecting reorganized intrinsic or higher-order inputs, and 4) higher-order substance P in the MDH is robust.

Topics: Animals; Animals, Newborn; Cholecystokinin; Female; Immunohistochemistry; Male; Medulla Oblongata; Neurons, Afferent; Pain; Peptides; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Trigeminal Nerve

Environmental stimuli that signal the occurrence of aversive or dangerous events activate endogenous opiate analgesia systems. Signals for safety (the nonoccurrence of aversive events) produce the opposite and inhibit environmentally produced analgesia. Stimuli that signal safety are now shown to abolish the analgesic effect of morphine, even when morphine is applied directly to spinal cord. Further, this antiopiate effect occurs because the environmental stimulus leads to release of the neuropeptide cholecystokinin in the spinal cord. This process may contribute to the regulation of pain and the development of opiate tolerance.

Topics: Analgesia; Animals; Benzodiazepinones; Cholecystokinin; Injections, Spinal; Morphine; Pain; Phenylurea Compounds; Rats; Receptors, Cholecystokinin; Safety; Spinal Cord

The intracerebroventricular injection of the cholecystokinin-A receptor antagonist L-364,718, at the doses of 0.5, 5, 10 or 20 micrograms/mouse, while having no effect on pain threshold (hot plate, 51 degrees C), antagonized the analgesic activity of morphine (10 mg/kg i.p.). This effect was obtained with a dose of 10 micrograms/mouse and was associated with a reduction of brainstem opiate-binding sites.

Topics: Analgesia; Animals; Benzodiazepinones; Brain Stem; Cholecystokinin; Devazepide; Female; Male; Mice; Morphine; Pain; Receptors, Cholecystokinin; Sensory Thresholds

Extracellular single unit recordings were made from dorsal horn nociceptive neurons of intact, urethane-anesthetized rats during controlled electrical stimulation of the hind paw. Neither local superfusion of cholecystokinin octapeptide (CCK; 6.4 pmol to 20 nmol) nor the CCK antagonist lorglumide (LGM; 145 fmol to 145 pmol) significantly altered A- or C-fiber evoked firing or spontaneous activity. Pretreatment with CCK, however, significantly attenuated, whereas LGM enhanced, morphine-induced inhibition of C-evoked firing. These findings provide further evidence that CCK functions as a selective antagonist of opioid-induced analgesia.

Topics: Animals; Cholecystokinin; Electric Stimulation; Evoked Potentials; Male; Morphine; Nerve Fibers; Neurons; Pain; Proglumide; Rats; Rats, Inbred Strains; Sincalide; Spinal Cord

The effects of systemic PD134308 [0.1-3 mg/kg; an antagonist of the cholecystokinin (CCK) type B receptor], morphine, and intrathecal (i.t.) galanin (GAL) on the excitability of the spinal nociceptive flexor reflex and in the hot plate test were examined in rats. PD134308 caused a weak naloxone-reversible depression of the flexor reflex and a moderate antinociceptive effect in the hot plate test. However, PD134308 significantly potentiated the antinociceptive effect of morphine as well as its depressive effect on the flexor reflex. PD134308 and i.t. GAL synergistically depressed the flexor reflex, an effect that was reversed by naloxone. Finally, the magnitude and duration of the depression of the flexor reflex by morphine were synergistically increased by coadministering PD134308 and GAL i.t. The results demonstrated that a CCK antagonist directed to the central CCK type B receptor potentiates the analgesic effects of opioids and nonopioid drugs at the spinal level, thus supporting the notion that CCK in the central nervous system may be an endogenous, physiological opioid antagonist.

Topics: Analgesics; Animals; Cholecystokinin; Drug Synergism; Female; Galanin; Indoles; Injections, Spinal; Kinetics; Male; Meglumine; Morphine; Naloxone; Nociceptors; Pain; Peptides; Rats; Rats, Inbred Strains; Receptors, Cholecystokinin; Reflex; Sorbitol; Spinal Cord; Time Factors

The potential antinociceptive effects of the selective cholecystokinin-B (CCK-B) antagonist L-365,260 were examined in the squirrel monkey tail withdrawal test. Pain threshold was measured in 6 male monkeys by recording the latency to remove the tail from a warm (55 degrees C) water bath. L-365,260 at doses of 100 ng/kg to 100 micrograms/kg significantly elevated tail withdrawal latencies throughout a 2 h test period. These data provide the first evidence that blockade of CCK-B receptors induces analgesia in primates.

