Capsaicin-sensitive Nerves Research Articles

Capsaicin-sensitive nerves regulate the metabolic response to abdominal sepsis

Background. Both the systemic release of inflammatory mediators and activation of the neuroendocrine axis by sensory afferent nerves (SANs) have been implicated as initiators of the metabolic response to infection. In this study, we investigate the role of SANs as mediators of protein catabolism and the insulin-like growth factor (IGF) axis during abdominal sepsis using capsaicin (Cap) to selectively destroy nociceptive sensory axons. Methods. Four groups of male Sprague-Dawley rats were studied: Control, Control+Cap, Sepsis, and Sepsis+Cap. Rats were injected with Cap (75 mg/kg) on day 1 and (50 mg/kg) on day 2 to destroy SANs. Time-matched control and septic rats were pair-fed and injected with vehicle on the same schedule. Controls underwent sham laparotomy, while septic rats had a fecal-agar pellet inoculated with Escherichia coli and Bacteroides fragilis implanted in the peritoneal cavity. Blood and tissues were harvested 5 days after the induction of sepsis. Plasma IGF-I, IGFBP-1, and -3 were measured by radioimmunoassay and Western blot analysis. IGF-I, acid-labile subunit (ALS), IGFBP-1 and -3 mRNA levels were determined by Northern blot analysis. Results. Mortality was 40% in septic rats vs 0% in the sepsis+Cap group. Capsaicin had no effect on muscle mass, protein content, or the IGF system in control rats. However, sepsis-induced reductions in gastrocnemius mass (25%) and protein content (35%) were ameliorated by capsaicin. The sepsis-induced decrease in hepatic IGF-I mRNA and circulating IGF-I (26%), as well as the 4-fold increase in plasma IGFBP-1 and hepatic IGFBP-1 mRNA were prevented by capsaicin. Conclusions. Capsaicin-sensitive nerves mediate mortality, the catabolism of skeletal muscle, and selected elements of the IGF system during abdominal sepsis. The results suggest an important role for nociceptive SANs and the neuroendocrine system in mediating the host response to abdominal infection.

Capsaicin sensitive-sensory nerves and blood pressure regulation.

Capsaicin (8-methyl-N-vannillyl-6-nonenamide), via binding to the vanilloid receptor subtype 1 (VR1), stimulates a subpopulation of primary afferent neurons that project to cardiovascular and renal tissues. These capsaicin-sensitive primary afferent neurons are not only involved in the perception of somatic and visceral pain, but also have a "sensory-effector" function. Regarding the latter, these neurons release stored neuropeptides through a calcium-dependent mechanism via the binding of capsaicin to the VR1. A subset of capsaicin-sensitive sensory nerves contains calcitonin gene-related peptide (CGRP) and substance P (SP). These sensory neuropeptides are potent vasodilators and natriuretic/diuretic factors. Neonatal degeneration of capsaicin-sensitive sensory nerves has revealed novel mechanisms that underlie increased salt sensitivity and several experimental models of hypertension. These mechanisms are reviewed, which include insufficient suppression of plasma renin activity and plasma aldosterone levels subsequent to salt loading, enhancement of sympathoexcitatory response in the face of a salt challenge, activation of the endothelin-1 receptor, and impaired natriuretic response to salt loading in capsaicin-pretreated rats. These data indicate that sensory nerves counterbalance the prohypertensive effects of several neuro-hormonal systems to maintain normal blood pressure when challenged with salt loading. Mechanisms underlying pneumotoxicity and pulmonary hypertension as revealed by degeneration of capsaicin-sensitive nerves are also discussed. Finally, the therapeutic utilities of capsaicin, endogenous anandamide, and CGRP agonists are assessed.

