vasoactive-intestinal-peptide and Pain

Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain.

Topics: Fracture Healing; Humans; Nerve Growth Factors; Pain; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide

Microglial cells are responsible for immune surveillance within the CNS. They respond to noxious stimuli by releasing inflammatory mediators and mounting an effective inflammatory response. This is followed by release of anti-inflammatory mediators and resolution of the inflammatory response. Alterations to this delicate process may lead to tissue damage, neuroinflammation, and neurodegeneration. Chronic pain, such as inflammatory or neuropathic pain, is accompanied by neuroimmune activation, and the role of glial cells in the initiation and maintenance of chronic pain has been the subject of increasing research over the last two decades. Neuropeptides are small amino acidic molecules with the ability to regulate neuronal activity and thereby affect various functions such as thermoregulation, reproductive behavior, food and water intake, and circadian rhythms. Neuropeptides can also affect inflammatory responses and pain sensitivity by modulating the activity of glial cells. The last decade has witnessed growing interest in the study of microglial activation and its modulation by neuropeptides in the hope of developing new therapeutics for treating neurodegenerative diseases and chronic pain. This review summarizes the current literature on the way in which several neuropeptides modulate microglial activity and response to tissue damage and how this modulation may affect pain sensitivity.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Ghrelin; Humans; Inflammation; Inflammation Mediators; Leptin; Macrophage Activation; Microglia; Neuralgia; Neurodegenerative Diseases; Neuroglia; Neuropeptide Y; Neuropeptides; Pain; Pro-Opiomelanocortin; Tachykinins; Vasoactive Intestinal Peptide

Mas-related genes (Mrgs) belong to a large family of G protein-coupled receptor genes found in rodents. Human MRGX proteins are G protein-coupled 7-transmembrane proteins sharing 41-52% amino acid identity with each other, but have no orthologs in rodents. MrgX2 is a member of the MrgX family. MRGX2 is expressed in the small neurons of sensory ganglia and mast cells. It can interact with a series of factors and genes such as the peptides substance P, vasoactive intestinal peptide, cortistatin (CST), proadrenomedullin N-terminal peptide (PAMP), LL-37, PMX-53 and β-defensins. MRGX2 is related to nociception, adrenal gland secretion and mast cell degranulation. Recent research on MrgX2 provides insights into its role in nociception and anti-microbial activities. This article reviewed the origin, expression and function of MrgX2, and discussed possible future research focus.

Topics: Adrenomedullin; Cell Degranulation; Dextrorphan; Evolution, Molecular; Ganglia, Sensory; Gene Expression Regulation; Humans; Mast Cells; Nerve Tissue Proteins; Neuropeptides; Nociception; Pain; Protein Isoforms; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Signal Transduction; Substance P; Vasoactive Intestinal Peptide

The nervous system contributes to the pathophysiology of peripheral inflammation and a neurogenic component has been implicated in many inflammatory disease, including oral diseases. Neurogenic inflammation should be regarded as a protective mechanism wich forms the first line of defense and protects tissue integrity. However, prolonged noxius stimulation may result in the inflammatory response. This review focuses on the evidence suggesting that neuropeptides have a pivotal role in the complex cascade of chemical activity associated with oral diseases. The pathophysiology is complex and neuropeptides are not solely responsible for the initiation and progression of the disease. However, since neuropeptides and inflammatory modulators are released together during the inflammatory response, it will be impossible to assign a specific role to each until work with selective antagonists is completed.

Topics: Animals; Disease Models, Animal; Disease Progression; Humans; Microcirculation; Mouth Diseases; Mouth Mucosa; Neurogenic Inflammation; Neuropeptides; Nociceptors; Pain; Rats; Substance P; Swine; Tongue; Vasoactive Intestinal Peptide

Neuropathic pain arising from direct trauma to, or compression injury of, peripheral nerves is a common clinical problem. It is characterized by the development of abnormal pain states (spontaneous pain, hyperalgesia, allodynia), which can persist long after the initial injury has resolved. The underlying mechanisms are poorly understood and, as a consequence, treatment is often unsatisfactory. Some of the main contributing factors are thought to be the morphological and phenotypic changes that occur centrally, including alterations in the expression of neurotransmitters and their associated receptors, both in the dorsal root ganglia and in the spinal dorsal horn. This article focuses on the functional role of the two structurally related peptides VIP and PACAP within the spinal cord, and their possible contribution to the altered transmission of sensory information in neuropathic conditions.

