Capsaicin-sensitive Fibers Research Articles

Capsaicin sensitive nervous fibers induce transforming growth factor-alpha and-beta expression in the rat colonic mucosa in vivo

Capsaicin sensitive nervous fibers induce transforming growth factor-alpha and-beta expression in the rat colonic mucosa in vivo

Pharmacological evidence for CGRP uptake into perivascular capsaicin sensitive nerve terminals.

Specific mechanisms, providing reuptake of cathecholamine and amino acid neurotransmitters (e.g. serotonin and glutamate) into cells of the central nervous system are well known, whereas neuronal uptake of neuropeptide transmitters have not previously been reported. In the present study we present evidence for uptake of the 37 amino acid neuropeptide, calcitonin gene-related peptide (CGRP) into perivascular terminals of capsaicin sensitive nerve fibres, innervating the guinea-pig basilar artery. Release of CGRP from perivascular nerve terminals was obtained by capsaicin-induced vanilloid receptor-stimulation and detected as CGRP receptor-mediated dilation of isolated segments of the guinea-pig basilar artery. Following three repeated capsaicin challenges, CGRP-depleted segments were incubated with CGRP. This caused significant reappearance of capsaicin-induced vasodilatory responses. These responses were dependent on duration and concentration of the preceding CGRP incubation and were inhibited by the CGRP receptor antagonist, CGRP(8 - 37). The CGRP-re-depletion was significantly reduced when CGRP(8 - 37) was present during the preceding CGRP incubation. Thus, presynaptic CGRP receptors are likely to be involved in neuronal CGRP uptake. Incubating the artery segments with (125)I-CGRP allowed subsequent detection of capsaicin-induced (125)I-release. Immunohistochemical experiments showed that only terminal CGRP is subject to capsaicin-induced depletion in vitro, whereas CGRP-immunoreactivity endures in the nerve fibres.

Mechanisms of the cutaneous vasodilator response to local external pressure application in rats: involvement of CGRP, neurokinins, prostaglandins and NO

1. Local pressure-induced vasodilation (PIV) is a neural vasodilator response to non-nociceptive externally applied pressure in the skin, previously described in humans. We first determined whether PIV exists in rats and depends on capsaicin-sensitive fibres as it does in humans. We then examined the mediators involved in the efferent pathway of PIV. 2. Cutaneous blood flow was measured by laser Doppler flowmetry during 11.1 Pa s(-1) increases in local applied pressure in anaesthetized rats. The involvement of capsaicin-sensitive fibres in PIV was tested in rats treated neonatally with capsaicin. To antagonize CGRP, neurokinin-1, -2, or -3 receptors, different groups of rats were treated with CGRP(8 - 37), SR140333, SR48968 or SR142801, respectively. Prostaglandins involvement was tested with indomethacin treatment. To inhibit nitric oxide synthase (NOS) activity or specific neuronal NOS, rats were treated with N(G)-nitro-L-arginine or 7-nitroindazole, respectively. 3. PIV was found in rats, as in humans. PIV was abolished by neonatal treatment with capsaicin and by administration of CGRP(8 - 37) but remained unchanged with SR140333, SR48968 and SR142801 treatments. Prostaglandin inhibition resulted in a significant decrease in PIV. Inhibition of NOS abolished PIV, whereas inhibition of neuronal NOS caused a diminution of PIV. 4. These data suggest that PIV depends on capsaicin-sensitive fibres in rats, as in humans. It appears that CGRP plays a major role in the PIV, whereas neurokinins have no role. Furthermore, PIV involves a contribution from prostaglandins and depends on endothelial NO, whereas neuronal NO has a smaller role.

Neural Route of Pyrogen Signaling to the Brain

In the pathogenesis of systemic inflammation and fever, peripheral inflammatory and pyrogenic signals gain access to the brain via humoral and neural routes. One of the neural routes is represented by chemosensitive afferent fibers of the abdominal vagus. We summarize our recent studies of the role of the abdominal vagus in fever. We conclude that capsaicin-sensitive fibers traveling within the hepatic vagal branch constitute a necessary component of the afferent mechanism of the febrile response to low, but not high, doses of circulating pyrogens. We speculate that this mechanism is triggered by blood-borne prostaglandins of the E series.