Role of Peripheral Tachykinin Receptors in Neurogenic Inflammation of the Respiratory, Genitourinary and Gastrointestinal Systems

A wide distribution of tachykinin-containing projections of capsaicin-sensitive primary afferent neurons is present in the peripheral organs of respiratory, gastrointestinal and genitourinary systems. Tachykinins, along with calcitonin gene-related peptide (CGRP) and other neuropeptides, can be released by adequate stimuli having pathological rather than physiological relevance. In most cases these stimuli are represented by chemical irritants penetrating through the respiratory tree or alimentary channel to the body, or being removed through the urinary system. Tachykinins produce in the visceral organs part of the responses obtained at somatic level by antidromic activation of capsaicin-sensitive nerve terminals and known as “neurogenic inflammation” that is, increase in vascular permeability and plasma protein leakage followed by oedema. In addition tachykinins produce at visceral level smooth muscle contraction, neuronal stimulation, mucus secretion and recruitment / activation of immune cells. The physiological significance of these effects is to afford protection toward chemical irritants or noxious stimuli by facilitating their removal from the body. Nonetheless, a large body of preclinical evidence exists indicating that tachykinins participate in the genesis and/or maintenance of symptoms accompanying various human diseases, such as asthma / bronchial hyperreactivity, cystitis of various aetiologies, inflammatory bowel diseases and irritable bowel syndrome. Tachykinin receptor antagonists, proved capable of preventing/reducing tachykinin-mediated effects in experimental animal models of these pathologies, are expected to afford therapeutically relevant effects in humans.

Endomorphin-1 causes synovial hypoaemia in rat knee joints via a capsaicin-sensitive neural pathway

In joints, synthetic μ-opioids reduce inflammatory changes such as protein extravasation and associated oedema formation. However, the effect of endogenous opioid peptides on other inflammatory processes such as altered tissue blood flow has not been investigated. The present study examined the peripheral effects of the endogenous μ-opioid ligand endomorphin-1 (EM-1) on rat knee joint blood flow using laser Doppler perfusion imaging. Topical application of EM-1 (10 −16–10 −9 mol) to exposed rat knee joints resulted in a dose-dependent increase in synovial vascular resistance with a maximum rise of 56% occurring with the 10 −9 mol dose. Destruction of unmyelinated articular afferents by capsaicin treatment completely abolished the hypoaemic effects of EM-1. These findings suggest that EM-1 acts peripherally in knee joints to decrease synovial blood flow, and this hypoaemic response is dependent on the presence of capsaicin-sensitive nerves.

Phoneutria nigriventer spider venom activates 5-HT4 receptors in rat-isolated vagus nerve.

1. The venom of Phoneutria nigriventer spider (PNV) causes intense pain and inflammation following an attack. We have investigated the involvement of capsaicin-sensitive nerve fibres by utilizing an in vitro nerve preparation. Extracellular DC potential recordings were made from the rat-isolated vagus nerve, a preparation that is rich in capsaicin-sensitive, that is, nociceptive, C-fibres. 2. PNV (1-10 microg ml(-1)), capsaicin (0.03-0.3 microM) or 5-hydroxytriptamine (5-HT) (0.3-3 microM) induced dose-dependent depolarizations of vagus nerve fibres. Depolarizing responses to capsaicin were blocked by ruthenium red (RR, 10 microM), but responses to PNV were not. Depolarizing responses to PNV or veratridine (50 microM) were inhibited by tetrodotoxin (TTX, 10 microM), but those to capsaicin were not. This suggests that capsaicin and PNV depolarize the nerve fibres by distinct mechanisms. 3. Depolarization in response to 5-HT (3 microM) was reduced by the 5-HT(3) receptor antagonists Y25130 (0.5 micro M) and tropisetron (10 nM) or, to a lesser extent, by the 5-HT(4) receptor antagonist RS39604 (1 or 10 microM). Depolarizing responses to PNV were not affected significantly by Y25130 or tropisetron, but were blocked by RS39604. 4. These data show that 5-HT(4) receptors play a significant role in the activation of nociceptive sensory nerve fibres by PNV and suggest that this is of importance in the development of the pain and inflammation associated with bites from the P. nigriventer spider.

Effects of resiniferatoxin desensitization of capsaicin-sensitive afferents on detrusor over-activity induced by intravesical capsaicin, acetic acid or ATP in conscious rats.