Topics: Analgesia; Animals; Benzodiazepinones; Cholecystokinin; Dose-Response Relationship, Drug; Injections, Intraperitoneal; Male; Pain; Phenylurea Compounds; Receptors, Cholecystokinin; Saimiri; Time Factors

The effects of the cholecystokinin antagonist devazepide on analgesia and respiratory depression induced by morphine in squirrel monkeys were examined. Pain thresholds were determined using the tail withdrawal procedure, in which monkeys restrained in chairs kept their tails in cool (35 degrees C) water for at least 20 sec, but withdrew them from warm (55 degrees C) water in less than 4 sec. Morphine produced a dose-related increase in tail withdrawal latencies from warm water. Devazepide (injected i.p. or p.o.) had no effect on tail withdrawal latencies when given alone but enhanced the analgesic effects of morphine. The devazepide dose-response curve for morphine enhancement was bell-shaped with doses of 3, 10, 30 and 100 micrograms/kg injected i.p. increasing morphine analgesia whereas higher and lower dose did not. In a separate group of monkeys, morphine produced dose-dependent decreases in respiratory rate and oxygen tension and increases in carbon dioxide tension. In contrast to its effects on morphine analgesia, devazepide had no effect on the various indices of morphine-induced respiratory depression. These data suggest that devazepide may have therapeutic utility as an adjuvant to morphine analgesia allowing lower dose of the opiate to be used to relieve pain and reducing the risk of opiate-induced respiratory depression.

Topics: Administration, Oral; Analgesia; Animals; Benzodiazepinones; Cholecystokinin; Devazepide; Dose-Response Relationship, Drug; Drug Synergism; Injections, Intraperitoneal; Male; Morphine; Naloxone; Pain; Pain Measurement; Receptors, Cholecystokinin; Respiration Disorders; Saimiri

Anthramycin (ATM) which is a product of some streptomyces micro-organisms was shown to antagonize the central effects of cholecystokinin (CCK) such as antinociception and satiety and to displace CCK bound to the slices from the brains of mice. Sulfated octapeptide CCK (CCK8) was administered intracisternally to mice at doses of 1 microgram/mouse for inducing antinociception and 200 ng/mouse for satiety. ATM was administered intraperitoneally to mice at doses such as 0.3 and 0.5 mg/kg. CCK8-induced antinociception and satiety were significantly reversed by ATM in those doses. [125I]CCK8 binding to the brain slices was observed autoradiographically. The autoradiograms from the slices were converted to false color images by using a microcomputer. The radioactivity in the autoradiograms was expressed by color spectra in the false color images. Comparison of the binding of [125I]CCK8 to the brain slices in the presence and the absence of ATM revealed that ATM (10(-6) M) clearly displaced the CCK8 binding in the various regions, especially in the cortex, of the brain. These findings suggest that ATM acts as an potent antagonist of CCK in the central nervous system in mice.

Topics: Animals; Anthramycin; Benzodiazepines; Benzodiazepinones; Cholecystokinin; Feeding Behavior; Mice; Pain; Sensory Thresholds

In adult mammals, cholecystokinin (CCK)-opiate interactions are complex and task dependent. Specifically, CCK antagonizes opiate effects in some cases, yet acts similarly to opiate agonists in others. The present study used behavioral measures to determine how CCK interacts with opiates in neonatal rats. CCK, at doses of 1 microgram/kg and higher, markedly reduced isolation-induced distress vocalization in rat pups. Moreover, CCK selectively prevented naltrexone antagonism of opiate-mediated reduction in distress vocalization in 3- and 11-day-old rats. Yet CCK did not affect opiate-induced analgesia, as measured by the hot-plate paw-lift response. Thus CCK either did not interact with opiates or did so agonistically, with the same (low) dose range, and within subjects. These findings suggest independence of stress and pain systems in neonatal rats and demonstrate a functional interaction between CCK and opioid systems.

Topics: Animals; Animals, Newborn; Cholecystokinin; Drug Interactions; Morphine; Motor Activity; Naltrexone; Pain; Rats; Rats, Inbred Strains; Reference Values; Sincalide; Stress, Psychological; Vocalization, Animal

The novel CCK antagonist L364,718 was tested on caerulein- and morphine-induced antinociception in rat using the paw pressure test. Caerulein-induced antinociception (ED50 = 30 micrograms/kg) was significantly inhibited by L354,718 (200 micrograms/kg i.p.) which on its own did not affect paw pressure threshold. In contrast, morphine-induced antinociception was significantly potentiated by L364,718. Since L364,718 is highly selective for 'peripheral' receptors which are found in tissue such as pancreas and gallbladder and a few discrete areas of brain, this receptor is likely to be implicated in the antinociceptive effect of caerulein.