Nociceptin and the micturition reflex

The i.v. administration of nociceptin (10–100 nmol/kg) inhibits the micturition reflex in a naloxone-resistant manner. The effects induced by i.v. nociceptin were not observed in capsaicin-pretreated animals indicating that i.v. nociceptin inhibits the micturition reflex by inhibiting afferent discharge from capsaicin-sensitive nerves. Supporting this interpretation, nociceptin also inhibited the reflex but not the local bladder contraction induced by topical capsaicin and protects this reflex (but not the local contraction) by desensitization. Intrathecal nociceptin (10 nmol/rat) produces urodynamic modifications similar to those induced by the i.v. administration. Intracerebroventricular (i.c.v.) administration of nociceptin (0.3–1 nmol/rat) also inhibited the micturition reflex in a naloxone-resistant manner suggesting a direct effect on supraspinal sites controlling the micturition. Beyond the inhibitory effects exerted by nociceptin on the micturition reflex, a peripheral excitatory effect mediated by capsaicin-sensitive fibers was also detected. The application of nociceptin (5–50 nmol/rat) onto the bladder serosa when the intravesical volume was subthreshold for the triggering of the micturition reflex, activated the reflex in a dose-dependent manner; the same treatment produced a biphasic effect on the ongoing reflex. In addition to the triggering of micturition reflex, topical nociceptin evokes a local tonic-type contraction that was abolished by the coadministration of tachykinin NK 1 and NK 2 receptor antagonists. Altogether these results indicate that ORL 1 receptors are present at several sites for the integration of the micturition reflex, and that their activation may produce both excitatory or inhibitory effects, depending on the route of administration and the experimental conditions.

Capsaicin sensitive efferent sensory nerve fibers inhibit epithelial cell proliferation, DNA-synthesis and TGFA-MRNA expression in the rat colon

Capsaicin sensitive efferent sensory nerve fibers inhibit epithelial cell proliferation, DNA-synthesis and TGFA-MRNA expression in the rat colon

Fedotozine, a kappa-opioid agonist, prevents spinal and supra-spinal Fos expression induced by a noxious visceral stimulus in the rat.

Fedotozine, a kappa opioid agonist, reverses digestive ileus caused by acetic acid (AA)-induced visceral pain in rats. The aims of this study were: to map, in conscious rats, central pathways activated by AA using Fos as a marker of neuronal activation; to characterize primary afferent fibres involved in this activation; and to investigate the effect of fedotozine on AA-induced Fos expression. AA (0.6%; 10 mL kg-1) was injected i.p. in conscious rats either untreated; pretreated 14 days before with capsaicin; pretreated 20 min previously with fedotozine; or pretreated 2 h prior to fedotozine with the kappa-antagonist nor-binaltorphimine (nor-BNI). Controls received the vehicle alone. 60 min after injection of AA, rats were processed for Fos immunohistochemistry. Visceral pain was assessed by counting abdominal cramps. AA induced Fos in the thoraco-lumbar spinal cord (laminae I, V, VII and X) and numerous brain structures such as the nucleus tractus solitarius, and paraventricular nucleus (PVN) of the hypothalamus, whereas almost no Fos labelling was observed in controls. Capsaicin pretreatment blocked AA-induced Fos in all structures tested. Fedotozine significantly decreased AA-induced abdominal cramps and Fos immunoreactivity in the spinal cord and PVN, this effect being reversed by nor-BNI pretreatment. AA induces Fos in the spinal cord and numerous brain nucuei, some of which are involved in the control of digestive motility in rats. This effect is mediated through capsaicin-sensitive afferent fibres and prevented by fedotozine most likely through a peripheral action on visceral afferents.