Recent studies have provided evidence for a major role of urothelially released ATP acting on a subpopulation of pelvic afferent nerves in mechano-afferent transduction in the bladder. We investigated whether desensitization of capsaicin-sensitive nerve fibres by systemic resiniferatoxin (RTX)-pretreatment can counteract the detrusor over-activity induced by intravesical capsaicin, acetic acid or ATP. Cystometric investigations were performed on awake female Sprague-Dawley rats before and 24 h after injection of RTX (0.3 mg/kg s.c.) or vehicle. The effects of intravesically instilled ATP (0.1 or 1.0 mM), capsaicin (30 microM) or acetic acid (pH 4.0) were compared with those of intravesical saline. RTX, but not its vehicle, significantly increased threshold pressure, voiding interval, micturition volume and bladder capacity. In the vehicle-pretreated rats, intravesical instillation of capsaicin or acetic acid significantly decreased voiding interval, micturition volume, and bladder capacity. However, in the RTX-pretreated rats, neither capsaicin nor acetic acid affected any parameter. On the other hand, intravesical ATP (0.1 mM) significantly decreased voiding interval and micturition volume in both groups of animals. At 1.0 mM, ATP also increased basal pressure and decreased the pressure threshold for micturition in both groups. The present results support the view that increased extracellular ATP has a role in mechano-afferent transduction in the rat bladder and that ATP-induced facilitation of the micturition reflex is mediated, at least partly, by nerves other than capsaicin-sensitive afferent nerves.

The role of capsaicin-sensitive afferents in autonomic dysreflexia in patients with spinal cord injury.

To determine whether capsaicin-sensitive nerves in the bladder form the afferent limb involved in autonomic dysreflexia (AD) in patients with spinal cord injury (SCI). Seven men with SCI (five cervical cord, two thoracic cord) with AD and detrusor hyper-reflexia (DH) were enrolled. Under general anaesthesia, capsaicin solution (100 mL of 2 mmol/L in 10% ethanol) was instilled in the bladder and retained for 30 min. The patients were assessed by medium-fill cystometry (CMG) just before and 50 min after the capsaicin treatment. Intra-arterial blood pressure (BP) and heart rate were monitored continuously throughout the procedure; 10% ethanol was instilled before capsaicin treatment in four patients as a control. Serum catecholamines were measured during bladder filling and capsaicin treatment, and the blood ethanol concentration also measured after instillation in all patients. The CMG with concomitant monitoring of BP and heart rate was repeated 1 week, 1, 3, 6, 12 and 24 months after instillation. In two patients the instillations were repeated 5 and 12 months after the first because of recurrence of DH. Urodynamic variables assessed were maximum cystometric capacity (MCC), maximum amplitude of uninhibited detrusor contraction (UICmax), the bladder capacity at 40 cmH2O detrusor pressure (Cdp40) and a systolic BP of> 140 mmHg or diastolic BP of> 90 mmHg (C(HT)). There was an increase in BP and a decrease in heart rate in all patients during bladder filling before capsaicin treatment. Instillation of capsaicin produced a significant increase in both systolic and diastolic BP and a significant decrease in heart rate. The maximum cardiovascular effects were at 5-10 min after instillation and gradually returned to baseline within 40 min. The vehicle had negligible effects on either BP or heart rate. After capsaicin treatment, the responses of BP and heart rate to bladder distension were significantly reduced. Both serum catecholamine values and the blood ethanol concentration remained within normal limits. The mean (range) follow-up after the first treatment was 15 (6-30) months. One month after treatment all seven patients became continent and their episodes of AD became negligible and well tolerable between catheterizations (for 3-4 h); the effects lasted for >or= 3 months in all. MCC was significantly increased at 4 weeks and 3 months, and UICmax significantly decreased at 4 weeks after treatment. Both mean Cdp40 and C(HT) increased 1 week, 1 and 3 months after treatment. Two patients received a second instillation, and have been continent with no symptomatic AD for 6 and 24 months. The remaining five patients have been continent with no symptomatic AD for 6-12 months. These results indicate that intravesical capsaicin, but not the vehicle, acutely triggers AD in patients with SCI, suggesting involvement of bladder capsaicin- sensitive afferents in AD in these patients. The results also suggest that intravesical capsaicin may be a promising therapy for both AD and DH in such patients. Further long-term follow-up studies are needed to evaluate the duration of its effect.