Topics: Animals; Ganglia, Spinal; Neuropeptides; Pain; Peripheral Nerve Injuries; Peripheral Nerves; Pituitary Adenylate Cyclase-Activating Polypeptide; Rats; Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; Receptors, Pituitary Hormone; Receptors, Vasoactive Intestinal Peptide; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Second Messenger Systems; Spinal Cord; Vasoactive Intestinal Peptide

Peptides which act as neurotransmitters or neuromodulators in the adult nervous system exert influences on brain development. Altering the levels of neuropeptide to which a developing animal is exposed produces a wide variety of physiological and behavioral effects which are apparent in adulthood. Many of the developmental effects involve neural systems in which the neuropeptide plays a role in the adult.

Topics: 5,7-Dihydroxytryptamine; Adrenocorticotropic Hormone; Animals; Animals, Newborn; Behavior, Animal; Brain; Hydroxydopamines; Learning; Melanocyte-Stimulating Hormones; Methadone; Mitosis; Narcotics; Neural Pathways; Neurotransmitter Agents; Organ Size; Oxidopamine; Pain; Peptides; Psychomotor Performance; Rats; Sensory Thresholds; Somatostatin; Substance P; Thyrotropin-Releasing Hormone; Vasoactive Intestinal Peptide

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

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

Pituitary adenylate cyclase-activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) belong to the same secretin-glucagon superfamily and are present in nerve fibers in dura and skin. Using a model of acute cutaneous pain we explored differences in pain perception and vasomotor responses between PACAP38 and VIP in 16 healthy volunteers in a double-blind, placebo-controlled, crossover study. All participants received intradermal injections of 200 pmol PACAP38, 200 pmol VIP and placebo into the volar forearm. Measurements included pain intensity on a visual analog scale (VAS), blood flow by laser Doppler flowmetry, visual flare and wheal. Pain intensities after PACAP38 and VIP were mild and limited to a short time of about 100 s after injection. The area under the VAS-time curve was larger following PACAP38 (P = 0.004) and VIP (P = 0.01) compared to placebo. We found no statistical difference in pain perception between PACAP38 and VIP. Skin blood flow increase, flare and wheal were larger after both PACAP38 (P = 0.011) and VIP (P = 0.001) compared to placebo. VIP induced a considerably larger increase in skin blood flow, flare and wheal than PACAP38 (P = 0.002). In conclusion, we found that peripheral nociceptive cutaneous responses elicited by PACAP38 and VIP are similar in healthy volunteers. This suggests that acute pain and vasomotor responses following intradermal injections of PACAP38 and VIP are primarily mediated by VPAC receptors.

Topics: Acute Disease; Administration, Cutaneous; Adult; Cross-Over Studies; Double-Blind Method; Female; Humans; Male; Middle Aged; Models, Neurological; Neurogenic Inflammation; Nociceptors; Pain; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide; Young Adult

Responses to acetylcholine (ACh) and vasoactive intestinal polypeptide (VIP) were investigated in atopic eczema (AE) patients. To elucidate the involvement of histamine to ACh-provoked vasoreactions and sensations, we applied a selective H1-antagonist (cetirizine) 3 h prior to the ACh-administration. Solutions of acetylcholine (ACh, 0.55 M) and vasoactive intestinal polypeptide (VIP, 1.5x 10(-5) M) were injected (10 microl) intracutaneously into the volar forearm of 14 healthy subjects and 14 atopic eczema (AE) patients. The substances were applied as single stimulus as well as in combination. Sensations evoked by the stimulation were recorded using 2 visual analog scales (VAS). Vasoreactions were analyzed with the new technique of computer assisted video image analysis. With this method we measured the dynamics of the flare development and the extension of the final flare size independent of the observer's assessment. In control subjects the development and extension of the final flare size was almost similar, regardless whether ACh and VIP were applied in combination or separately. Compared to healthy controls, after injection of ACh, VIP and the combination of VIP and ACh smaller flare sizes were recorded in AE patients. After VIP was given, the control subjects reported pruritus, which was significantly augmented compared to AE patients. In contrast, controls reported a burning pain after the injection of ACh, whereas AE patients felt predominantly pruritus. Itch sensation after the combined application of VIP and ACh was significantly elevated in AE patients. Consequently, we assume that mediators of sudomotor neurons, i.e., VIP and ACh meet in AE patients apparently sensitized nociceptive primary afferents and induce exaggerated itch, pain and flare responses. When pretreated with the selective H1-antagonist cetirizine before ACh was injected, pain and erythema due to ACh was diminished in healthy controls. In contrast, cetirizine did not influence the size of erythema and the magnitude of sensation in AE patients. We conclude, that the release of histamine is not involved in ACh-induced erythema and pruritus in AE. These data provide evidence that pruritus can be elicited in atopic eczema by a cholinergic, histamine independent mechanism.