Topics: Analgesics; Animals; Benzodiazepinones; Ceruletide; Cholecystokinin; Devazepide; Drug Interactions; Female; Morphine; Pain; Rats; Rats, Inbred Strains; Reaction Time; Sensory Thresholds

Two beta-carboline esters, methyl or ethyl beta-carboline-3-carboxylate, beta-CCM and beta-CCE, were found to antagonize the antinociceptive and satiety action of the sulfated octapeptide cholecystokinin (CCK8) which was administered intracisternally to mice. beta-CCM did not affect the antinociception induced by morphine. The two beta-carboline esters weakly inhibited the food intake in mice. However, when they were administered after CCK8 administration, they reversed the CCK8-induced satiety. Since the two beta-carboline esters have been previously shown to act as selective cholecystokinin (CCK) receptor antagonists in the isolated guinea-pig gallbladder muscle, they are suggested to antagonize the central action of CCK through acting on the CCK receptor in the central nervous system. The results obtained from the present paper also suggest that benzodiazepine receptor ligands seem in general to act as CCK receptor antagonists as well.

Topics: Animals; Brain; Carbolines; Cholecystokinin; Eating; Male; Mice; Mice, Inbred Strains; Morphine; Nociceptors; Pain; Time Factors

In mice, intraperitoneally injected chlordiazepoxide and proglumide, both of which are regarded as cholecystokinin (CCK) receptor antagonists in the peripheral tissues, dose-dependently inhibited the satiety induced by 200 ng of intracisternally administered CCK octapeptide (CCK8). Intraperitoneally administered diazepam (1 mg/kg) and/or Ro 15-1788 (5 mg/kg), a benzodiazepine antagonist, both prevented the elevation in the pain threshold induced by 1 microgram of CCK8. However, Ro 15-1788 did not antagonize the effect of diazepam that reversed the CCK-induced antinociception. Ro 15-1788 also inhibited the satiety induced by CCK8. From these results, it was considered that the antagonism, which was observed in the present work, of benzodiazepines and proglumide to CCK8 seemed to occur at the CCK receptor and not at the benzodiazepine receptor in the brain.

Topics: Animals; Anti-Anxiety Agents; Benzodiazepines; Brain; Cholecystokinin; Eating; Male; Mice; Mice, Inbred Strains; Nociceptors; Pain; Proglumide; Receptors, Cholecystokinin; Satiation

Course and prognosis of 125 patients with chronic pancreatitis (CP) were evaluated. Follow-up period ranged from 1-20 years with a median of 6.3 years. The following conclusions were obtained. Recent increase of CP in our clinics was ascribed to alcoholic CP and idiopathic CP in the aged. Of 106 patients with pain, 74 showed improvement or disappearance of pain. Drinking habit and observation period were the main factors determining the rate of pain relief. Serial endoscopic retrograde pancreatography (ERP) showed aggravation in 17/47 patients, cholecystokinin-pancreozymin (CCK-PZ) secretin test in 4/40 patients, and oral glucose tolerance test (OGTT) in 7/25 patients. Exocrine function showed improvement in five patients, whereas endocrine function showed none. Improvement or aggravation of exocrine function was closely related to drinking habit. Main complications included 15 cases of peptic ulcer, 19 of pancreatic pseudocyst, and 15 of bile duct stenosis. Twenty-six patients died, often due to malignant neoplasms and diabetic complications. Those who continued drinking as much showed a lower survival rate than those who discontinued or decreased alcohol intake. The socioeconomic status deteriorated often due to pain or alcoholism. Three patients had to degrade jobs and six fell into inactive social life.

Topics: Age Factors; Alcoholism; Calcinosis; Cholecystokinin; Chronic Disease; Female; Glucose Tolerance Test; Humans; Longitudinal Studies; Male; Pain; Pancreatitis; Peptic Ulcer; Prognosis; Quality of Life; Sex Factors

Fifteen patients with history of biliary colic, induceable by cholecystokinin, but normal oral cholecystogram and ultrasonogram were studied prior to and after cholecystectomy. Fasting duodenal bile, obtained preoperatively after administration of cholecystokinin, and gallbladder bile obtained at operation were analyzed. The lipid composition as well as the cholesterol saturation were within the range seen in gallstone-free subjects. The total lipid concentration of gallbladder bile was normal, whereas that of duodenal bile was reduced by about 50%, indicating a less efficient gallbladder emptying. In 10 of the 15 patients, the analysis of the excised gallbladder displayed macro- or microscopic abnormalities; two patients had cholesterol gallstones. At re-examination 9-27 months after the operation, 12 of the patients were completely symptom-free and two patients reported a clear improvement while on still had unchanged symptoms. It is concluded that cholecystectomy is the treatment to prefer in patients with "acalculous" biliary pain, induceable by cholecystokinin.

