ceruletide and Pain

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

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

The decapeptide from the frog Hyla caerulea, caerulein (caerulein diethylammonium hydrate, ceruletide, CER) is chemically closely related to the C-terminal octapeptide of cholecystokinin (CCK-8). Like CCK-8, CER and some of its analogues produce many behavioural effects in mammals: inhibition of intake of food and water; antinociception; sedation; catalepsy; ptosis, antistereotypic, anticonvulsive and tremorolytic effects; inhibition of self-stimulation. Effects of CER in man comprise sedation, satiety, changes in mood, analgesia and antipsychotic effects. A modulation of central dopaminergic functions appears to be one possible mechanism of CER and its analogues. A common denominator for all effects of CER is, at present, not evident.

Topics: Animals; Anticonvulsants; Avoidance Learning; Behavior, Animal; Blepharoptosis; Body Temperature Regulation; Catalepsy; Ceruletide; Drinking Behavior; Electrophysiology; Feeding Behavior; Humans; Hypnotics and Sedatives; Motor Activity; Pain; Psychotic Disorders; Self Stimulation; Sleep; Stereotyped Behavior; Structure-Activity Relationship; Substance-Related Disorders; Tremor

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

Caerulein (CRL) (5 micrograms i.m.) and morphine (10 mg i.m.) have been tested for their analgesic activity in a double blind randomized study in a total of 36 patients with medium to severe tumor pains. A decrease of more than 20 mm on a visual analogue scale (VAS) was taken as a criterion for successful therapy. This was the case in 67% of the patients treated with morphine and 50% of those treated with CRL. This difference is statistically not significant, but CRL has significantly fewer side-effects than morphine. The present data do not permit a definitive judgement on the value of CRL in the treatment of tumor pains. Further studies with more patients and different doses and administration routes are warranted.

Topics: Adult; Aged; Aged, 80 and over; Ceruletide; Chronic Disease; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Morphine; Neoplasms; Pain; Pain Measurement; Random Allocation

The effects of ceruletide on jejunal motility and experimentally induced pain were studied in 16 healthy men, who participated each in four experiments and received in random double blind fashion 5, 10, or 20 micrograms ceruletide intramuscularly or placebo. Jejunal pressures were recorded by three perfused catheters with orifices between 10 and 20 cm aboral of the ligament of Treitz. Ceruletide dose dependently diminished phase I and increased phase II type activity and tended to reduce the number, but not the duration, of activity fronts. The number and amplitude of contractions as well as the area under the curve increased significantly and dose dependently as did threshold and tolerance to electrically and threshold to thermally induced pain. Only mild sedative and other side effects occurred.

Topics: Adult; Ceruletide; Dose-Response Relationship, Drug; Double-Blind Method; Gastrointestinal Motility; Humans; Jejunum; Male; Pain; Reaction Time

The effect of ceruletide (CRL), a synthetic decapeptide analogue of cholecystokinin, on rest pain and arterial blood flow was evaluated in 8 patients with advanced, occlusive atherosclerosis of the lower extremities. CRL 1, 2, or 4 ng kg-1 or placebo were infused intravenously in random order, and in a double-blind fashion. Pain relief, assessed by a scoring system, was significantly better (p less than 0.01) following the 2 and 4 ng kg-1 doses of CRL (2.71 and 2.66, respectively) than following placebo (0.75). Arterial blood flow was not affected by either CRL in any dose or by placebo. Pretreatment with naloxone, a pure opioid antagonist, abolished the analgesic effect of CRL. Following the 2 ng dose of CRL, beta-endorphin levels were significantly elevated from a basal value of 125 +/- 15 pg/ml to 191 +/- 35 pg/ml 5 h after CRL administration (p less than 0.05). Circulating levels of ACTH, prolactin and GH were not affected by CRL. It is concluded that CRL was effective in relieving ischaemic rest pain, and that the mechanism was related to the release of endogenous opioids.