Topics: Acetylcholine; Adult; Cetirizine; Cholinergic Agents; Cross-Over Studies; Dermatitis, Atopic; Double-Blind Method; Erythema; Female; Histamine H1 Antagonists; Humans; Injections, Intradermal; Male; Pain; Pruritus; Psychophysics; Skin; Vasoactive Intestinal Peptide

Osteoarthritis (OA) is a debilitating disease in which primarily weight-bearing joints undergo progressive degeneration. Despite the widespread prevalence of OA in the adult population, very little is known about the factors responsible for the generation and maintenance of OA pain. Vasoactive intestinal peptide (VIP) was identified in the synovial fluid of arthritis patients nearly 20 years ago and the aim of this study was to examine whether VIP could be involved in the generation of OA pain. Hindlimb weight bearing was used as a measure of joint pain, while von Frey hair algesiometry applied to the plantar surface of the ipsilateral hindpaw tested for secondary mechanical hyperalgesia. Intra-articular injection of VIP into normal rat knee joints caused a significant shift in weight bearing in favour of the contralateral non-injected hindlimb as well as causing a reduction in ipsilateral paw withdrawal threshold. These pain responses were blocked by co-administration of the VPAC receptor antagonist VIP6-28. Induction of OA by intra-articular sodium monoiodoacetate injection resulted in a reduction in weight bearing on the affected leg, but no evidence of secondary hyperalgesia in the paw. Treatment of OA knees with a single injection of VIP6-28 diminished hindlimb incapacitance while increasing paw withdrawal threshold. This study showed for the first time that peripheral application of VIP causes increased knee joint allodynia and secondary hyperalgesia. Furthermore, antagonists that inhibit VIP activity may prove beneficial in the alleviation of OA pain.

Topics: Animals; Disease Models, Animal; Drug Evaluation, Preclinical; Hindlimb; Hyperalgesia; Injections, Intra-Articular; Iodoacetates; Male; Osteoarthritis, Knee; Pain; Pain Threshold; Peptide Fragments; Rats; Rats, Wistar; Receptors, Vasoactive Intestinal Peptide, Type II; Receptors, Vasoactive Intestinal Polypeptide, Type I; Stifle; Stress, Mechanical; Vasoactive Intestinal Peptide; Weight-Bearing

The present study examined whether local administration of the neuropeptide vasoactive intestinal polypeptide (VIP) could modulate joint nociception in normal rat knee joints and if the VIP antagonist VIP(6-28) could ameliorate joint mechanosensitivity in an animal model of osteoarthritis (OA).. OA was induced in male Wistar rats by intra-articular injection of 3mg sodium monoiodo-acetate with a recovery period of 14 days. Electrophysiological recordings were made from knee joint primary afferents in response to normal rotation and noxious hyper-rotation of the joint both before and following close intra-arterial injection of different doses of VIP and VIP(6-28).. Local application of VIP to normal knees caused afferent firing rate to be significantly enhanced during normal rotation (up to 180% P<0.01; n=17) and during hyper-rotation (up to 37% P<0.01; n=17) of the knee. VIP-induced sensitization was blocked by pre-administration of the VIP receptor antagonist VIP(6-28). In the OA group, application of VIP(6-28) caused afferent firing rate to be significantly reduced during normal rotation (up to 45% P<0.05; n=17) and during hyper-rotation (up to 34% P<0.01; n=15) of the knee joint.. These findings indicate that VIP is involved in peripheral sensitization of knee joint afferents especially in response to normal joint movements. OA-induced sensitization of knee joint afferents was inhibited by local administration of VIP(6-28), indicating that VIP is released into OA knee joints, potentially contributing to joint pain. As such, VIP(6-28) may prove to be a beneficial agent for the treatment of arthritis pain.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Electrophysiology; Hindlimb; Injections, Intra-Arterial; Joints; Male; Movement; Nerve Fibers; Neurons, Afferent; Osteoarthritis; Pain; Peptide Fragments; Rats; Rats, Wistar; Receptors, Vasoactive Intestinal Peptide; Rotation; Vasoactive Intestinal Peptide