Topics: Adult; Bile; Bile Duct Diseases; Cholecystectomy; Cholecystokinin; Cholelithiasis; Colic; Female; Gallbladder; Humans; Lipid Metabolism; Male; Middle Aged; Pain

Plasma cholecystokinin (CCK) responses after ingestion of a test meal in patients with mild chronic pancreatitis having abdominal pain were studied with a radioimmunoassay using the CCK specific antiserum (OAL-656) produced by a novel immunization procedure. Mean concentration of the fasting plasma CCK determined using CCK-8 as a standard was 31.5 +/- 5.8 pg/ml in six patients who had mild impaired exocrine function with pain, and was significantly higher than 10 healthy subjects (9.8 +/- 1.8 pg/ml). In those patients, the ingestion of a liquid test meal led to a peak of 75.1 +/- 25.4 pg/ml at 30 min, and the 120-min integrated CCK response (5427 +/- 1217.3 pg X min/ml) was significantly higher than in healthy subjects (1538 +/- 110.1 pg X min/ml).

Topics: Abdomen; Adult; Blood Glucose; Cholecystokinin; Chronic Disease; Fasting; Feedback; Female; Food; Humans; Insulin; Male; Middle Aged; Pain; Pancreas; Pancreatic Diseases; Pancreatic Polypeptide; Radioimmunoassay

The putative peptide neurotransmitter cholecystokinin (CCK) is co-localized with substance P (SP) in a dense cluster of neurons located in the rat Edinger-Westphal (EW) nucleus. In an attempt to record electrophysiologically from these CCK-containing neurons, we have identified a group of nociceptive neurons located within the confines of the EW nucleus. The firing pattern of these nociceptive neurons is erratic, sometimes with a bursting pattern and at other times with fairly regular rates which vary generally from 1 to 7 Hz. These neurons respond to noxious stimuli, such as toe pinch, with an increase in rate and sometimes enter an apparent depolarization blockade (preceded by an increase in the duration and a decrease in the amplitude of the action potential). Systemically administered morphine suppresses both the spontaneous firing rate and the toe pinch-induced increase in firing rate. Naloxone is able to reverse the effects of morphine. Although we have identified in the EW area a moderate density of terminals containing enkephalin-like immunoreactivity, morphine locally applied via microiontophoresis is largely without effect on the firing of these neurons. We hypothesize that the opiate-induced suppression of these nociceptive neurons is not mediated directly on the EW cells, but rather indirectly through afferent systems.

Topics: Animals; Chloral Hydrate; Cholecystokinin; Lysergic Acid Diethylamide; Male; Microscopy, Electron; Morphine; Nociceptors; Pain; Rats; Superior Colliculi

Adult frogs (Rana esculenta) were given subcutaneous injections of 10, 20, 30, 50 and 100 mg/kg capsaicin in sequential order over 5 days, or the vehicle only. The nociceptive thresholds to electrical, thermal and chemical stimuli were measured before, and 1, 5 and 24 h after each injection. Capsaicin was followed by a dose-related reduction of nociceptive responses to all stimuli, but these effects lasted for only 1-5 h after the given injection. Water/acetic extracts of undivided brains and spinal cords were prepared at the corresponding time periods for the radioimmunoassay of peptides. Spinal cord concentrations of immunoreactive substance P were essentially unaffected by capsaicin, while those of immunoreactive somatostatin were significantly increased after the second for fourth injections (20, 30 and 50 mg/kg) of capsaicin. Brain extracts showed an increase of somatostatin and substance P concentrations after the dose of 50 mg/kg. In an additional experiment, immunoreactive substance P, somatostatin and cholecystokinin were measured in tissue samples taken at 2 and 10 min, and 1, 5 and 24 h after a single dose of either 50 mg/kg capsaicin or the vehicle. The only significant effect of capsaicin was an increase of immunoreactive somatostatin concentration in brain homogenates at 5 h, while the vehicle in itself elicited major variations of all three peptides in spinal cord and/or brain. These results indicate that capsaicin reduces the nociceptive responses to cutaneous stimuli in adult frogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain Chemistry; Capsaicin; Cholecystokinin; Chromatography, Gel; Electric Stimulation; Hot Temperature; Nerve Tissue; Pain; Radioimmunoassay; Rana esculenta; Sensory Thresholds; Somatostatin; Spinal Cord; Stimulation, Chemical; Substance P; Time Factors