Role of capsaicin sensory nerves and EGF in the healing of gastric ulcer in rats

Accumulating evidence indicates that capsaicin sensitive afferent fibers play a pivotal role not only in gastroprotection but also in ulcer healing. Denervation of capsaicin sensitive afferent fibers exerts an adverse action on these effects. However, whether such an action is mediated through a depression on epidermal growth factor (EGF) is undefined. In this study, the effects of denervation of sensory neurons with capsaicin (100 mg/kg, s.c.) on acetic acid-induced chronic gastric ulcers and their relationship with the EGF expression in salivary glands, serum and gastric mucosa were investigated. Capsaicin significantly increased ulcer size, decreased gastric mucosal cell proliferation at the ulcer margin, angiogenesis in the granulation tissue and also gastric mucus content. Ulcer induction by itself dramatically elevated EGF levels in salivary glands and serum on day 1 and 4, and also in the gastric mucosa on day 4. However, capsaicin completely abolished these effects. It is concluded that stimulation of EGF expression in salivary glands and serum may be one of the mechanisms by which capsaicin sensitive nerves contribute to the gastroprotective and ulcer healing actions in the stomach.

Menthol desensitization of capsaicin irritation: Evidence of a short-term anti-nociceptive effect

Evidence is presented of a short-term antinociceptive effect of menthol that was discovered in the course of investigating menthol's potential to sensitize the mouth to capsaicin. Previous research had shown that treating the tongue with menthol 15 min before exposure to capsaicin could enhance the irritancy of capsaicin, and we wished to learn if this effect would increase as the time between exposure to menthol and capsaicin decreased. We found instead that when capsaicin followed menthol by only 3.5 min, or when it was presented in mixture with menthol for 2–3 min, sensory irritation was reduced rather than enhanced. We examined the duration of this apparent crossdesensitization in a second experiment by varying the delay between exposure to menthol and a block of three consecutive capsaicin stimuli. Cross-desensitization tended to decline as the interstimulus interval (ISI) increased to 5 min, and even when desensitization was maximal, it was significant only for the first of the three capsaicin stimuli. In the final experiment we investigated how menthol self- and cross-desensitization can influence the perception of menthol–capsaicin mixtures. During a series of five, 90-s stimulations, self- and cross-desensitization became evident at the beginning of the second exposure, but the effect on mixture intensity again diminished rapidly as stimulation continued. We infer from these results that method can transiently desensitize capsaicin-sensitive fibers, but that exposure to capsaicin rapidly overrides the effect. The implications these findings have for menthol's potential as a topical analgesic are discussed.

Role of capsaicin-sensitive nerves in gastric and hepatic injury induced by cold-restraint stress.

The role of capsaicin-sensitive afferent fibers on cold-restraint stress-induced gastric and hepatic injury was examined at the macroscopic and ultrastructural levels. Wistar albino rats were treated with capsaicin either locally (intragastric, perivagal, and periceliac) or systemically (neonatal, intraperitoneal). Perineural and neonatal treatment with capsaicin was used to denervate afferent fibers, while intragastric capsaicin treatment would have activated mucosal afferent fibers just before the stress exposure. Capsaicin decreased significantly the formation of macroscopic gastric lesions caused by stress in all treatment groups. At the electron microscopic level, however, denervation of vagal afferent fibers with capsaicin was most effective in prevention of cellular injury in gastric mucosa. In the liver, systemic denervation of afferent fibers completely inhibited stress-induced cellular damage, while denervation of afferent fibers in vagus and splanchnic nerve was partially effective. Central neural pathways sensitive to capsaicin may mediate formation of both gastric and hepatic injury resulting from stress.