Visceral pain/hypersensitivity is a cardinal symptom of functional gastrointestinal disorders. With their peripheral and central (spinal) projections, sensory neurons in the dorsal root ganglia (DRG) are the "gateway" for painful signals emanating from both somatic and visceral structures. In contrast to somatic pain, the neurochemical pathways involved in visceral pain/hypersensitivity have not been well studied. We hypothesized the neuropeptide changes in spinal cord and DRG during visceral pain would mirror similar changes in somatic nociception. Noxious (painful) colorectal distension (CRD) was done by distending a rectal balloon up to 60 mm Hg phasically for 1 h in Sprague-Dawley rats. The spinal content of calcitonin gene-related peptide (CGRP), substance P (SP), galanin and vasoactive intestinal peptide (VIP) as well as their mRNAs in DRG were measured at 0, 4 and 24 h after the CRD. Visceromotor reflex (VMR) was measured by recording the electromyogram at the abdominal muscle in response to CRD. Distal colorectum was removed for evaluating the presence of inflammation. No significant evidence of histological inflammation was seen in the colonic mucosa/submucosa after repeated CRD, which is confirmed by myeloperoxidase assay. The spinal content of CGRP and SP decreased significantly 4 h after CRD, while galanin and VIP levels increased gradually and reached highest level at 24 h (p<0.05). The mRNAs in DRG of the neuropeptides were significantly upregulated after CRD (p<0.05). VMR recording showed the rat's colon became hypersensitive 4 h after CRD, a sequence parallel to the spinal changes of CGRP and SP in timeframe. Noxious mechanical distension of the colorectum causes an acute change in the spinal levels of excitatory neurotransmitters (CGRP and SP), probably reflecting central release of these peptides from sensory neurons and contributing to the hypersensitivity following the noxious CRD. This is followed by a slower change in the levels of the inhibitory neurotransmitter galanin and VIP. Such stimulation results in significant alternation of the gene expression in DRG, reflecting the plasticity of the neuronal response. In the absence of visceral inflammation, the aforementioned neuropeptides are important mediators in the processing of visceral pain/hypersensitivity.

Topics: Animals; Calcitonin Gene-Related Peptide; Colon; Dilatation, Pathologic; Galanin; Ganglia, Spinal; Humans; Male; Neuropeptides; Pain; Protein Precursors; Rats; Rats, Sprague-Dawley; Rectum; Reflex; RNA, Messenger; Spinal Cord; Substance P; Tachykinins; Vasoactive Intestinal Peptide; Visceral Afferents

This laboratory recently demonstrated a multiplicative interaction between the pelvic visceral afferent transmitter vasoactive intestinal polypeptide (VIP) and the delta-opioid receptor (DOR)-selective agonist [D-Pen2,5] enkephalin (DPDPE) to regulate cAMP levels in spinal cord [Brain Res. 959 (2003) 103]. Although DOR activation is required for the manifestation of the VIP-DPDPE facilitative interaction, its relevance to opioid antinociception remains unclear. The current study investigates whether or not the VIP-DPDPE facilitation of cAMP formation is subject to tolerance formation, a hallmark characteristic of opioid antinociception. Chronic morphine exposure abolishes the VIP-DPDPE facilitative interaction, consistent with its relevance to DOR antinociception. However, acute in vitro inhibition of protein kinase C (PKC) reinstates the VIP-DPDPE multiplicative interaction characteristic of opioid naïve spinal tissue. This suggests that its chronic morphine-induced loss requires a PKC phosphorylation. PKC phosphorylation negatively modulates phospholipase C (PLC)beta, enzymes intimately associated with phosphoinositide turnover and calcium trafficking. These are essential determinants of acute and chronic opioid effects. Accordingly, the effect of chronic morphine on their state of phosphorylation was also investigated. Central nervous system opioid tolerance is associated with the reciprocal phosphorylation (regulation) of two PLCbeta isoforms, PLCbeta1 and PLCbeta3. However, although chelerythrine reinstates the chronic morphine-induced loss of the multiplicative VIP-DPDPE interaction, it does not alter the associated changes in PLCbeta phosphorylation, possibly indicating different time courses of restitution of function and/or involvement of different kinases for different components of tolerance. These results could provide a mechanistic rubric for understanding positive modulation of opioid antinociception by afferent transmission.

Topics: Analgesics, Opioid; Animals; Calcium Signaling; Central Nervous System; Cyclic AMP; Down-Regulation; Drug Administration Schedule; Drug Tolerance; Enkephalin, D-Penicillamine (2,5)-; Female; Isoenzymes; Morphine; Nociceptors; Pain; Phosphatidylinositols; Phospholipase C beta; Phosphorylation; Protein Isoforms; Protein Kinase C; Rats; Rats, Sprague-Dawley; Receptors, Opioid, delta; Spinal Cord; Type C Phospholipases; Vasoactive Intestinal Peptide; Visceral Afferents

Aquadynia (water-related cutaneous pain) is a very rare disorder, recently described.. A 40 year-old woman suffered from aquagenic pruritus, complicated by paresthesia and pain. There was no clinical argument in favor of a psychiatric disorder, Fabry's disease or any other disease. Clinical and histological cutaneous examinations were normal. Immunohistochemical study of neurotransmitters (substance P, calcitonin gene-related peptide or CGRP, vasoactive intestinal peptide or VIP, somatostatine) did not show any modification in nerve density. However, VIP-immunoreactive epidermal cells were observed. Electromyography and study of somesthesic-evoked potentials were normal. No treatment had provided any efficacy. Clonidine and capsaicin had been prescribed with partial success.. Three other cases of aquadynia have been reported. Differential diagnoses of aquadynia are aquagenic pruritus and urticaria, hysteria or simulation, Fabry's disease, erythermalgia, peripheral neuropathy or polycythemia vera. The presence of VIP-immunoreactive cells suggests that VIP could be produced by these cells after contact with water. The effects of propanolol and clonidine on aquadynia are in favor of an adrenal component.