Intraperitoneally administered benzodiazepines, chlordiazepoxide (2-5 mg/kg), diazepam (1 mg/kg), flurazepam (1 mg/kg) and a benzodiazepine antagonist, Ro 15-1788 (0.5 mg/kg), reversed the antinociceptive effect in mice which was induced by intracisternal administration of 1 microgram of sulfated cholecystokinin octapeptide. The antinociceptive effect of cholecystokinin was reversed by naloxone, suggesting that the antinociceptive action involves endogenous opioid peptides in its production. On the other hand, morphine-induced analgesia was not reversed by diazepam and Ro 15-1788. These facts rule out opioid receptors as the site of the antagonism between the benzodiazepines or Ro 15-1788 and cholecystokinin on the antinociceptive effect. Benzodiazepines and Ro 15-1788 seem to inhibit the release of opioid peptides induced by cholecystokinin.

Topics: Analgesics; Animals; Anti-Anxiety Agents; Benzodiazepinones; Chlordiazepoxide; Cholecystokinin; Diazepam; Flumazenil; Flurazepam; Male; Mice; Morphine; Naloxone; Pain; Sensory Thresholds; Time Factors

Recent evidence has suggested that cholecystokinin (CCK) may act as a physiological opiate antagonist. Both the overlap of CCK and opiate systems within the central nervous system and the fact that exogenous CCK can antagonize opiate analgesia suggest that endogenous CCK systems interact with opiate-mediated pain inhibitory systems. In the present series of experiments, we examined the effect of the CCK receptor antagonist proglumide on various forms of morphine analgesia. We have observed that proglumide can potentiate morphine analgesia following systemic, intrathecal or intracerebral administration of these drugs. Endogenous CCK systems do not appear to be tonically active since neither systemic, intrathecal nor intracerebral proglumide typically produced measurable analgesia in the absence of morphine. These data suggest that CCK may be released in response to opiate administration and acts to return the organism toward its basal level of pain sensitivity. If such a hypothesis is in fact true, then CCK blockade may be of clinical value in the treatment of pain.

Topics: Analgesia; Animals; Cholecystokinin; Dose-Response Relationship, Drug; Drug Synergism; Glutamine; Injections, Spinal; Male; Microinjections; Morphine; Pain; Periaqueductal Gray; Proglumide; Rats; Rats, Inbred Strains; Reaction Time; Time Factors

Topics: Adult; Cholecystokinin; Chronic Disease; Humans; Middle Aged; Narcotics; Nerve Block; Pain; Pain Management; Pancreas; Pancreatic Ducts; Pancreatic Extracts; Pancreatic Pseudocyst; Pancreatitis; Peptic Ulcer; Secretin

Proglumide, a cholecystokinin antagonist, potentiates analgesia produced in rats by morphine and endogenous opiates, and appears to reverse tolerance in rats to opiate analgesia. Therefore, proglumide and other cholecystokinin antagonists may be clinically valuable. We have tested proglumide's possible opiate analgesic potentiating effects by examining, in volunteers, the effects of morphine and proglumide on human pain visual analogue scale responses to 45-51 degrees C skin temperature stimuli. Proglumide (50-100 micrograms intravenously) potentiated both the magnitude and duration of analgesia produced by small doses of morphine. This study provides indirect evidence for a cholecystokinin-opiate interaction in humans. Therefore, cholecystokinin antagonists such as proglumide may serve to potentiate exogenous or endogenous opiate action.

Topics: Adult; Cholecystokinin; Dose-Response Relationship, Drug; Double-Blind Method; Drug Synergism; Glutamine; Humans; Injections, Intravenous; Morphine; Pain; Proglumide; Random Allocation