Topics: Adrenocorticotropic Hormone; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Arteriosclerosis; beta-Endorphin; Ceruletide; Endorphins; Female; Gas Gangrene; Humans; Leg; Leg Ulcer; Male; Middle Aged; Naloxone; Pain; Rest

Acute pancreatitis (AP) and recurring AP are serious health care problems causing excruciating pain and potentially lethal outcomes due to sepsis. The validated caerulein- (CAE) induced mouse model of acute/recurring AP produces secondary persistent hypersensitivity and anxiety-like behavioral changes for study.. To determine efficacy of acetyl-L-carnitine (ALC) to reduce pain-related behaviors and brain microglial activation along the pain circuitry in CAE-pancreatitis.. Pancreatitis was induced with 6 hly intraperitoneal (i.p.) injections of CAE (50 µg/kg), 3 d a week for 6 wk in male C57BL/6J mice. Starting in week 4, mice received either vehicle or ALC until experiment's end. Mechanical hyper-sensitivity was assessed with von Frey filaments. Heat hypersensitivity was determined with the hotplate test. Anxiety-like behavior was tested in week 6 using elevated plus maze and open field tests. Microglial activation in brain was quantified histologically by immunostaining for ionized calcium-binding adaptor molecule 1 (Iba1).. Mice with CAE-induced pancreatitis had significantly reduced mechanical withdrawal thresholds and heat response latencies, indicating ongoing pain. Treatment with ALC attenuated inflammation-induced hypersensitivity, but hypersensitivity due to abdominal wall injury caused by repeated intraperitoneal injections persisted. Animals with pancreatitis displayed spontaneous anxiety-like behavior in the elevated plus maze compared to controls. Treatment with ALC resulted in increased numbers of rearing activity events, but time spent in "safety" was not changed. After all the abdominal injections, pancreata were translucent if excised at experiment's end and opaque if excised on the subsequent day, indicative of spontaneous healing. Post mortem histopathological analysis performed on pancreas sections stained with Sirius Red and Fast Green identified wide-spread fibrosis and acinar cell atrophy in sections from mice with CAE-induced pancreatitis that was not rescued by treatment with ALC. Microglial Iba1 immunostaining was significantly increased in hippocampus, thalamus (intralaminar nuclei), hypothalamus, and amygdala of mice with CAE-induced pancreatitis compared to naïve controls but unchanged in the primary somatosensory cortex compared to naïves.. CAE-induced pancreatitis caused increased pain-related behaviors, pancreatic fibrosis, and brain microglial changes. ALC alleviated CAE-induced mechanical and heat hypersensitivity but not abdominal wall injury-induced hypersensitivity caused by the repeated injections.

Topics: Acetylcarnitine; Acute Disease; Animals; Brain; Ceruletide; Disease Models, Animal; Male; Mice; Mice, Inbred C57BL; Microglia; Pain; Pancreas; Pancreatitis