Capsaicin-sensitive vagal fibres and 5-HT 3-, gastrin releasing peptide- and cholecystokinin A-receptors are involved in distension-induced inhibition of gastric emptying in the rat

The present study was undertaken to investigate how the activation of gastric mechanoreceptors by distension of the stomach in conscious gastric fistula rats influences gastric emptying; and the roles of capsaicin sensitive vagal afferent fibres and the 5-HT 3, GRP and CCK-A receptors involved in mediating these responses. To activate mechanoreceptors by non-nutrient dependent pathways, methylcellulose in saline was used to distend the stomach (5 cm H 2O) and the subsequent emptying of saline was examined immediately, and at 3, 5 and 10 min following distension. Prior distension delayed the subsequent emptying of saline instilled into the stomach compared with non-distended controls (2.28±0.09 ml/5 min; P<0.001). Topical application of capsaicin, completely abolished the distension-induced inhibition of gastric emptying when compared with vehicle treated rats (2.82±0.09 vs. 2.38±0.04 ml/5 min; P<0.001). Peripheral administration of a GRP antagonist (2258 U89UJ, 1 mg/kg), and a 5-HT3 antagonist (BRL4369UA, 50 μg/kg) significantly reversed (2.56±0.14 ml/5 min; P<0.05 and 2.61±0.07 ml/5 min; P<0.01; respectively) the delay in gastric emptying induced by distension. When the rats were treated with the CCK-A antagonist, gastric emptying of saline following distension was also significantly facilitated (2.56±0.07 ml/5 min; P<0.001). In contrast, the CCK-B/gastrin receptor antagonist had no significant effect on the distension induced delay in gastric emptying (1.95±0.12 ml/5 min). The present results suggest that gastric distension in conscious gastric fistula rats delays gastric emptying by activating capsaicin-sensitive extrinsic afferent nerve fibres. Moreover, the results also indicate that distension-induced mechanisms involve GRP, 5-HT 3 and CCK-A receptors, but not CCK-B receptors.

Nociceptin protects capsaicin-sensitive afferent fibers in the rat urinary bladder from desensitization.

Chemical stimulation of primary afferent nerves in the rat urinary bladder in vivo with topical capsaicin (1 microg in 50 microl saline) determines a dual motor response, consisting of a contractile effect mediated by tachykinins released from sensory nerves in the bladder wall and a transient activation of a bladder-to-bladder micturition reflex organized at the supraspinal level (chemoceptive micturition reflex). Both responses undergo complete desensitization upon repeated applications of capsaicin. The i.v. administration of the novel neuropeptide nociceptin (100 nmol/kg) produced a long-lasting protection from capsaicin desensitization of afferent nerves which mediate the chemoceptive micturition reflex. In fact a chemoceptive micturition reflex could be repeatedly evoked by topical capsaicin in nociceptin-pretreated rats. In sharp contrast, nociceptin did not influence the development of desensitization of the local response to capsaicin, corresponding to the 'efferent' function of capsaicin-sensitive afferent neurons. These results suggest that the afferent and 'efferent' function of capsaicin-sensitive primary afferent neurons (CSPANs) in the rat bladder are differentiated by nociceptin. Alternative mechanisms underlying this phenomenon are discussed.

Capsaicin-sensitive fibers are required for the anorexic action of systemic but not central bombesin.

Bombesin (BN) suppresses food intake in rats whether given centrally or systemically. Although the brain BN-sensitive receptors are known to be essential for the anorexic effect of systemic BN, the mode of communication between the gut and the brain remains unclear. This study assessed whether the anorexic effect of systemic BN is mediated humorally or via neural circuits. Afferent neurons were lesioned using capsaicin (50 mg/kg sc) on postnatal day 2, and responses to BN were assessed during adulthood. Capsaicin treatment decreased body weight gain significantly from postnatal age 4-7 wk. Peripheral BN (4-16 micrograms/kg ip) dose dependently suppressed food intake in control animals. However, this effect was completely blocked in capsaicin-treated rats. In contrast to systemic effects, feeding-suppressant effects of centrally administered BN (0.01-0.5 microgram icv) were not affected by capsaicin treatment. This research suggests that peripheral BN communicates with the brain via a neuronal system(s) whose afferent arm is constituted of capsaicin-sensitive C and/or Adelta-fibers, whereas the efferent arm of this satiety- and/or anorexia-mediating circuitry is capsaicin resistant.