Intrathecal injections of capsaicin (CAP) and 4 other homovanillic acid (HMV) derivatives related to the structure of CAP were carried out. Capsaicin, 1-nonenoylvanillylamide (NVA), HMV-dodecylamide (DCA) (but not HMV-cyclohexylamide (CHA) or HMV-hexadecylamide (HDC] reduced the spinal content of substance P (SP), as measured by radioimmunoassay (RIA), and increased the tail-flick latency. Similar injection of kainic acid and piperine reduced levels of SP but failed to affect the tail-flick latency. None of the agents used affected spinal levels of cholecystokinin (CCK) or vasoactive intestinal peptide (VIP) as measured by RIA. In experiments using in vivo superfusion of the rat spinal cord, CAP, DCA and NVA were found to stimulate release of SP. Capsaicin had no effect on the levels of CCK or VIP immunoreactivity in the spinal superfusate. A tachyphylaxis to the effect of CAP and DCA on spinal SP release was demonstrated. Pretreatment with either agent blocked the releasing effect of the second. Pretreatment with an inactive analogue (HDC) had no effect on the subsequent activity of CAP. Kainic acid and piperine did not induce release of SP from the spinal cord. The relative selectivity of spinally administered capsaicinoids with regard to their effects on the content and release of peptides known to be contained in primary afferents and the presence of a similar structure-activity relationship for depletion and release of SP, desensitization and antinociception suggest the presence of a specific receptor site associated with a specific population of primary afferents through which pain information may pass. Whether SP is an 'afferent pain transmitter' is not clear, but at the least, it appears to serve as a marker for a population of afferents acted upon by spinally administered capsaicinoids.

Topics: Animals; Capsaicin; Cholecystokinin; Homovanillic Acid; Injections, Spinal; Male; Pain; Phenylacetates; Rats; Rats, Inbred Strains; Spinal Cord; Substance P; Tachyphylaxis; Vasoactive Intestinal Peptide

Topics: Adrenocorticotropic Hormone; Animals; beta-Endorphin; Bombesin; Bradykinin; Cholecystokinin; Dynorphins; Endorphins; Enkephalins; Melanocyte-Stimulating Hormones; Mice; Nervous System; Neurotensin; Pain; Peptide Fragments; Peptides; Rats; Somatostatin; Substance P; Thyrotropin-Releasing Hormone; Vasopressins

Administration of cholecystokinin was recently found to attenuate opiate analgesia. In the present study, the role of endogenous cholecystokinin in opiate analgesia was examined. Endogenously released cholecystokinin was sequestered by antibodies to cholecystokinin developed in response to an active immunization procedure. Morphine analgesia was potentiated and prolonged in rats immunized against cholecystokinin. The rate of development of morphine tolerance, however, was not affected by the antibodies. Endogenous cholecystokinin appears to function as a short-term modulator of opiate action.

Topics: Animals; Antibodies; Cholecystokinin; Drug Tolerance; Immunization; Male; Morphine; Pain; Rats; Rats, Inbred Strains; Time Factors

The endogenous neuropeptide cholecystokinin, when administered systemically or perispinally, potently antagonizes opiate analgesia produced by foot shock and morphine. Nonopiate foot-shock analgesia is not reduced by this neuropeptide. The spinal cord appears to be a critical site of cholecystokinin action. These experiments suggest a physiological role for cholecystokinin as a specific opiate antagonist in analgesia-mediating systems. A similar mode of action may explain other behavioral effects of cholecystokinin, such as suppression of food intake.

Topics: Animals; Cholecystokinin; Conditioning, Classical; Morphine; Pain; Receptors, Cell Surface; Receptors, Opioid

Topics: Acupuncture Therapy; Animals; Body Temperature Regulation; Brain; Brain Diseases; Cerebrospinal Fluid; Cholecystokinin; Endorphins; Enkephalins; Epilepsy; Feeding Behavior; Humans; Learning; Memory; Nervous System Diseases; Neurotransmitter Agents; Pain; Peptides; Pituitary Hormones; Substance P; Synaptic Transmission

The general profile of pain in the evolution of pancreatitis was analysed in relation to exocrine and endocrine pancreatic function in 127 patients with primary chronic pancreatitis followed up over 3 years. Pain decreased or disappeared in 67.8% and 55.9% of calcifying pancreatitis, respectively. While pancreatic exocrine function remained abnormal in spite of an improvement of pain in 72% of 18 patients with calcifying pancreatitis, it improved with the amelioration of pain in 64% of 25 patients with non-calcifying pancreatitis during the follow-up period. Alcohol abstinence seems most important for pain relief in patients with non-calcifying pancreatitis but not calcifying pancreatitis. Changes in glucose tolerance test were not related with those in pain. In calcifying pancreatitis, 69.2% of patients with calcifying pancreatitis were diabetic or became so, while 66.7% of patients with non-calcifying pancreatitis remained non-diabetic during the observation period.