Chaiqin chengqi decoction (CQCQD) and its derivatives have been widely used in China for the early management of patients with acute pancreatitis (AP). Numerous studies demonstrate the anti-inflammatory and anti-oxidative effects of CQCQD and derivatives, but whether these effects can be attributed to suppressing neurogenic inflammation, has never been studied.. To investigate the effects of CQCQD on substance P (SP)-neurokinin 1 receptor (NK1R) based neurogenic inflammation in an experimental AP model.. For AP patients on admission, pain score was accessed by visual analog scale (VAS); the levels of serum SP and expressions of pancreatic SP and NK1R were also determined. For in vivo study, mice received 7 intraperitoneal injections of cerulein (50 μg/kg) at hourly intervals to induce AP, whilst controls received normal saline injections. In the treatment groups, CQCQD (10 g/kg, 200 μl) was intragastrically given at the third, fifth, and seventh of the cerulein injection or the NK1R antagonist CP96345 (5 mg/kg) was intraperitoneally injected 30 min before the first cerulein administration. The von Frey test was performed to evaluate pain behavior. Animals were sacrificed at 12 h from the first cerulein/saline injection for severity assessment. Pharmacology network analysis was used to identify active ingredients of CQCQD for AP and pain. In vitro, freshly isolated pancreatic acinar cells were pre-treated with CQCQD (5 mg/ml), CP96345 (1 μM), or selected active compounds of CQCQD (12.5, 25, and 50 μM) for 30 min, followed by SP incubation for another 30 min.. The VAS score as well as the levels of serum SP and expressions of pancreatic SP-NK1R were up-regulated in moderately severe and severe patients compared with those with mild disease. CQCQD, but not CP96345, consistently and significantly ameliorated pain, pancreatic necrosis, and systemic inflammation in cerulein-induced AP as well as inhibited NK1R internalization of pancreatic acinar cells. These effects of CQCQD were associated with reduction of pancreatic SP-NK1R and neuron activity in pancreas, dorsal root ganglia, and spinal cord. Baicalin, emodin, and magnolol, the top 3 active components of CQCQD identified via pharmacology network analysis, suppressed NK1R internalization and NF-κB signal pathway activation in isolated pancreatic acinar cells.. CQCQD ameliorated cerulein-induced AP and its associated pain via inhibiting neuron activation-mediated pancreatic acinar cell SP-NK1R signaling pathways and its active compounds baicalin, emodin, and magnolol contributed to this effect.

Topics: Acinar Cells; Analgesics; Animals; Anti-Inflammatory Agents; Biphenyl Compounds; Ceruletide; Drugs, Chinese Herbal; Emodin; Flavonoids; Ganglia, Spinal; Humans; Lignans; Male; Mice, Inbred C57BL; Neurons; Pain; Pancreas; Pancreatitis; Receptors, Neurokinin-1; Signal Transduction; Spinal Cord; Substance P

Chronic pancreatitis (CP) is characterized by pancreatic inflammation and fibrosis, associated with increased pancreatic expression of transforming growth factor beta (TGFB). It is not clear how these might contribute to pain. We investigated whether TGFB signaling via SMAD induces sensitization of pancreatic sensory neurons to increase nociception.. CP was induced in Sprague-Dawley rats by infusion of trinitrobenzene sulfonic acid; some rats were given intrathecal infusions of TGFB1. CP was induced in control mice by administration of cerulein; we also studied β1glo/Ptf1acre-ER mice, which on induction overexpress TGFB1 in pancreatic acinar cells, and TGFBr1. Overexpression of TGFB in pancreatic acinar cells of mice and infusion of TGFB1 into rats resulted in sensory neuron hyperexcitability, SMAD3 activation, and increased nociception. This was accompanied by a reduction in the transient A-type current in pancreas-specific sensory neurons in rats, a characteristic of nociceptive sensitization in animal models of CP. Conversely, pancreata from TGFBr1. In pancreata of mice and rats, TGFB promotes peripheral nociceptive sensitization via a direct effect on primary sensory neurons mediated by intra-neuronal SMAD3. This is distinct from the central nervous system, where TGFB reduces nociception. These results provide an explanation for the link between fibrosis and pain in patients with CP. This signaling pathway might be targeted therapeutically to reduce pain in patients with CP.

Topics: Animals; Ceruletide; Disease Models, Animal; Fibrosis; Humans; Hyperalgesia; Male; Mice; Mice, Transgenic; Nociceptors; Pain; Pancreas; Pancreatitis, Chronic; Patch-Clamp Techniques; Protein Serine-Threonine Kinases; Rats; Rats, Sprague-Dawley; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Recombinant Proteins; Signal Transduction; Smad3 Protein; Synaptic Potentials; Transforming Growth Factor beta; Trinitrobenzenesulfonic Acid

