Capsaicin-sensitive Afferent Fibers Research Articles

Stimulation of capsaicin-sensitive sensory fibers induces vasodilation in rat mesenteric bed

Stimulation of capsaicin-sensitive sensory fibers induces vasodilation in rat mesenteric bed

Vascular effects of capsaicin in isolated perfused rat mesentric bed

The effects of intra- and extraluminal capsaicin administration were evaluated in isolated perfused rat mesenteric bed. Capsaicin (10 nM-1 μM) produced a potent concentration-dependent relaxation of the tonic vasoconstriction induced by norepinephrine (1 μM) but not by high-K + (60 mM). The capsaicin-induced relaxation was nearly abolished in preparations pretreated in vitro with a high concentration of capsaicin (1 μM, for 10 min, 1 h before). Capsaicin-induced relaxation was reduced but not abolished in preparations obtained from rats pretreated neonatally with capsaicin. The capsaicin effects were unaffected by atropine, guanethidine, propranolol, hexamethonium or tetrodotoxin. The observation that capsaicin (0.1 μM)-induced relaxation was virtually abolished in presence of the proteolytic enzyme α-chymotrypsin (1 U/ml) supports the involvement of neuropeptide(s) in this response. Bolus injections of calcitonin gene-related peptide (CGRP) elicited a potent and rapidly ensuing relaxation which underwent tachyphlaxis. However, no cross-desensitization with capsaicin was observed. It is concluded that activation of capsaicin-sensitive sensory fibers could release neuropeptides locally with a potent effect on intestinal blood flow.

Sensory fibres modulate histamine-induced catecholamine secretion from the rat adrenal medulla and sympathetic nerves.

1. We have studied the mechanism of catecholamine secretion induced by histamine from the adrenal medulla and sympathetic noradrenergic neurones in the rat, and the role of capsaicin-sensitive sensory nerves in this secretion. 2. Histamine at a dose of 1 mg/kg induced adrenaline and noradrenaline secretion by a non-neurogenic mechanism. In contrast, at a dose of 3 mg/kg it induced adrenaline and noradrenaline secretion by both non-neurogenic and neurogenic mechanisms. 3. The adrenaline released in response to histamine at 3 mg/kg was exclusively of adrenal origin whereas the noradrenaline released was of non-adrenal origin (most probably noradrenergic sympathetic nerves). As with its action on the adrenal, histamine induced noradrenaline secretion from these extra-adrenal tissues by both neurogenic and non-neurogenic mechanisms. 4. When adrenaline secretion from the adrenal gland was impaired by adrenal denervation and/or adrenalectomy, the plasma noradrenaline secretion was increased. This is most probably due to compensation from the rest of the sympathetic nervous system. This compensatory increase in noradrenaline was abolished by hexamethonium, which indicates that it was mediated by a cholinergic mechanism. 5. Pre-treatment of rats as neonates subcutaneously with capsaicin (a selective neurotoxin for certain sensory nerves) at a dose of 50 mg/kg, had no effect on the non-neurogenic secretion of catecholamine induced by histamine. In contrast, capsaicin pre-treatment abolished the neurogenic catecholamine secretion in response to histamine as well as the neurogenic compensatory increase in plasma noradrenaline levels that occurred when adrenaline secretion by the adrenal gland was impaired. 6. In the present study, by using histamine as a form of stress, we have been able to provide evidence not only (a) to confirm a role for capsaicin-sensitive sensory fibres in modulating neurogenic adrenaline secretion from the adrenal gland, but also (b) to suggest a similar role for these fibres in modulating neurogenic noradrenaline release from sympathetic noradrenergic nerves in response to histamine and in response to impairment of adrenaline secretion by the adrenal gland.

Capsaicin‐induced inhibition of motility of the rat isolated vas deferens: do multiple neuropeptides mediate the visceromotor effects of capsaicin?