Role of capsaicin sensitive afferent nerves in different models of gastric inflammation in rats

Role of capsaicin sensitive afferent nerves in different models of gastric inflammation in rats

Endogenous neurokinins facilitate synaptic transmission in guinea pig airway parasympathetic ganglia.

Neurokinin-containing nerve fibers were localized to guinea pig airway parasympathetic ganglia in control tissues but not in tissues pretreated with capsaicin. The purpose of the present study was to determine whether neurokinins, released during axonal reflexes or after antidromic afferent nerve stimulation, modulate ganglionic synaptic neurotransmission. The neurokinin type 3 (NK(3)) receptor antagonists SB-223412 and SR-142801 inhibited vagally mediated cholinergic contractions of bronchi in vitro at stimulation voltages threshold for preganglionic nerve activation but had no effect on vagally mediated contractions evoked at optimal voltage or field stimulation-induced contractions. Intracellular recordings from the ganglia neurons revealed that capsaicin-sensitive nerve stimulation potentiated subsequent preganglionic nerve-evoked fast excitatory postsynaptic potentials. This effect was mimicked by the NK(3) receptor agonist senktide analog and blocked by SB-223412. In situ, senktide analog markedly increased baseline tracheal cholinergic tone, an effect that was reversed by atropine and prevented by vagotomy or SB-223412. Comparable effects of intravenous senktide analog on pulmonary insufflation pressure were observed. These data highlight the important integrative role played by parasympathetic ganglia and indicate that activation of NK(3) receptors in airway ganglia by endogenous neurokinins facilitates synaptic neurotransmission.

Local Skin Lesions in the Rat after Subcutaneous Deposition of Capsaicin

Capsaicin is used to investigate the role of peripheral sensory nerve fibers. In previous studies of rats treated by injection of capsaicin into the skin of the neck, ‘spontaneous’ lesions in the head and neck region were observed. In this study, the course of development over time, the regional distribution and the innervation of capsaicin-induced dermal lesions were assessed in young male Sprague-Dawley rats. In one experiment, capsaicin was administered subcutaneously by injection in the skin of the neck. In a second experiment, capsaicin was injected in the back by a long needle that tunneled under the skin and allowed the capsaicin to be deposited in the subcutaneous fat of the neck. The density and the distribution of dermal nerve fibers were investigated by immunohistochemistry, using antisera against a panneuronal marker, protein gene product 9.5 (PGP), and calcitonin gene-related peptide (CGRP). In the first experiment, rats developed lesions in the neck area 11 days after injection. In the second experiment, lesions appeared in the skin of the back and occasionally in the neck area 10 days after injection. Development of lesions in the afflicted areas was paralleled by local reduction in the density of CGRP-immunoreactive (IR) nerve fibers, 80% in the first experiment and 72% in the second. The number of PGP-IR fibers was likewise reduced, by 39 and 41%, respectively. The density of the CGRP-IR fibers in the wound area was the same as in the adjacent, nonlesioned skin. The healing of the capsaicin-induced lesions was slow compared with surgical wounds in control animals. The wounds healed with hypertrophic scars. The healing process in the skin of the back was associated with the proliferation of CGRP-IR fibers. The study shows cutaneous lesions to appear in the region of the subcutaneous deposition of capsaicin. A uniform depletion of capsaicin-sensitive nerve fibers in the area of deposition suggests that an additional factor is needed to induce lesions. Possibly, impaired nociception in the afflicted area results in more vigorous grooming behavior and this, in turn, in a local skin damage.

Alterations in capsaicin-evoked electrolyte transport during the evolution of guinea pig TNBS ileitis.

The efferent secretomotor activity of capsaicin-sensitive nerves was monitored during the evolution of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced ileitis in the guinea pig by recording changes in short-circuit current (DeltaI(sc)) in response to capsaicin, substance P (SP), and carbachol. Submucosal-mucosal preparations mounted in standard Ussing chambers were studied at time 0, at 8 h, and 1, 3, 5, 7, 14, and 30 days following the intraluminal instillation of TNBS or saline. Maximal DeltaI(sc) responses to capsaicin were dramatically attenuated (54%) by 24 h. By day 7, SP- and TTX-insensitive carbachol-stimulated DeltaI(sc) were also significantly reduced. Similar attenuation in capsaicin and carbachol responses was observed in jejunal tissue 20 cm proximal to the inflamed site at day 7. These studies demonstrate that efferent secretomotor function of capsaicin-sensitive nerves is maintained early in TNBS ileitis but significantly reduced by 24 h. By day 7, defects in enterocyte secretory function at inflamed and noninflamed sites also occurred, an effect that may be mediated by circulating cytokines.