Transient receptor potential vanilloid-1 (TRPV1) expressed in nociceptors is directly phosphorylated and activated by protein kinase C, and involved in the signaling of pancreatic pain. On the other hand, Cav3.2 T-type Ca2+ channels expressed in nociceptors are functionally upregulated by phosphorylation with protein kinase A and also play a role in pancreatitis-related pain. Calcineurin, a phosphatase, negatively regulates various channel functions including TRPV1, and calcineurin inhibitor-induced pain syndrome by tacrolimus, a calcineurin inhibitor, used as an immunosuppressant, has been a clinical problem. We thus examined the effect of tacrolimus on pancreatitis-related pain in mice. Repeated treatment with cerulein caused referred hyperalgesia accompanying acute pancreatitis, which was unaffected by tacrolimus. Pancreatitis-related symptoms disappeared in 24 h, whereas the referred hyperalgesia recurred following the administration of tacrolimus, which was abolished by the blockers of TRPV1 but not T-type Ca2+ channels. Thus, tacrolimus appears to cause the TRPV1-dependent relapse of pancreatitis-related pain, suggesting the involvement of calcineurin in the termination of pancreatic pain.

Topics: Anilides; Animals; Benzimidazoles; Ceruletide; Cinnamates; Cyclopropanes; Hyperalgesia; Male; Mice; Naphthalenes; Pain; Pancreatitis; Recurrence; Tacrolimus; TRPV Cation Channels

TRPV4 ion channels represent osmo-mechano-TRP channels with pleiotropic function and wide-spread expression. One of the critical functions of TRPV4 in this spectrum is its involvement in pain and inflammation. However, few small-molecule inhibitors of TRPV4 are available. Here we developed TRPV4-inhibitory molecules based on modifications of a known TRPV4-selective tool-compound, GSK205. We not only increased TRPV4-inhibitory potency, but surprisingly also generated two compounds that potently co-inhibit TRPA1, known to function as chemical sensor of noxious and irritant signaling. We demonstrate TRPV4 inhibition by these compounds in primary cells with known TRPV4 expression - articular chondrocytes and astrocytes. Importantly, our novel compounds attenuate pain behavior in a trigeminal irritant pain model that is known to rely on TRPV4 and TRPA1. Furthermore, our novel dual-channel blocker inhibited inflammation and pain-associated behavior in a model of acute pancreatitis - known to also rely on TRPV4 and TRPA1. Our results illustrate proof of a novel concept inherent in our prototype compounds of a drug that targets two functionally-related TRP channels, and thus can be used to combat isoforms of pain and inflammation in-vivo that involve more than one TRP channel. This approach could provide a novel paradigm for treating other relevant health conditions.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Astrocytes; Cell Line, Tumor; Ceruletide; Chondrocytes; Disease Models, Animal; Humans; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Nociception; Pain; Pancreatitis, Acute Necrotizing; Primary Cell Culture; Rats; Swine; Thiazoles; Trigeminal Ganglion; TRPA1 Cation Channel; TRPV Cation Channels

Visceral afferents expressing transient receptor potential (TRP) channels TRPV1 and TRPA1 are thought to be required for neurogenic inflammation and development of inflammatory hyperalgesia. Using a mouse model of chronic pancreatitis (CP) produced by repeated episodes (twice weekly) of caerulein-induced AP (AP), we studied the involvement of these TRP channels in pancreatic inflammation and pain-related behaviors. Antagonists of the two TRP channels were administered at different times to block the neurogenic component of AP. Six bouts of AP (over 3 wks) increased pancreatic inflammation and pain-related behaviors, produced fibrosis and sprouting of pancreatic nerve fibers, and increased TRPV1 and TRPA1 gene transcripts and a nociceptive marker, pERK, in pancreas afferent somata. Treatment with TRP antagonists, when initiated before week 3, decreased pancreatic inflammation and pain-related behaviors and also blocked the development of histopathological changes in the pancreas and upregulation of TRPV1, TRPA1, and pERK in pancreatic afferents. Continued treatment with TRP antagonists blocked the development of CP and pain behaviors even when mice were challenged with seven more weeks of twice weekly caerulein. When started after week 3, however, treatment with TRP antagonists was ineffective in blocking the transition from AP to CP and the emergence of pain behaviors. These results suggest: (1) an important role for neurogenic inflammation in pancreatitis and pain-related behaviors, (2) that there is a transition from AP to CP, after which TRP channel antagonism is ineffective, and thus (3) that early intervention with TRP channel antagonists may attenuate the transition to and development of CP effectively.