Topics: Adult; Alcohol Drinking; Calcinosis; Cholecystokinin; Chronic Disease; Dietary Fats; Female; Follow-Up Studies; Glucose Tolerance Test; Humans; Male; Middle Aged; Pain; Pancreatitis

Topics: Adult; Biliary Tract Diseases; Cholecystography; Cholecystokinin; Cholelithiasis; Colic; Female; Humans; Middle Aged; Pain

Topics: Analgesia; Angiotensin II; beta-Endorphin; Cholecystokinin; Endorphins; Enkephalins; Humans; Neurotensin; Neurotransmitter Agents; Pain; Peptides; Somatostatin; Substance P

An approach to the diagnosis and treatment of patients with presumed functional disorders of the biliary tract (biliary dyskinesia) is described. The current diagnostic criteria are pain compatible with biliary pain in the absence of gallstones and other organic gastrointestinal disease, or other disorders which might produce abdominal pain, together with reproduction of the patient's symptoms by cholecystokinin, or morphine, or both. Other diagnostic methods are described together with their limitations. The results of operation in 38 of 45 patients seen in this Unit during the past six years are presented. The results were poor in 20% of patients, but two-thirds of the group have had good results in the short term.

Topics: Biliary Tract Diseases; Cholangiography; Cholecystectomy; Cholecystography; Cholecystokinin; Cholelithiasis; Diagnosis, Differential; Humans; Morphine; Pain; Pressure

The group of conditions variously termed biliary dyskinesia, acalculous cholecystitis, biliary pain without stones, or functional disorders of the biliary tract, is poorly defined clinically, and no consistent pathological abnormalities have been previously described in patients with this diagnosis. In this paper we report histological abnormalities encountered in operative live biopsies in such patients. The criteria for the diagnosis of a functional biliary tract disorders were: pain typical of biliary pain, negative results of investigations for organic biliary tract or other gastrointestinal disease, and reproduction of the patient's symptoms by cholecystokinin, or morphine, or both. Twenty of 45 patients with a presumptive diagnosis satisfied these criteria, and had a wedge liver biopsy at the time of operation. The 20 liver biopsy specimens were compared in a blind fashion with similar ones taken from patients having diagnostic laparotomies; patients with stones confined to the gallbladder; patients with gallstone pancreatitis; and patients with proven common bile duct stones. The biopsy findings were found to be similar to those in the latter two groups. Thus the abnormalities were similar to those found in partial or intermittent biliary obstruction, and it is suggested that they may be due to intermittent increases in biliary pressure.

Topics: Adult; Aged; Biliary Dyskinesia; Biliary Tract Diseases; Cholecystitis; Cholecystokinin; Cholelithiasis; Female; Humans; Liver; Male; Middle Aged; Morphine; Pain; Pancreatitis

Thirty-one patients with recurrent symptoms of the biliary tract and repeated normal oral cholecystograms were studied by a combination of cholecystokinin cholangiography and biliary drainage. Ten patients had reduplication of their symptons because of dyskinetic contractions or obstruction of the cystic duct, and seven patients had delayed gallbladder emptying without pain due to hypokinetic contractions. Five patients had abnormal duodenal bile characterized by supersaturation and the presence of crystals or bacteria. Based upon these studies, 22 patients had cholecystectomy and 20 were cured, while two showed improvement. There were no therapeutic failures. Cholecystokinin cholangiography capably detects the presence of neuromuscular disease of the gallbladder wall, whereas the oral cholecystogram tests for mucosal function or the presence of filling defects. An additional group of patients who have cholesterosis, cholecystitis, or cholelithiasis missed by the oral cholecystogram will not be diagnosed by cholecystokinin cholangiography unless the duodenal bile is also examined.

Topics: Abdomen; Adolescent; Adult; Aged; Bile; Bile Acids and Salts; Biliary Tract Diseases; Cholangiography; Cholecystectomy; Cholecystography; Cholecystokinin; Cholesterol; Clostridium; Cystic Duct; Duodenum; Escherichia coli; Female; Humans; Male; Middle Aged; Movement Disorders; Pain; Phospholipids; Prospective Studies; Recurrence

Ten adolescent and young adults with cystic fibrosis (CF) have had well-documented recurrent attacks of acute pancreatitis. The diagnosis of CF in each patient was delayed because they did not have pancreatic insufficiency. The diagnosis of CF was documented by the typical pulmonary involvement and elevated sweat sodium and chloride levels in all cases and a positive family history in six of the ten patients. Two patients were diagnosed as having acute pancreatitis before the diagnosis of CF was made, thus indicating that acute pancreatitis may be the presenting complaint in the young adult with CF. The diagnosis of acute pancreatitis was based on the presence of severe abdominal pain, usually with vomiting, tenderness in the mid-epigastrium, elevated serum and urinary amylase and serum lipase. Attacks were precipitated by fatty meals, alcohol ingestion; postcholecystectomy and tetracycline administration. In some patients no precipitating event could be elicited. Intravenous secretin-pancreozymin stimulation tests revealed a diminished bicarbonate secretion with little effect on the secretion of the zymogen enzymes. A mild attack of pancreatitis occurred after secretin-pancreozymin stimulation. The endocrine pancreatic function tested in four patients was normal as revealed by the glucose tolerance tests and determinations of serum insulin, growth hormone and free fatty acid. Transduodenal pancreatograms were performed in three patients; one showed a normal pancreatic duct, one showed duct obstruction and in the third patient a beady type of narrowing was found. The selenomethionine Se 75 uptake of the pancreas was noted only in the head of the pancreas. This suggests that loss of function occurs initially to a greater extent in the tail and body of the pancreas. Three patients died and showed characteristic lesions of CF.