Topics: Adult; Electromyography; Female; Humans; Pain; Paresthesia; Pruritus; Vasoactive Intestinal Peptide; Water

We tested the hypothesis that increases in the spinal levels of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) were related to the development of neuropathic pain. To this aim, we compared two groups of rats. One group showed well-developed neuropathic pain in the tail following unilateral transection of the inferior and superior caudal trunks between the S1 and S2 spinal nerves, and the other group showed poorly-developed neuropathic pain despite the same nerve injury. The increases in immunoreactivity of VIP and NPY in the S1 dorsal horn (injured segment) were not significantly different between the two groups. These results suggested that increases in the spinal levels of VIP and NPY after peripheral nerve injury were not sufficient for the development of neuropathic pain.

Topics: Animals; Cold Temperature; Hot Temperature; Immunohistochemistry; Male; Neuropeptide Y; Pain; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Nerves; Vasoactive Intestinal Peptide

The purpose of this study was to determine whether intrathecal injection of aqueous (random coil) vasoactive intestinal peptide (VIP) and VIP self-associated with sterically stabilized phospholipid micelles (alpha-helix VIP) at the lower lumbar vertebral level modulates foot withdrawal latency to low and high rate noxious radiant skin heating in anesthetized rats. We found that intrathecal random coil VIP evoked a significant bimodal, concentration-dependent response, early potent antinociception followed by hyperalgesia, during exposure to low and high rates of skin heating (P<0.05). Intrathecal alpha-helix VIP elicited a qualitatively similar response to that of random coil VIP except that the rate of decay of antinociception was faster and slower at low and high rates of skin heating, respectively. In addition, a low concentration of alpha-helix VIP evoked a potent late antinociception not observed with random coil VIP. Taken together, these data indicate that VIP modulates somatosensory processing in the lumbosacral spinal cord of rats in a complex fashion, and that this response is dependent, in part, on the conformation of VIP in the vicinity of target cells in the peripheral nervous system.

Topics: Animals; Humans; Male; Neuropeptides; Pain; Peripheral Nervous System; Phospholipids; Protein Conformation; Rats; Rats, Sprague-Dawley; Skin; Spinal Cord; Temperature; Time Factors; Vasoactive Intestinal Peptide

Topics: Humans; Inflammation; Neuropeptides; Pain; Pituitary Adenylate Cyclase-Activating Polypeptide; Vasoactive Intestinal Peptide

Our recent experiments suggest that vasoactive intestinal polypeptide (VIP) enhances neurite outgrowth of dissociated rat dorsal root ganglion cells, indirectly, via the release of a trophic factor from the spinal cord. In this study, we have examined the possible contribution of activity-dependent neurotrophic factor (ADNF) to the trophic actions of VIP. In addition, as we have shown that the factor mediating the trophic actions of VIP acts via protein kinase A we have also examined the contribution of CREB, which is a transcription factor activated by protein kinase A. As previously shown, supernatant taken from spinal cord incubated with VIP, significantly increased the percentage of sensory neurons with neurites. Antiserum against ADNF attenuated the trophic effect of the VIP-conditioned supernatant. Consistently, the ADNF agonist, ADNF(14) (0.001-0.1 fM), significantly enhanced the percentage of cells with neurite outgrowth. Furthermore, the trophic action of ADNF(14) was attenuated by a protein kinase A inhibitor, Rp-cAMPS, whereas the inactive isomer, Sp-cAMPS, had no effect. Preincubation of cells with 5 mcM CREB antisense oligonucleotides, attenuated the increase in neurite outgrowth induced by either the supernatant or ADNF(14). The sense oligonucleotide had no influence on the enhanced neurite outgrowth. We also found that both the supernatant and ADNF(14) induced an increase in the percentage of cells expressing phosphorylated CREB. The data suggests that VIP induces a release of neurotrophic factors, such as ADNF, which enhance neurite outgrowth. In addition, protein kinase A and CREB appear to contribute to the neurotrophic actions of VIP and ADNF. The mechanisms underlying the neurotrophic action of VIP, may have important implications for sprouting and/or synaptic reorganization of central terminals of sensory neurons, which may contribute to neuropathic pain that commonly occurs following peripheral nerve damage.