Topics: Amidines; Analgesics, Opioid; Analysis of Variance; Animals; Antigens, Differentiation; Calcitonin Gene-Related Peptide; Calcium; Ceruletide; Disease Models, Animal; Disease Progression; Exploratory Behavior; Extracellular Signal-Regulated MAP Kinases; Ganglia, Spinal; Gene Expression Regulation; Injections, Intraperitoneal; Male; Mice; Mice, Inbred C57BL; Monocytes; Morphine; Neutrophil Infiltration; Nodose Ganglion; Oximes; Pain; Pain Measurement; Pancreas; Pancreatitis, Chronic; Peroxidase; Pyridines; RNA, Messenger; Sensory Receptor Cells; Time Factors; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Although the way for pain management associated with acute pancreatitis has been searched for, there are not enough medications available for it. The aim of the present study was to investigate the role of bradykinin (BK) in pain related to acute pancreatitis. After repeated injections of caerulein (50 μg/kg and 6 times), mice showed edema in the pancreas, and blood concentrations of pancreatic enzymes (amylase and lipase) were clearly elevated. A histopathological study demonstrated that caerulein caused tissue damage characterized by edema, acinar cell necrosis, interstitial hemorrhage, and inflammatory cell infiltrates. Furthermore, the mRNA levels of interleukin-1β and monocyte chemotactic protein (MCP)-1 were significantly increased in the pancreas of caerulein-treated mice. The sensitivity of abdominal organs as measured by abdominal balloon distension was enhanced in caerulein-injected mice, suggesting that caerulein caused pancreatic hyperalgesia. Moreover, repeated treatment with caerulein resulted in cutaneous tactile allodynia of the upper abdominal region as demonstrated by the use of von Frey filaments, indicating that caerulein-treated mice exhibited referred pain. Under this condition, the mRNA levels of bradykinin B1 receptor (BKB1R) and bradykinin B2 receptor (BKB2R) were significantly increased in the dorsal root ganglion (DRG). Finally, we found that des-Arg⁹-(Leu⁸)-bradykinin (BKB1R antagonist) and HOE-140 (BKB2R antagonist) attenuated the acute pancreatitis pain-like state in caerulein-treated mice. These findings suggest that the upregulation of BK receptors in the DRG may, at least in part, contribute to the development of the acute pancreatitis pain-like state in mice.

Topics: Animals; Ceruletide; Ganglia, Spinal; Gene Expression; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Pain; Pancreatitis; Receptors, Bradykinin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Up-Regulation

Proteinase-activated receptor-2 (PAR2) and transient receptor potential vanilloid-1 (TRPV1) are co-localized in the primary afferents, and the trans-activation of TRPV1 by PAR2 activation is involved in processing of somatic pain. Given evidence for contribution of PAR2 to pancreatic pain, the present study aimed at clarifying the involvement of TRPV1 in processing of pancreatic pain by the proteinase/PAR2 pathway in mice.. Acute pancreatitis was created by repeated administration of cerulein in conscious mice, and the referred allodynia/hyperalgesia was assessed using von Frey filaments. Injection of PAR2 agonists into the pancreatic duct was achieved in anesthetized mice, and expression of Fos in the spinal cord was determined by immunohistochemistry.. The established referred allodynia/hyperalgesia following cerulein treatment was abolished by post-treatment with nafamostat mesilate, a proteinase inhibitor, and with capsazepine, a TRPV1 antagonist, in mice. Injection of trypsin, an endogenous PAR2 agonist, or SLIGRL-NH(2), a PAR2-activating peptide, into the pancreatic duct caused expression of Fos protein in the spinal superficial layers at T8-T10 levels in the mice. The spinal Fos expression caused by trypsin and by SLIGRL-NH(2) was partially blocked by capsazepine, the former effect abolished by nafamostat mesilate.. Our data thus suggest that the proteinase/PAR2/TRPV1 cascade might impact pancreatic pain, in addition to somatic pain, and play a role in the maintenance of pancreatitis-related pain in mice.