Sensitizing effects of lafutidine on CGRP-containing afferent nerves in the rat stomach.

1. Capsaicin sensitive afferent nerves play an important role in gastric mucosal defensive mechanisms. Capsaicin stimulates afferent nerves and enhances the release of calcitonin gene-related peptide (CGRP), which seems to be the predominant neurotransmitter of spinal afferents in the rat stomach, exerting many pharmacological effects by a direct mechanism or indirectly through second messengers such as nitric oxide (NO). 2. Lafutidine is a new type of anti-ulcer drug, possessing both an antisecretory effect, exerted via histamine H(2) receptor blockade, and gastroprotective activities. Studies with certain antagonists or chemical deafferentation techniques suggest the gastroprotective actions of lafutidine to be mediated by capsaicin sensitive afferent nerves, but this is an assumption based on indirect techniques. In order to explain the direct relation of lafutidine to afferent nerves, we conducted the following studies. 3. We determined CGRP and NO release from rat stomach and specific [(3)H]-resiniferatoxin (RTX) binding to gastric vanilloid receptor subtype 1 (VR1), which binds capsaicin, using EIA, a microdialysis system and a radioreceptor assay, respectively. 4. Lafutidine enhanced both CGRP and NO release from the rat stomach induced by a submaximal dose of capsaicin, but had no effect on specific [(3)H]-RTX and capsaicin binding to VR1. 5. In conclusion, our findings demonstrate that lafutidine modulates the activity of capsaicin sensitive afferent nerves in the rat stomach, which may be a key mechanism involved in its gastroprotective action.

Effects of Capsaicin Application to Peripheral Nerves in a Rat Model for Human Postoperative Pain

Background: The interest in management of postoperative pain has increased with the development of medicine. The mechanism of postoperative pain should be understood first. Capsaicin has been proven to be a powerful agent acting selectively on nociceptive afferent fibers. This study was focused on how the perineural treatment of capsaicin affects pain after an incision in the rat model. Methods: Capsaicin was applied directly to sciatic nerve branches, on the are tibial, sural, and saphenous nerves. Pain behaviors to von Frey filaments, blunt probe stimulation, resting pain, and heat were evaluated on the incised feet. The grade of wound healing was assessed according to clinical findings of the wound 3 days postoperatively. Results: Capsaicin applied directly onto nerves elevated withdrawal latency to heat during the study. There were statistically significant increases of withdrawal latencies in the capsaicin group compared with the vehicle group. Capsaicin produced agreater increase of the withdrawal threshold to von Frey than the vehicle 2 days after the incision. Resting pain scores were lower in capsaicin - treated rats than in the vehicle group for 2 days. The grade of wound healing was poor in capsaicin - treated rats. Conclusions: The perineural application of capsaicin appears to affect the pathway of transmission of postoperative pain. Current results suggest that capsaicin has a strong analgesic effect on thermal hyperalgesia and attenuates mechanical hyperalgesia by an incision. Capsaicin sensitive nerves could be involved in wound healing.

Effect of lafutidine, a histamine H2-receptor antagonist, on gastric mucosal blood flow and duodenal HCO3- secretion in rats: relation to capsaicin-sensitive afferent neurons.