Topics: Animals; Antibodies; Cells, Cultured; Cyclic AMP Response Element-Binding Protein; Ganglia, Spinal; Nerve Tissue Proteins; Neurites; Neurons, Afferent; Pain; Phosphorylation; Rats; Rats, Wistar; RNA, Antisense; Vasoactive Intestinal Peptide

Topics: Analgesia; Animals; Body Temperature Regulation; Cerebral Ventricles; Drug Implants; Drug Tolerance; Ethanol; Injections, Intraperitoneal; Injections, Intraventricular; Injections, Subcutaneous; Male; Mice; Mice, Inbred Strains; Morphine; Neuropeptides; Pain; Pituitary Adenylate Cyclase-Activating Polypeptide; Reflex; Vasoactive Intestinal Peptide

The levels of dorsal root ganglia and paravertebral sympathetic ganglia innervating the lumbar facet joint were investigated in rats using the retrograde transport method. The pathways and functions of the nerve fibers supplying the lumbar facet joint were determined immunohistochemically.. To study lumbar facet pain in relation to its innervation.. The lumbar facet joints have been reported to be innervated segmentally. Little is known, however, about the origins and functions of the nerve fibers.. Cholera toxin B subunit, a neural tracer, was placed in the L5-L6 facet joint, and the bilateral dorsal root ganglia and paravertebral sympathetic ganglia were examined immunohistochemically. The serial sections of lumbar vertebrae of newborn rats and the sections of the facet joint capsules, dorsal root ganglia, and paravertebral sympathetic ganglia of adult rats were investigated immunohistochemically. The pathways of the nerve fibers supplying the facet joint were reconstituted.. Labeled neurons existed in ipsilateral dorsal root ganglia from L1 to L5 and in paravertebral sympathetic ganglia from T12 to L6. The dorsal ramus of the spinal nerve and rami communicantes were connected to each other by calcitonin gene-related peptide immunoreactive fibers and dopamine beta-hydroxylase immunoreactive fibers.. The L5-L6 facet joint was innervated by ipsilateral dorsal root ganglia and paravertebral sympathetic ganglia, segmentally and nonsegmentally. Some of the sensory fibers from the facet joint may pass through the paravertebral sympathetic trunk, reaching L1 and/or L2 dorsal root ganglia. Inguinal and/or anterior thigh pain with lower lumbar facet joint lesions may be explained as referred pain.

Topics: Animals; Antibody Specificity; Calcitonin Gene-Related Peptide; Cell Count; Cholera Toxin; Dopamine beta-Hydroxylase; Ganglia, Spinal; Ganglia, Sympathetic; Immunohistochemistry; Lumbar Vertebrae; Male; Nerve Fibers; Neurons, Afferent; Neuropeptide Y; Pain; Rats; Rats, Sprague-Dawley; Substance P; Vasoactive Intestinal Peptide

A series of experiments were designed to develop and validate an animal model of lumbar radiculopathy. More specifically, these investigations introduced a model of chronic neuropathic pain in the rat associated with clinically relevant lumbar nerve root trauma and evaluated the ability of the model to effect symptoms and begin to understand the underlying neurochemical and neurophysiologic factors associated with these neurologic abnormalities.. A search of the literature suggested that these studies were a first attempt to distinguish and elucidate an experimental lumbar radiculopathy.. Two basic approaches to nerve trauma were considered, direct damage to the nerve via compression, and introduction of foreign materials in proximity to the nerve root that might cause irritation and inflammation leading to chronic symptoms. Ligature around the nerve (i.e., surrounding the nerve with a suture) was considered a plausible irritant that might behave in an animal model in a similar way that nerve root entrapment, often observed in HNP and stenosis cases, might function in humans. Further, varying levels of irritation was modeled by using 4-0 silk as a mild and 4-0 chromic gut as a more harsh irritant.. Five distinct treatments of the nerve roots were investigated initially: 1) a sham intervention, where the surgery simply exposed the nerve roots and dorsal root ganglion followed by standard closing procedures; 2) nerve root clipping, where the nerve roots were clipped with a microhemoclip; 3) 4-0 silk ligature, where two loose ligatures of 4-0 silk were placed around the nerve roots; 4) 4-0 chromic gut 1, where one loose ligature of 4-0 chromic gut was placed around the nerve roots; and 5) 4-0 chromic gut 2, where four 0.3 cm pieces of 4-0 chromic gut were laid adjacent to the nerve roots and secured by two loose ligatures of 4-0 chromic gut. ANOVA techniques were used to test for differential effects across time for the five treatment groups in terms of animal function and biochemistry in the DRG.. Rats treated with chromic gut ligature in large quantity demonstrated differential patterns of results on the injured and noninjured sides consistent with a lumbar radiculopathy. The injured side demonstrated significantly worse thermal hyperalgesia related to neuropathic pain (P < 0.0001); initial mechanical hypoalgesia (P < .001), and motor dysfunction (P < .001) resolving within 2 weeks; significantly increased c-fos counts (P < .0001) 2 weeks postoperatively, which showed a consistent trend toward baseline and return to baseline by 12 weeks; significantly greater and highly increased VIP concentrations in the dorsal root ganglia 2 weeks postoperatively (P < .0001) that did not resolve or tend towards baseline after 12 weeks of follow-up in conjunction with a trend toward VIP depletion in the spinal cord 2 weeks postoperatively that did resolve to baseline until a 12-week concentration indicated a significant increase in concentration (P < .002). Quantitative and qualitative changes in c-fos and VIP, correlated with the patterns of behavior and function. Thus, for the first time, evidence to link outcome behaviors and function with underlying neurochemical processes is suggested.. When the same apparent conditions can be demonstrated in some situations to be causing pain and in other situations to be independent of pain, some additional factor or factors not considered in the original investigations may be mediating the outcome. Neurochemical consequences of nerve root irritation provide a theoretical framework for hypothesizing about various types of mediating events that might explain how similar apparent pathology might reasonably lead to different predictions about behavior consequences of the pathology.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Calcitonin Gene-Related Peptide; Ganglia, Spinal; Genes, fos; Hot Temperature; Male; Nerve Compression Syndromes; Pain; Pain Threshold; Paralysis; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Spinal Cord; Spinal Nerve Roots; Substance P; Sutures; Vasoactive Intestinal Peptide