Effects of Capsaicin and Capsaicin Desensitization on Alanine Accumulation in Rat Hemidiaphragms

1. Alanine accumulation in rat hemidiaphragms is significantly inhibited by capsaicin in a dose-dependent pattern that produced maximal effect at 1 mM. 2. The inhibitory effect of capsaicin on alanine accumulation by rat hemidiaphragms was enhanced upon preincubation with 5 mM ouabain. However, preincubation with 1 mM Verapamil did not alter the inhibitory effect of capsaicin. 3. Chemical ablation of the capsaicin-sensitive primary afferent fibers abolished the inhibitory effect of capsaicin on alanine accumulation in the rat hemidiaphragms.

Capsaicin-sensitive vagal fibers and mechanoreceptor-mediated inhibition of gastric emptying in the rat

Capsaicin-sensitive vagal fibers and mechanoreceptor-mediated inhibition of gastric emptying in the rat

A novel procedure for mediastinal vagotomy inhibits neurogenic inflammation in rat bronchial tree

Tachykinin-containing sensory axons originating from the cervical vagal nerves and the first several pairs of thoracic spinal nerves are involved in neurogenic inflammation evoked by capsaicin in the bronchial tree. Unilateral degeneration of the cervical vagal trunk by surgical lesion inhibits neurogenic inflammation in the ipsilateral bronchial airways. The vagal trunk has two main branches, the thoracic vagus nerve and recurrent laryngeal nerve in the thorax. The main purpose of this study was to determine whether the thoracic vagus nerve or recurrent laryngeal nerve was significantly involved in the neural control of bronchial inflammation in the rat. A novel and safe surgical procedure was used for selectively cutting the right thoracic vagal trunk, thoracic vagus nerve, or recurrent laryngeal nerve by introducing the surgical instrument through an aperture between the first and second ribs in the ventral wall of the rostral mediastinum. This surgical operation could be completed without causing a pneumothorax. After 2 postoperative weeks, the effects of denervation on capsaicin-induced plasma extravasation in the respiratory tract were tested. Either right thoracic vagal trunk transection or thoracic vagus section significantly decreased plasma extravasation in the right bronchial tree. Thoracic vagus section was obviously more effective. Evans blue extravasation in the right lobar bronchi was reduced by 44–78% after thoracic vagal trunk transection, while that in the right mainstem and lobar bronchi was reduced by 58–81% after thoracic vagus section. Area densities of India ink-labeled leaky blood vessels in the right lobar bronchi were reduced by 40–65% after thoracic vagal trunk transection, and those in the right mainstem and lobar bronchi were reduced by 83–88% after thoracic vagus neurectomy. Recurrent laryngeal neurectomy did not change the plasma extravasation induced by capsaicin in the trachea and bronchi. These results suggest that capsaicin-sensitive fibers running in the vagal trunk, which largely mediated neurogenic inflammation in the bronchial tree, were projected into the thoracic vagus nerve which, in turn, sent these nerve fibers to the ipsilateral bronchial tree. For the trachea, the remaining sensory fibers surviving denervation might provide sufficient tachykinins to trigger neurogenic inflammation.

Role of capsaicin-sensitive afferent nerves in initiation and maintenance of pathological pain

This commentary provides experimental data in support of the critical role of capsaicin-sensitive primary afferent fibers in the initiation and maintenance of pathological pain. The demonstration of capsaicin-induced, centrally-evoked cutaneous hyperalgesia, and of neuroplastic changes elicited by the degeneration of C-fiber primary afferent terminals following peripheral nerve damage, indicates a significant contribution of capsaicin-sensitive sensory ganglion neurons in the development of pathological pain conditions. [coderre &amp; katz]

Effect of amylin in various experimental models of gastric ulcer

Subcutaneous administration of amylin (20 to 40 μg/kg) prevented, in a dose-dependent manner, reserpine- and serotonin-induced gastric damage, but the anti-ulcer effect was not present when lesions were induced by pylorus ligation. The protective effect of amylin was inhibited by pretreatment with capsaicin as well as CGRP-(8-37), a calcitonin gene-related peptide (CGRP) and amylin receptor antagonist, and was significantly reduced by domperidone, a dopamine D 2 receptor antagonist, or neostigmine, an inhibitor of acetylcholinesterase. Our data suggest that the gastroprotective activity of amylin in some experimental models of gastric ulcers involves capsaicin-sensitive fibers and CGRP receptors. Moreover, the peptide interferes, at least in part, with the dopaminergic and parasympathetic systems.