Lafutidine is a new type of antiulcer drug, possessing both an antisecretory effect, exerted via a blockade of the histamine H2 receptor, and gastroprotective activity, mediated by capsaicin-sensitive afferent nerves (CSN). In the present study, we examined the effect of lafutidine on gastric mucosal blood flow (GMBF) and duodenal HCO3- secretion (DAS) under basal and acid-stimulated conditions in rats. Under urethane anesthesia, GMBF was measured using a laser Doppler flowmeter in a chambered stomach before and after exposure to 20 mM taurocholate (TC) plus 50 mM HCl, while DAS was measured in a proximal duodenal loop before and after mucosal acidification (10 mM HCl for 10 min) by titrating the perfusate at pH 7.0 using a pH-stat method and by adding 10 mM HCl. Lafutidine given intraperitoneally affected neither GMBF nor DAS under basal conditions, but augmented an increase in both GMBF and DAS induced by mucosal acidification. Although the acid-induced GMBF and DAS responses were significantly mitigated by both indomethacin and sensory deafferentation but not by ruthenium red (RT), the vanilloid receptor (VR)-1 antagonist, the responses were preserved in lafutidine-treated animals, even in the presence of indomethacin. Both GMBF and DAS were significantly increased by local application of capsaicin, the responses being attenuated by indomethacin and RT as well as sensory deafferentation. Lafutidine augmented the GMBF and DAS responses to capsaicin and preserved the responses, even in the presence of indomethacin. Capsaicin evoked an increase in [Ca2+]i in rat VR1-transfected HEK293 cells, while lafutidine had no effect by itself on [Ca2+]i in these cells and did not affect the increase in [Ca2+]i evoked by capsaicin. In conclusion, these results suggest that lafutidine mimics endogenous effects of prostaglandins to augment the GMBF and DAS responses to acid or capsaicin, probably by sensitizing CSN through an unknown site other than VR1. The luminal H+ itself is not a ligand for the RT-sensitive site of VR1 but plays a modulator role in the CSN-mediated physiological responses.

Capsaicin-Sensitive Nerve Fibres Induce Epithelial Cell Proliferation, Inflammatory Cell Immigration and Transforming Growth Factor-alpha Expression in the Rat Colonic Mucosa In Vivo

Background: Capsaicin-sensitive nerve fibres protect gastrointestinal mucosa in animal models of mucosal injury by modulation of mucosal blood flow and mucus secretion. The aim of our study was to evaluate the effects of capsaicin-sensitive nerve fibres in rat colonic mucosa on epithelial cell proliferation and transforming growth factor-alpha (TGF α ) expression, which is important in mucosal defence, protection and repair. Methods: Male Wistar rats received either a capsaicin enema with or without giving antagonists to calcitonin-gene-related-peptide (CGRP) or substance P (SP) i.v. immediately prior to the capsaicin enemas; a capsaicin enema after sensory desensitization as described previously; or a vehicle enema. In all experiments, animals received 50 mg/kg BrdU i.v. and were killed at 2, 4, 8, 12, 24 and 48 h after the various treatments. Colonic mucosal specimens were evaluated microscopically for mucosal damage, changes in the numbers of inflammatory cells and BrdU-immunoreactive epithelial cell nuclei. In the same specimens, TGF α -mRNA and-protein expression were evaluated by RT-PCR and Western blot analysis using standardized procedures. Results: A significant increase in the number of mucosal inflammatory cells and an increase in BrdU-immunoreactive nuclei were detected following mucosal exposure to capsaicin. A 2-fold increase of TGF α mRNA and a 10-fold increase of TGF α protein expression were obtained 2-12 h after capsaicin enemas. The effects on the invading number of inflammatory cells and on the increase in BrdU immunoreactive epithelial cell nuclei were significantly reduced by both CGRP and SP antagonists and were abolished in rats previously sensory-desensitized. Conclusion: Capsaicin-sensitive nerve fibres modulate epithelial cell proliferation and TGF α expression in colonic mucosa as well as a migration of inflammatory cells into the colonic mucosa. These effects are mediated by the neurotransmitters CGRP and SP.