Topics: Acute Disease; Adolescent; Adult; Amylases; Chlorides; Cholecystokinin; Chymotrypsin; Cystic Fibrosis; Female; Glucose Tolerance Test; Humans; Intubation, Gastrointestinal; Lipase; Magnesium; Male; Methionine; Pain; Pancreas; Pancreatitis; Potassium; Recurrence; Secretin; Selenium; Sodium; Trypsin

Topics: Adult; Cholangiography; Cholecystography; Cholecystokinin; Diagnosis, Differential; Evaluation Studies as Topic; False Positive Reactions; Female; Follow-Up Studies; Gallbladder; Gallbladder Diseases; Humans; Informed Consent; Injections, Intravenous; Male; Middle Aged; Pain; Posture; Time Factors

Topics: Biliary Tract Diseases; Cholangiography; Cholecystokinin; False Positive Reactions; Humans; Injections, Intravenous; Pain

Topics: Abdomen; Adult; Cholecystokinin; Colon, Sigmoid; Colonic Diseases, Functional; Eating; Female; Gastrointestinal Motility; Humans; Injections, Intravenous; Male; Middle Aged; Pain

Topics: Abdomen; Administration, Oral; Cholecystokinin; Colon; Eating; Gastrointestinal Motility; Humans; Magnesium Sulfate; Pain

Magnesium sulphate, a substance known to cause release of cholecystokinin (CCK) from the small intestinal mucosa, was given by mouth (dose 0.1g/kg in 150 ml water) to 20 patients with the irritable bowel syndrome. A rapid increase in colonic segmental motor activity (onset within two to six minutes in most cases) was seen (percentage activity increased from 16.2 to 23.7 p<0.05; mean wave amplitude from 7.1 to 9.1 cm H(2)O, NS; motility index from 144 to 259, p<0.01). This increase was most marked in 10 patients who complained of attacks of abdominal pain after food (16.1 to 29.8%, p<0.01; 6.8 to 9.6 cm H(2)O, p<0.05; 135 to 350, p<0.05), and after the magnesium sulphate three of these patients experienced an attack of their usual pain. These findings provide further evidence that ;functional' abdominal pain after food may in some cases be related to an exaggerated intestinal motor response to cholecystokinin.

Topics: Cholecystokinin; Colon; Colon, Sigmoid; Colonic Diseases, Functional; Eating; Fasting; Gastrointestinal Motility; Humans; Magnesium Sulfate; Pain; Pressure; Sigmoidoscopy

Topics: Ascites; Biopsy; Cholecystokinin; Chronic Disease; Diagnosis, Differential; Duodenum; Emaciation; Endoscopy; Humans; Pain; Pancreas; Pancreatectomy; Pancreatic Cyst; Pancreatic Ducts; Pancreatic Neoplasms; Pancreatitis; Secretin

Topics: Bethanechol Compounds; Catheterization; Cholecystokinin; Contrast Media; Humans; Injections, Intravenous; Male; Manometry; Middle Aged; Morphine; Nitroglycerin; Pain; Pancreatic Diseases; Pancreatic Ducts; Pancreatic Fistula; Pancreatitis; Pressure; Radiography

Topics: Adolescent; Adult; Age Factors; Celiac Disease; Child; Cholecystokinin; Chronic Disease; Clinical Enzyme Tests; Diabetes Mellitus; Feces; Female; Follow-Up Studies; Humans; Male; Middle Aged; Pain; Pancreas; Pancreatitis; Time Factors

Topics: Adult; Asthenia; Cholecystectomy; Cholecystography; Cholecystokinin; Cholelithiasis; Colon; Colon, Sigmoid; Constipation; Desensitization, Immunologic; Diarrhea; Dyspepsia; Female; Headache; Histamine H1 Antagonists; Humans; Hypersensitivity; Middle Aged; Pain; Postoperative Complications; Sleep Wake Disorders; Stomach