Topics: Acute Disease; Animals; Benzamidines; Capsaicin; Ceruletide; Disease Models, Animal; Gene Expression Regulation; Guanidines; Hyperalgesia; Male; Mice; Oligopeptides; Pain; Pancreatitis; Proto-Oncogene Proteins c-fos; Receptor, PAR-2; Spinal Cord; TRPV Cation Channels

The functional involvement of the endocannabinoid system in modulation of pancreatic inflammation, such as acute pancreatitis, has not been studied to date. Moreover, the therapeutic potential of cannabinoids in pancreatitis has not been addressed.. We quantified endocannabinoid levels and expression of cannabinoid receptors 1 and 2 (CB1 and CB2) in pancreas biopsies from patients and mice with acute pancreatitis. Functional studies were performed in mice using pharmacological interventions. Histological examination, serological, and molecular analyses (lipase, myeloperoxidase, cytokines, and chemokines) were performed to assess disease pathology and inflammation. Pain resulting from pancreatitis was studied as abdominal hypersensitivity to punctate von Frey stimuli. Behavioral analyses in the open-field, light-dark, and catalepsy tests were performed to judge cannabinoid-induced central side effects.. Patients with acute pancreatitis showed an up-regulation of cannabinoid receptors and elevated levels of endocannabinoids in the pancreas. HU210, a synthetic agonist at CB1 and CB2, abolished abdominal pain associated with pancreatitis and also reduced inflammation and decreased tissue pathology in mice without producing central, adverse effects. Antagonists at CB1- and CB2-receptors were effective in reversing HU210-induced antinociception, whereas a combination of CB1- and CB2-antagonists was required to block the anti-inflammatory effects of HU210 in pancreatitis.. In humans, acute pancreatitis is associated with up-regulation of ligands as well as receptors of the endocannabinoid system in the pancreas. Furthermore, our results suggest a therapeutic potential for cannabinoids in abolishing pain associated with acute pancreatitis and in partially reducing inflammation and disease pathology in the absence of adverse side effects.

Topics: Acute Disease; Animals; Biopsy; Cannabinoid Receptor Modulators; Cannabinoids; Ceruletide; Dronabinol; Female; Gene Expression Regulation; Humans; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Pain; Pancreas; Pancreatitis; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

In the present study we investigated the effects of intracerebroventricular injection of caerulein, the cholecystoki nin receptor agonist and proglumide, the receptor antagonist on morphine response in the sciatic nerve ligation in mice. Subcutaneous administration of morphine induced antinociception in the both intact and ligated mice, however, the response of the opioid was lower in the ligated mice as compared with the intact animals. Caerulein induced antinociception in the non-ligated but not in the nerve-ligated animals. Combination of caerulein with morphine elicited higher response in ligated animals, however, the response induced in ligated animals was much more prominent. Proglumide alone did not elicit any response in both animal groups. The antagonist decreased the response of caerulein in the nonligated mice. Low doses of proglumide in the combination with caerulein induced antinociception in the ligated mice. We conclude that cholecystokinin receptor mechanism(s) may alter morphine resistance induced by nerve ligation.