The rabbit dorsal root ganglion is an important model of pain mechanisms in the human spine. A morphometric model of the normal rabbit dorsal root ganglion was constructed to provide quantitative comparisons with injured ganglia. Lumbar ganglia were studied under light and electron microscopy using simple stereologic methods. Neuronal diameter ranged from 18 to 85 microns, with 60% between 30 and 50 microns. Neurons constituted approximately 30% of dorsal root ganglion volume, and neuronal nuclei accounted for 14% of neuronal volume and 4% of dorsal root ganglion volume. Contributions from organelles to dorsal root ganglion volume were: mitochondria, 1.5%; rough endoplasmic reticulum, 9.4%; lysosomes, 0.2%; golgi, 0.5%. This morphometric model facilitates quantitative analysis of ganglia exposed to direct or indirect stimuli, providing important information on the structural changes that influence pain production.

Topics: Animals; Ganglia, Spinal; Low Back Pain; Microscopy, Electron; Models, Neurological; Neurons; Pain; Rabbits; Substance P; Vasoactive Intestinal Peptide; Vibration

We have previously presented evidence for a non-adrenergic, vagally mediated colono-gastric inhibitory reflex induced by distension of the colon. We also found that pain stimulation by putting pressure on a testicle induced a pronounced gastric relaxation mediated by both adrenergic and vagal non-adrenergic fibres in anesthetized rats. Previous in vitro studies by other workers have strongly indicated that vasoactive intestinal polypeptide (VIP) is a neural mediator of gastric relaxation. The aim of the present in vivo study was to investigate, in anesthetized rats, whether VIP is involved in the gastric reflex relaxation induced by colonic distension and pain stimulation. A volumetric method was used to monitor changes in gastric volume. Gastric reflex relaxation following colonic distension was significantly and markedly inhibited by VIP antiserum as compared to the control relaxation before administration of the antiserum. Non-immunized control serum did not significantly influence gastric relaxation caused by colonic distension. Pain-induced gastric relaxation was moderately but significantly reduced after the administration of VIP antiserum but not after control serum. The selective beta 2-adrenoceptor agonist, salbutamol, induced a pronounced gastric relaxation of the same magnitude before and after the administration of VIP antiserum. VIP antiserum changed the pattern of gastric motility by inducing a specific type of gastric contraction appearing spontaneously or in response to colonic distension. A close intra-arterial injection of VIP induced gastric relaxation and inhibition of phasic gastric contractions. The present results in the rat suggest that VIP or a VIP-like peptide is involved in gastric reflex relaxation induced by colonic distension and pain stimulation.

Topics: Animals; Colon; Gastrointestinal Motility; Muscle Contraction; Muscle Relaxation; Muscle, Smooth; Pain; Rats; Rats, Sprague-Dawley; Reflex; Stomach; Vasoactive Intestinal Peptide

We sought to identify characteristics of peptidergic innervation that altered in patients with chronic pancreatitis. Pancreatic tissue removed from patients with chronic pancreatitis was analyzed by immunohistochemistry using antisera against neuropeptide Y, tyrosine hydroxylase, vasoactive intestinal polypeptide, peptide histidine isoleucine, calcitonin gene-related peptide, and substance P, respectively. In accordance with recent findings, the number and diameter of intralobular and interlobular nerve bundles were found to be increased as compared with control pancreas from organ donors. The striking change in the peptidergic innervation pattern in chronic pancreatitis concerned these altered nerves. It consisted of an intensification of the immunostaining for calcitonin gene-related peptide and substance P in numerous fibers contained in these nerves. Adjacent sections showed that immunoreactive substance P and immunoreactive calcitonin gene-related peptide coexisted in these fibers. Because both of these peptides are generally regarded as pain transmitter candidates, our findings provide further evidence that changes in pancreatic nerves themselves might be responsible for the long-lasting pain syndrome in chronic pancreatitis.