1 The effects of capsaicin have been investigated in the field-stimulated (0.1 Hz) or unstimulated rat isolated vas deferens and compared with those of some neuropeptides (neurokinins, calcitonin gene-related peptide (CGRP) putatively stored in capsaicin-sensitive sensory fibres. 2 Capsaicin (0.01-3 microM) produced a concentration-related transient inhibition of the field-stimulation-induced twitches. This effect was characterized by marked desensitization and could not be elicited in preparations excised from capsaicin-pretreated rats (50 mg/kg s.c., 4 days before). The amplitude of the nerve-mediated twitches was unaffected by capsaicin-desensitization. 3 Neurokinins (substance P, Kassinin) produced a potentiation of the nerve-mediated contractions while CGRP had a potent inhibitory effect. In the presence of Kassinin, CGRP still inhibited twitches although the time course of this inhibitory effect was delayed as compared to controls. 4 In the unstimulated rat vas deferens neither capsaicin (3 microM) nor CGRP (0.1 microM) had any significant motor effect. However, when phasic contractions were initiated by previous exposure to Kassinin (0.2 microM), both capsaicin (3 microM) or CGRP (10-100 nM) had a prompt inhibitory effect. Capsaicin inhibition exhibited a marked desensitization while the effect of CGRP was still evident after capsaicin-desensitization. 5 The inhibitory effect of capsaicin or CGRP on the Kassinin-stimulated rhythmic contractions of the rat isolated vas deferens was unaffected by a previous exposure to tetrodotoxin (0.5 microM). 6 Storage at 4 degrees C for 24 h produced a 65% reduction of the response of the rat isolated vas deferens to nerve-stimulation. The residual response was tetrodotoxin-sensitive and could be potentiated by Kassinin (0.2 microM) or inhibited by CGRP (10-100 nM) as observed in controls. In these preparations the inhibitory effect of capsaicin (3 microM) was significantly reduced (approximately equal to 50%) and in some preparations abolished, as compared to controls. 7 These findings indicate the existence, in the rat isolated vas deferens, of capsaicin-sensitive sensory innervation which, upon chemical stimulation, releases, through a tetrodotoxin-insensitive mechanism, a substance(s) which inhibits motility at postjunctional level. CGRP is a possible candidate for the role of inhibitory sensory transmitter released from capsaicin-sensitive nerve endings in this preparation.

Epicardial application of bradykinin elicits pressor effects and tachycardia in guinea pigs. Possible mechanisms

Topical application of bradykinin (BK) to the surface of the left ventricle (epicardial application) of anesthetized guinea pigs elicited dose-dependent pressor effects and tachycardia. The pressor effect of epicardial BK was reduced by prior systemic treatment of animals with pentolinium or a combination of phentolamine and propranolol, but it was not affected by acute bilateral vagotomy or systemic administration of atropine, indomethacin, naloxone or a combination of mepyramine and cimetidine. The tachycardia caused by epicardial BK was not affected by any of the aforementioned drugs or by section of the vagi. Both the pressor effect and tachycardia evoked by epicardial BK were abolished by prior epicardial application of lidocaine, a local anesthetic, or by chronic systemic capsaicin treatment. These results suggest that the pressor effect of epicardial BK is partially reflex in nature and likely to result from the stimulation by BK of cardiac sympathetic, capsaicin-sensitive primary afferents, whereas the tachycardia caused by epicardial BK could be mediated by an intracardiac release of (a) cardioaccelerating substance(s) from cardiac, capsaicin-sensitive sensory nerve fibers and/or terminals.

The contribution of capsaicin-sensitive innervation to activation of the spinal vesico-vesical reflex in rats: relationship between substance P levels in the urinary bladder and the sensory-efferent function of capsaicin-sensitive sensory neurons

In acute spinal rats (C 2–C 3) the transvesical infusion of saline activates a vesico-vesical excitatory reflex (Brain Res., 380 (1986) 83–93). In bladders containing a subthreshold amount of fluid the topical application of capsaicin on the outer surface of the bladder dome activated this spinal reflex and also produced a transient rise in blood pressure and heart rate. The effects of systemic capsaicin desensitization (50 mg/kg s.c. 5 min, 60 days before) on the sensory (activation of the spinal vesico-vesical reflex) and ‘efferent’ (tetrodotoxin-insensitive capsaicin-induced contraction) functions mediated by the capsaicin-sensitive sensory fibers were correlated to changes in substance P-like immunoreactivity (SP-LI) content of the urinary bladder in adult rats. Blockade of both sensory and efferent functions was observed at a time (60 min from capsaicin administration) when the SP-LI content of the urinary bladder was unaffected. Four days after capsaicin desensitization the SP-LI levels of the bladder are almost depleted indicating that the neuropeptide(s) are entirely stored in sensory structures. At this time the sensory-efferent functions mediated by these fibers are still blocked. At 15–60 days from systemic capsaicin desensitization there was a progressive, time-related recovery of SP-LI levels in the bladder as well as of the sensory-efferent functions. These findings indicate a role of the capsaicin-sensitive innervation of the urinary bladder in activating the spinal vesico-vesical reflex. The present findings suggest that measurement of SP-LI levels in the rat bladder may be a useful biochemical index for monitoring the function(s) of the capsaicin-sensitive, peptidergic sensory neurons.

Blockade by theophylline of capsaicin-induced motor effects in guinea-pig airways

The effect of theophylline was tested on the capsaicin-induced (a) increase in insufflation pressure in anaesthetized guinea-pigs and (b) contraction of isolated tracheal spirals. Theophylline (6.25–25 mg/kg i.v.) inhibited in a marked, prolonged and dose-related manner the increase in insufflation pressure elicited by i.v. injection of capsaicin (2–10 μg/kg). Theophylline, even at plasma concentrations as low as 15–23 μg/ml (which are within or slightly higher than the therapeutic range in humans) produced an inhibition of about 30–50% of capsaicin-induced bronchospasm. Theophylline was significantly less effective in antagonizing the bronchospasm elicited by maximally effective dose (100 μg/kg i.v.) of acetylcholine as well as by a dose equieffective to capsaicin 10 μg/kg (i.e. acetylcholine 50 μg/kg). Theophylline (30 μM-1 mM) also inhibited potently and concentration dependently the capsaicin-induced contraction in vitro and, again, it was significantly less effective against cholinomimetic-induced responses. These data suggest that theophylline can interfere, at therapeutic doses, with some process(es) selectively involved in capsaicin-induced neuropeptide-mediated bronchoconstriction. Since capsaicin-sensitive sensory fibers are thought to be involved in the pathogenesis of bronchial hyperreactivity and asthma, these inhibitory actions of theophylline might be relevant for its therapeutic effects.