Mechanisms mediating gastric hyperemic and acid responses to central TRH analog at a cytoprotective dose.

Gastric hyperemic and acid responses to the stable thyrotropin-releasing hormone (TRH) analog RX-77368 injected intracisternally at a cytoprotective dose were investigated, as well as the underlying mechanisms of the responses. Gastric acid secretion (GAS), mucosal blood flow (GMBF; measured by the hydrogen gas clearance technique), and mucosal vascular resistance (GMVR) and mean arterial pressure (MAP) were assessed simultaneously for 30 min before and after RX-77368 (1.5 ng) administration in urethan-anesthetized rats. RX-77368 increased GMBF from 46.8 +/- 5.3 to 100.6 +/- 20.9 ml.min-1.100 g-1 and MAP from 70.3 +/- 2.1 to 84.3 +/- 5.9 mmHg and decreased GMVR from 1.50 +/- 0.33 to 0.84 +/- 0.08 mmHg.ml-1.min.100 g, whereas GAS was not significantly altered (1.8 +/- 0.4 vs. 4.7 +/- 1.7 mumol/30 min) in vehicle-pretreated rats. The GMBF, MAP, and GMVR responses to RX-77368 were not modified by indomethacin (5 mg/kg ip), whereas GAS was increased. In rats pretreated with capsaicin (125 mg/kg sc) or calcitonin gene-related peptide (CGRP) antagonist hCGRP-(8-37), intracisternal RX-77368 did not increase GMBF or decrease GMVR but did stimulate GAS. These data show that vagal stimulation by the TRH analog RX-77368 injected intracisternally at a nonacid secretory dose increases GMBF. Gastric hyperemia is mediated by CGRP contained in capsaicin-sensitive afferent fibers, whereas acid secretion is under the inhibitory influence of prostaglandins and CGRP.

Capsaicin and the stomach. A review of experimental and clinical data

Capsaicin, the pungent principle of hot pepper, because of its ability to excite and later defunctionalize a subset of primary afferent neurons, has been extensively used as a probe to elucidate the function of these sensory neurons in a number of physiological processes. In the rat stomach, experimental data provided clear evidence that capsaicin-sensitive (CS) sensory nerves are involved in a local defense mechanism against gastric ulcer. Stimulation of CS sensory nerves with low intragastric concentrations of capsaicin protected the rat gastric mucosa against injury produced by different ulcerogenic agents. High local desensitizing concentrations of capsaicin or systemic neurotoxic doses of the agent markedly enhanced the susceptibility of the rat gastric mucosa to later noxious challenge. Resiniferatoxin, a potent analogue of capsaicin possesses an acute gastroprotective effect similar to that of capsaicin in the stomach. The gastroprotective effect of capsaicin-type agents involves an enhancement of the microcirculation effected through the release of mediator peptides from the sensory nerve terminals with calcitonin gene-related peptide being the most likely candidate implicated. They do not depend on vagal efferent or sympathetic neurons or involve prostanoids. The gastric mucosal protective effect of prostacyclin is retained after systemic or topical capsaicin desensitization. Capsaicin-sensitive fibers are involved in the repair mechanisms of the gastric mucosa. A protective role for CS sensory nerves has also been demonstrated in the colon. In most studies, capsaicin given into the stomach of rats or cats inhibited gastric acid secretion. In humans, although recent studies provide evidence in favor of a beneficial effect of capsaicin on the gastric mucosa, an exact concentration-related assessment of the effect of the agent is still lacking.