Topics: Analgesics, Opioid; Animals; Anti-Ulcer Agents; Ceruletide; Dose-Response Relationship, Drug; Drug Interactions; Injections, Intraventricular; Ligation; Male; Mice; Morphine; Pain; Proglumide; Receptors, Cholecystokinin; Sciatic Nerve

1. The effects of a novel, potent and orally active nonpeptide bradykinin B2 receptor antagonist, FR167344 (N-[N-[3-[(3-bromo-2-methylimidazo[1,2-a]pyridin-8-yl)oxymethyl]-2 ,4-dichlorophenyl]-N-methylaminocarbonylmethyl]-4-(dimethylamin ocarbonyl) cinnamylamide hydrochloride) were tested in three different in vivo models of inflammation. 2. Oral administration of FR167344 inhibited carrageenin-induced paw oedema in rats (carrageenin: 1%, 0.1 ml per animal, intraplantar), with an ID50 of 2.7 mg kg(-1) at 2 h after carrageenin injection (n=10 or 11). 3. Oral administration of the compound also inhibited kaolin-induced writhing (kaolin: 250 mg kg(-1), i.p.) in mice, with ID50 of 2.8 mg kg(-1) in 10 min writhing and 4.2 mg kg(-1) in 15 min writhing (n=19 or 20). 4. Additionally, oral administration of FR167344 inhibited caerulein-induced pancreatic oedema with an ID50 of 13.8 mg kg(-1) as well as increases in amylase and lipase of blood samples with ID50 of 10.3 and 7.4 mg kg(-1), respectively, in rats (n=10). 5. These results show that FR167344 is an orally active, anti-inflammatory and anti-nociceptive agent in carrageenin-induced paw oedema, kaolin-induced writhing and caerulein-induced pancreatitis. FR167344 may have therapeutic potential against inflammatory diseases by oral administration and it may be a useful tool for studying the involvement of B2 receptors in various in vivo models of inflammation.

Topics: Administration, Oral; Animals; Antidiarrheals; Bradykinin Receptor Antagonists; Carrageenan; Ceruletide; Disease Models, Animal; Excipients; Gastrointestinal Agents; Inflammation; Kaolin; Male; Mice; Mice, Inbred ICR; Pain; Pancreatitis; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Bradykinin B2; Receptors, Bradykinin

The severity of pain occurring in the right hypochondrium after transcatheter hepatic arterial embolization carried out in the treatment of malignant hepatic tumors was compared between a caerulein-treated group and a non-caerulein-treated group. The caerulein-treated group and the non-treated group each comprised nine patients Gelfoam powder was used as an occlusive agent. Even though there were no statistically significant differences between the two groups, the caerulein-treated group tended to demonstrate milder pain in the right hypochondricus, less incidence of tenderness and needed fewer administrations of analgesic than did the non-treated group. None of the three patients showing cystic artery contraction after the caerulein administration developed right hypochondricus pain or tenderness, or required the administration of analgesic. It was concluded that caerulein is useful in relieving right hypochondricus pain occurring after transcatheter hepatic arterial embolization.

Topics: Abdomen; Adolescent; Adult; Aged; Antineoplastic Agents; Catheterization, Peripheral; Ceruletide; Embolization, Therapeutic; Gallbladder; Hepatic Artery; Humans; Liver Neoplasms; Middle Aged; Pain

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

Benzodiazepines, chlordiazepoxide and diazepam reversed the antinociceptive action of caerulein in mice. Benzodiazepines (1-5 mg/kg) were administered intraperitoneally and 100 ng of caerulein was injected intracisternally to mice. Benzodiazepines did not change the basal pain threshold of mice but significantly antagonized the antinociceptive effect of caerulein. Proglumide (200 mg/kg, i.p.), which has been claimed to be a specific cholecystokinin receptor antagonist, could also antagonize the antinociceptive effects of caerulein. Naloxone (5 mg/kg) partially but significantly antagonized the antinociceptive effect of caerulein, suggesting that one of the mechanisms of antinociceptive action of caerulein is related to endogenous opioid peptides since benzodiazepines do not act on opioid receptors. Benzodiazepines may decrease the antinociceptive effect of caerulein through acting on cholecystokinin receptors in the central nervous system.