Distribution and characterization of vanilloid receptors in the rat stomach

The cloned vanilloid receptor-1 (VR1) is recognized as a common molecular target for protons, noxious heat, and vanilloids. The presence of VR1 in the dorsal root, trigeminal, and nodose ganglia has been firmly established, but it is unclear in the gut, despite this VR1 may be important for gastric mucosal homeostasis. In this study we used an antibody and a radioligand to show the distribution of vanilloid receptors (VRs) in rat stomach and to characterize it. The deafferentiation of capsaicin-sensitive nerves in rats was induced by consecutive injections of capsaicin. VR1-immunopositive nerve endings were predominantly found in the mucous neck cells of the proliferation zone, and around blood vessels in the submucosa. Radioreceptor assay using [ 3H]-resiniferatoxin (RTX) revealed the existence of high affinity and single-class binding site in the membrane fractions of the mucosa. Capsaicin completely inhibited the specific binding of [ 3H]-RTX. Both the VR1 immunoreactivity and the receptor density of [ 3H]-RTX binding sites significantly reduced by the application of capsaicin for prolonged periods of time in the mucosa of rats. Our results indicate that VRs are expressed in the rat stomach, and suggest that they may be involved in mucosal protection by increasing cell proliferation and blood flow.

A novel mechanism for the reuptake of CGRP

Unlike classical amine or amino acid transmitters, which are synthesized close to their sites of release, neuropeptides such as the 37-amino-acid calcitonin gene-related peptide (CGRP) are synthesized in the neuronal soma and transported through the axon to sites of release in the nerve terminals. The transport process is time- and energy-consuming, and an intense stimulation could deplete releasable pools of neuropeptides rendering the nerve terminals unresponsive (in terms of release) until this pool has been replenished by newly synthesized and transported peptide. Uptake mechanisms that remove neurotransmitters from the synaptic cleft and spare the synthesis of new molecules of neurotransmitters have been described for small amine or amino acid neurotransmitters. Now, Sams-Nielsen et al. 1xPharmacological evidence for CGRP uptake into perivascular capsaicin sensitive nerve terminals. Sams-Nielsen, A. et al. Br. J. Pharmacol. 2001; 132: 1145–1153Crossref | PubMedSee all References1 provide indirect evidence for a reuptake mechanism for CGRP into capsaicin-sensitive afferent neurones and suggest that this mechanism might have functional relevance for the refilling of a releasable neuropeptide pool in nerve terminals following CGRP release.Isolated segments of the guinea-pig basillary artery, precontracted with prostaglandin F2α (PGF2α), were challenged with capsaicin (10 μm), which caused a CGRP-dependent (blocked by the antagonist CGRP8–37), capsazepine-sensitive relaxation. When the capsaicin challenge was repeated twice again, the relaxation underwent a significant fading (from ∼60% to 20% of PGF2α contraction). At this point, preparations were incubated with CGRP (100 nm) for 20 min and the capsaicin challenges repeated another three times. Following this protocol, the fourth capsaicin challenge (the first after the CGRP incubation) caused a significant relaxation (capsazepine-resistant, but still CGRP-dependent), which showed a significant fading during the fifth and sixth capsaicin challenge. Control experiments showed that repeated challenges with exogenous CGRP induced reproducible relaxations, thus excluding the possibility that desensitization occurs at the smooth-muscle level. In another series of experiments, arterial segments were incubated with [125I]CGRP and [125I] outflow was monitored following relaxation induced by capsaicin in PGF2?-precontracted preparations. Capsaicin induced a significant radioactivity release, which suggests that [125I]CGRP had been taken up by capsaicin-sensitive nerve terminals, even in the absence of a previous capsaicin challenge. Intriguingly, the restoration of capsaicin-induced relaxation was inhibited when CGRP was co-incubated with its antagonist CGRP8–37, suggesting that prejunctional CGRP receptors are involved in the refilling of the neuropeptide in nerve terminals.These results provide indirect evidence for a CGRP reuptake mechanism in capsaicin-sensitive perivascular nerve terminals, possibly mediated through the activation of prejunctional CGRP receptors. Thus, following the activation of prejunctional CGRP receptors and the consequent internalization of the complex peptide ligand–receptor, the peptide ligand might be spared from metabolism and recycled locally for the preservation of physiological functions. In addition, these results highlight a novel role for peptide prejunctional receptors in neurones, as well as in the modulation of neurotransmitter release. Other examples for the transport of relatively large peptides across biological barriers include those mediated by multi-drug resistance protein, other peptide transporters, or specific peptide receptors located at the blood–brain barrier or the choriod plexus epithelium; however, this uptake mechanism for CGRP is the first example of a neuronal uptake of peptides. It will be interesting to assess whether this process represents an exception or similar mechanisms spare other neuropeptides.