Topics: Adult; Calcitonin Gene-Related Peptide; Chronic Disease; Female; Humans; Male; Nerve Fibers; Neuropeptide Y; Neuropeptides; Pain; Pancreas; Pancreatitis; Peptide PHI; Substance P; Tyrosine 3-Monooxygenase; Vasoactive Intestinal Peptide

Chronic pelvic pain in women is associated with radiological evidence of pelvic venous dilatation and reduced flow, termed 'pelvic congestion'. The aim of this study was to elucidate a possible role in this condition for vasoactive intestinal peptide and calcitonin gene-related peptide, both localized in perivascular nerves in the ovaries and uterus. Healthy volunteers and women with chronic pelvic pain and venous congestion received intravenous infusions of vasoactive intestinal peptide (n = 15), calcitonin gene-related peptide (n = 15) or a bland infusate (n = 7). Changes in the uterovaginal and skin blood flow were assessed by continuous measurement of vaginal, axillary, cheek and hand temperature. During calcitonin gene-related peptide infusion median hand temperature changes were +0.97 degrees C in women with pelvic pain and -0.03 degrees C in healthy volunteers (p < 0.05). There were no differences between groups in hand and cheek temperature responses to vasoactive intestinal peptide infusion. Vasoactive intestinal peptide and calcitonin gene-related peptide appeared to dilate the uterovaginal vasculature in healthy subjects but not in those with pelvic pain. Vasoactive intestinal peptide and calcitonin gene-related peptide did not provoke pain in healthy subjects but in those with pelvic pain, symptoms were significantly exacerbated during calcitonin gene-related peptide infusion but not by vasoactive intestinal peptide. Changes in plasma follicle stimulating hormone, luteinizing hormone and oestradiol during either infusion were not significant. These findings indicate greater sensitivity to calcitonin gene-related peptide in women with pelvic pain and suggest a possible underlying neurovascular disorder.

Topics: Adult; Blood Pressure; Body Temperature; Calcitonin Gene-Related Peptide; Chronic Disease; Female; Humans; Infusions, Intravenous; Pain; Pain Measurement; Pelvis; Vasoactive Intestinal Peptide

Lumbar discography is a commonly employed diagnostic tool, but important questions about it remain unresolved. Why is an abnormal discogram painful in one patient and not in another? This study was performed to investigate the changes in Substance P (SP) and Vasoactive-Intestinal Peptide (VIP), found in the dorsal root ganglion, following discography in normal and abnormal canine lumber intervertebral discs. The data from this study suggest that dorsal root ganglion SP and VIP are indirectly affected by manipulations of the intervertebral disc. It may be that various neurochemical changes within the intervertebral disc are expressed by sensitized (injured) annular nociceptors, and in part modulated by the dorsal root ganglion. Therefore, the concomitant pain sometimes associated with an abnormal discogram image may in part be related to the chemical environment within the intervertebral disc and the sensitized state of its annular nociceptors.

Topics: Animals; Coloring Agents; Dogs; Ganglia, Spinal; Injections, Spinal; Intervertebral Disc; Osmolar Concentration; Pain; Radiography; Substance P; Vasoactive Intestinal Peptide

The effect of intrathecally (i.t.) injected vasoactive intestinal polypeptide (VIP) on spinal nocifensive flexor reflex excitability was examined in decerebrate, spinalized, unanesthetized rats. The hamstring reflex was evoked by intense cutaneous mechanical or thermal stimulation of the ipsilateral foot. I.t. VIP increased the excitability of the spinal cord to thermal much more than to mechanical stimuli. It is suggested that this neuropeptide is released by thermosensitive cutaneous afferents that respond poorly to mechanical stimuli.

Topics: Animals; Decerebrate State; Dose-Response Relationship, Drug; Hindlimb; Hot Temperature; Injections, Spinal; Pain; Rats; Rats, Inbred Strains; Reflex, Monosynaptic; Skin; Spinal Cord; Vasoactive Intestinal Peptide

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: Animals; Fluorescent Antibody Technique; Ganglia, Autonomic; Neural Inhibition; Neurotransmitter Agents; Nociceptors; Pain; Somatostatin; Sympathectomy; Sympathetic Nervous System; Vasoactive Intestinal Peptide