Topics: Analgesics; Animals; Anti-Anxiety Agents; Benzodiazepines; Ceruletide; Dose-Response Relationship, Drug; Male; Mice; Naloxone; Pain; Proglumide; Sensory Thresholds; Time Factors

Topics: Biliary Tract Diseases; Ceruletide; Colic; Common Bile Duct; Humans; Pain; Pressure

Ceruletide is a decapeptide isolated from the skin of an Australian frog. Its chemical and biologic relationship to cholecystokinin and its potent relaxant effect on the sphincter of Oddi makes it useful in biliary colic. In this double-blind placebo-controlled experiment, 60 subjects with moderate to severe pain caused by biliary colic were injected with ceruletide, 1 ng/kg iv or with an equal volume of saline solution. Pain in the right hypochondrium, referred pain, and Murphy's sign were scored before and after treatment. Data indicate that ceruletide is effective in biliary colic.

Topics: Adult; Aged; Analgesics; Biliary Tract Diseases; Ceruletide; Colic; Double-Blind Method; Drug Evaluation; Female; Humans; Injections, Intravenous; Male; Middle Aged; Pain; Random Allocation

Decapeptide ceruletide (CRL), chemically related to cholecystokinin and gastrin, proved to have remarkable analgesic properties when administered to a group of 22 burned patients, 15 patients with acute myocardial infarction, and 8 patients suffering from pain caused by malignant tumours with metastases. Its effect was such, that many of the patients required no other analgesics (opiates) even after a prolonged administration (up to 10 days) of CRL. In some of the patients a marked euphoria developed. There were no substantial changes in EEG records during CRL administration in 15 controls, among them 4 epileptics. It is probable that CRL helps to activate the internal analgesic system. In the burned patients cortisol, testosterone, renin, prolactin and tri-iodothyronine (T3) levels in serum (plasma) were measured (radio-immunoassays). CRL did not block the stress response (no drop of increased cortisol levels, no increase in low T3 levels), but it modified (influenced) it (drop of the high renin levels, and a tendency to increase the very low testosterone levels). CRL appears to act as an endorphin releaser, as evidenced by the plasma levels of beta-endorphins (quotations). CRL and similar drugs may represent a new, more physiological and probably safer approach to the management of pain.

Topics: beta-Endorphin; Burns; Ceruletide; Endorphins; Humans; Male; Myocardial Infarction; Neoplasm Metastasis; Neoplasms; Pain

In pentobarbital-anaesthetized rats (60 mg/kg, i.p.) renal pelvis distension with a pressure of 80 cm H2O caused a decline in mean arterial blood pressure. This pressure response, which disappeared rapidly after cessation of the distension, was used to study the effects of analgesic drugs known to be effective in renal colic pain in man. Morphine (0.75 and 1 mg/kg, s.c.) and the decapeptide caerulein (1.6, 4 and 8 microgram/kg, s.c.) abolished the pressure response. The effects of the largest doses lasted for at least 30 min. Ineffective in this respect were (a) desulphated caerulein (40 microgram/kg, s.c.) and (b) additional doses of pentobarbital (20 and 40 mg/kg, s.c.). This shows (a) the importance of the sulphated tyrosine (known from previous studies on central effects) and (b) the missing influence of the depth of anaesthesia. Naloxone (0.5 mg/kg, s.c.) abolished the effect of morphine (1 mg/kg, s.c.) but failed to influence that of caerulein (8 microgram/kg, s.c.). Even a fourfold dose of naloxone (2 mg/kg, s.c.) did not weaken the effect of caerulein. Naloxone, per se, was ineffective. These results suggest different mechanisms of the present effects of morphine and caerulein. It appears that renal pelvis distension in the anaesthetized rat can serve as a model of renal colic.

Topics: Animals; Blood Pressure; Ceruletide; Disease Models, Animal; Kidney Pelvis; Male; Morphine; Naloxone; Pain; Pentobarbital; Rats; Rats, Inbred Strains

Topics: Ceruletide; Endorphins; Humans; Pain