Antinociceptive and pro-inflammatory roles for NPY Y 1 receptors

Neuropetide Y (NPY) is a 36-amino-acid neuropeptide that is widely distributed in the CNS and PNS, where it is stored along with noradrenaline in sympathetic postganglionic fibres, and is also expressed in other autonomic (possibly parasympathetic) and sensory neurones. The physiological effects of NPY are mediated by at least six receptors (Y1–6), showing variable expression among mammalian species. An inhibitory modulation by NPY on the release of substance P (SP) from capsaicin-sensitive primary afferent neurones, from both central and peripheral nerve endings, was confirmed in many experimental conditions. Therefore, until recently, there was a general consensus that NPY had a putative anti-inflammatory effect at the peripheral level and an antinociceptive effect in the CNS. Y1, Y2 and possibly other NPY receptors are expressed by dorsal root ganglion neurones. The recent availability of Y1 receptor knockout (Y1−/−) mice was expected to elucidate whether this receptor is involved in the inhibitory effect of NPY on neurogenic inflammation and nociception.Naveilhan and colleagues 1xReduced antinociception and plasma protein extravasation in mice lacking a neuropeptide Y receptor. Naveilhan, P. et al. Nature. 2001; 409: 513–517Crossref | PubMed | Scopus (129)See all References1 showed that Y1−/− mice displayed a hyperalgesic phenotype in tests of thermal (hot plate and tail flick), chemical (first phase of formalin test, acetic-acid- and magnesium-sulfate-induced writhings), mechanical (Von Frey hairs) and neuropathic (partial nerve injury) nociception, and the antinociceptive effect observed following the intrathecal administration of NPY in wild-type animals was not evident in Y1−/− mice. Concomitantly, however, the capsaicin-induced, SP-mediated pro-inflammatory effects were blunted in Y1−/− mice. In fact, the administration of capsaicin in a paw did not induce plasma extravasation and oedema in Y1−/− mice, and the effects of mustard oil were also attenuated. By contrast, neither the inflammatory responses induced by carrageenan nor those induced by SP were modified in Y1−/− animals. Furthermore, the pro-inflammatory effects of capsaicin in wild-type mice were mimicked by a Y1 receptor agonist and were prevented by the selective Y1 receptor antagonist BIBP3226. In Y1−/− mice, tissue concentrations of SP were comparable with those found in normal mice, but capsaicin failed to induce SP release and subsequent neuropeptide depletion.These results led the authors to conclude that Y1 receptors exert a tonic physiological role in reducing nociceptive inputs at the spinal cord level, whereas at the peripheral level, the stimulation of these receptors is both necessary and sufficient for triggering neurogenic inflammation. An alternative hypothesis could reconcile previous and present findings on the role of NPY and NPY receptors in neurogenic inflammation: an opposing role of Y1 and Y2 receptors (or other Y receptors) in the excitability of capsaicin-sensitive nerve terminals could exist if both receptors are tonically stimulated by endogenous NPY. In wild-type animals, the exogenous administration of NPY has an inhibitory effect on capsaicin-induced inflammatory responses, possibly because of a preferential stimulation of Y2 receptors. In Y1−/− animals, endogenous NPY could be sufficient for the inhibition of the excitability of capsaicin-sensitive nerve terminals through the stimulation of Y2 receptors. This hypothesis could be tested either through the construction of Y2−/− mice, or with the use of already available selective Y2 receptor antagonists.

Lafutidine, a novel H2 receptor antagonist, reduces the stress-induced gastric mucosal injury by inhibiting neutrophil activation through activation of capsaicin sensitive nerve in rats

Lafutidine, a novel H2 receptor antagonist, reduces the stress-induced gastric mucosal injury by inhibiting neutrophil activation through activation of capsaicin sensitive nerve in rats

Lafutidine, a novel H2 receptor antagonist, reduces the stress-induced gastric mucosal injury by inhibiting neutrophil activation through activation of capsaicin sensitive nerve in rats

Lafutidine, a novel H2 receptor antagonist, reduces the stress-induced gastric mucosal injury by inhibiting neutrophil activation through activation of capsaicin sensitive nerve in rats