Selective degeneration by capsaicin of a subpopulation of primary sensory neurons in the adult rat

The morphological effects of systemic capsaicin treatment have been studied in adult rats. Light and electron microscopy revealed that a subpopulation of small-to-medium sized B-type primary sensory neurons, representing about 17% of the total neuronal population in the 4th lumbar spinal ganglion, underwent rapid degeneration after the administration of capsaicin. Quantitative electron microscopy demonstrated a decrease of about 45% in the number of unmyelinated axons in the saphenous nerve. Light microscopy showed extensive axon terminal degeneration in the brainstem and spinal cord confined to the central projection areas of capsaicin-sensitive afferent fibers, as has already been revealed in the newborn rat. The present results furnish evidence for a hitherto unrecognized selective neurodegenerative action of capsaicin in the adult rat.

Vascular permeability changes and smooth muscle contraction in relation to capsaicin-sensitive substance P afferents in the guinea-pig.

The occurrence of neurogenic inflammation as indicated by Evans blue extravasation was studied in various organs of the guinea-pig. Electrical stimulation of the trigeminal nerve caused Evans blue extravasation due to increased vascular permeability in the nasal mucosa and gingiva. Vagal stimulation induced extravasation in the epiglottis, larynx, trachea, bronchial tree and esophagus. Splanchnic stimulation induced Evans blue extravasation in the gall bladder, bile ducts and superior mesenteric artery. Stimulation of the inferior mesenteric ganglion caused a marked extravasation in the upper and middle part of both ureters, while pelvic activation induced a reaction in the lower ureter, urinary bladder, urethra and vagina. I.v. substance P (SP) (3 nmol X kg11) or capsaicin (1 mumol X kg-1) both induced extravasation in many tissues including those in which nerve stimulation produced a response. The extravasation responses to SP, capsaicin or nerve stimulation all had similar border-line zones, such as esophagus to stomach, bile ducts to duodenum, rectum to anal mucosa, pulmonary artery to heart and vagina to uterus. Quantitative determinations showed especially large permeability effects in the trachea, umbilical ligament and ureter. The permeability effect of capsaicin and nerve stimulation was abolished in capsaicin-pretreated animals, while the response to SP was still present. Capsaicin pretreatment caused an almost total loss of SP in several visceral organs including the respiratory and urinary tracts. The SP content in these tissues was correlated (r = 0.97) to the Evans blue extravasation following nerve stimulation or i.v. capsaicin. SP and capsaicin caused contractions in vitro of the esophagus, ureter, urinary bladder, trachea and gall bladder. The capsaicin-induced contraction of the trachea was resistant to tetrodotoxin pretreatment. The non-cholinergic, non-adrenergic contraction of the urinary bladder upon field stimulation was still present in capsaicin-pretreated animals. In conclusion, neurogenic inflammation occurs in several organs with a highly region-specific distribution, which is accompanied by the presence of capsaicin-sensitive SP neurons. Both parasympathetic and sympathetic pathways contain capsaicin-sensitive afferent fibres which mediate an increase in vascular permeability most likely by releasing SP. In addition, both capsaicin and SP cause smooth muscle contraction in several visceral organs.

Reflex fall in blood pressure mediated by capsaicin-sensitive afferent fibers of the rat splanchnic nerve.

1. Capsaicin treated rats, in which the function of substance P-containing primary sensory neurons was impaired, were used to investigate the function of afferent fibers within the splanchnic nerve. The effects of electrical stimulation of the splanchnic nerve either distal or proximal to the site of its transsection on blood pressure and heart rate were investigated. 2. Distal splanchnic nerve stimulation evoked an equal rise in blood pressure in capsaicin treated rats and in their controls. Distal splanchnic nerve stimulation did not cause plasma extravasation in the adrenal medulla, an effect which is produced by antidromic stimulation of cutaneous sensory nerves. Peripheral effects of stimulation of primary afferent fibers within the splanchnic nerve cannot be assumed from these experiments. 3. Proximal stimulation of the splanchnic nerve evoked a reflex fall in blood pressure but no bradycardia. The fall in blood pressure was absent in capsaicin treated rats, which indicates that this effect is mediated by primary afferent fibers. Since the reflex fall in blood pressure was abolished by adrenergic blockade with guanethidine, it can be explained by vasodilatation resulting from reduction of sympathetic vasoconstrictor tone.