High-dose Capsaicin Research Articles

A calcitonin gene‐related peptide (CGRP) antagonist (CGRP8–37) inhibits microvascular responses induced by CGRP and capsaicin in skin

1. The effect of the calcitonin gene-related peptide (CGRP) antagonist CGRP8-37 on responses to CGRP and other mediators was investigated in rabbit dorsal skin. 2. Blood flow changes at intradermally-injected sites were measured by a multiple site 133xenon clearance technique. CGRP8-37 had little effect on blood flow at doses up to 0.3 nmol/site, when injected alone, although a significant increase in blood flow was observed at the highest dose tested (1 nmol/site). 3. CGRP8-37 dose-dependently inhibited the increased blood flow induced by human alpha CGRP and human beta CGRP, but had no effect on equivalent vasodilator responses induced by vasoactive intestinal peptide (VIP) and prostaglandin E1 (PGE1). CGRP8-37 showed a preferential ability to inhibit alpha CGRP (IC50 0.04 nmol), when compared with beta CGRP (IC50 greater than or equal to 0.3 nmol). 4. Capsaicin, which selectively activates sensory nerves, caused a dose-dependent increase in blood flow when injected intradermally into rabbit skin. The effects of capsaicin (0.01-0.1 mumol/site) were inhibited by CGRP8-37 (0.3 nmol/site), with a partial but significant attenuation of blood flow induced by the highest dose of capsaicin. 5. Oedema formation, induced by intradermal histamine injection (3 nmol/site), was measured in rabbit skin by the local accumulation of intravenously-injected 125I-labelled albumin. Vasodilator doses of CGRP, PGE1 and capsaicin potentiated, in a synergistic manner, oedema formation induced by histamine. GRP8-37 totally inhibited the potentiating effect of CGRP, partially inhibited the synergistic effect of capsaicin, but did not affect PGE1-induced responses.6. The results suggest that capsaicin acts to release a rabbit form of CGRP in skin and that CGRP8 37 is a useful antagonist for investigating the potential of CGRP as a neurogenic mediator of inflammation.

Capsaicin-induced release of tachykinins: effects of enzyme inhibitors

We studied the effects of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE) inhibition on the airway responses and the recovery of endogenously released substance P- and neurokinin A-like immunoreactivities (SP-LI and NKA-LI) after tracheal injection of capsaicin in isolated guinea pig lungs superfused through the trachea. Capsaicin in doses from 10(-10) to 10(-7) mol induced a dose-dependent increase in airway opening pressure and release of SP-LI and NKA-LI. Airway opening pressure changes and the recovery of SP-LI and NKA-LI were significantly greater in lungs superfused with the NEP inhibitor SCH 32615 than in control lungs. ACE inhibition with captopril did not increase the mechanical response or the recovery of SP-LI compared with lungs not receiving captopril. In lungs from guinea pigs pretreated with high doses of capsaicin 7-10 days before study, a regimen designed to deplete endogenous tachykinins, there was a significant decrease in the content and release of NKA-LI and SP-LI. There were no detectable airway effects of acute capsaicin infusion even after doses of 10(-5) mol. Because NEP is important in modulating the airway effects of endogenously released tachykinins after tracheal infusion of capsaicin, but ACE is not, it seems likely that tracheal administration of capsaicin releases tachykinins from epithelial rather than endothelial loci.

Chemical activation of thin-fiber phrenic afferents: respiratory responses

In supine chloralose-anesthetized and mechanically ventilated dogs, we assessed the effects of group III and IV thin-fiber phrenic afferents on cardiorespiratory control by injecting capsaicin into the phrenic artery of an in situ isolated and innervated left diaphragm. Inspiratory motor drive was assessed by measuring the electromyogram of left and right diaphragm, left parasternal, and mylohyoid muscles in five protocols. 1) Three boluses (2 ml) of capsaicin (1, 10, and 50 micrograms/ml) were injected 30 min apart. Only the 50-micrograms/ml injection elicited a significant increase in arterial pressure, heart rate, and inspiratory motor drive. 2) Repeated doses of capsaicin were tested. The pressor and hyperpneic responses were weakened. 3) High doses of capsaicin (100 and 500 micrograms/ml) were given. Hyperpneic and pressor responses were similar to those elicited by the 50-micrograms/ml dose. 4) When the left phrenic nerve was sectioned, the pressor and hyperpneic responses to the 50-micrograms/ml injection were abolished. 5) Capsaicin (50 micrograms/ml) was infused into the arterial supply of the in situ vascularly isolated and innervated gastrocnemius. Arterial pressure, breathing frequency, and inspiratory motor drive to all inspiratory muscles increased significantly and to a greater degree than in the diaphragm. In conclusion, diaphragmatic thin-fiber afferents have an excitatory effect on the inspiratory motor drive and arterial pressure that is similar to that seen in limb muscles.

Influence of capsaicin‐sensitive afferent neurones on the acid secretory responses of the rat stomach in vivo

1. The influence of capsaicin-sensitive afferent neurones in modulating acid-secretory responses has been investigated in the continuously perfused stomach of the anaesthetized rat. 2. Ablation of primary afferent neurones, after systemic neonatal pretreatment with high doses of capsaicin, did not modify acid responses to direct stimuli of the oxyntic cell with histamine (5 mg kg-1), pentagastrin (20 micrograms kg-1) or carbachol (4 micrograms kg-1). 3. Acid responses to hypoglycaemia induced by insulin (0.3 iu kg-1) were not influenced by systemic capsaicin pretreatment or by acute coeliac ganglionectomy. Vagotomy abolished this secretory response. 4. The increase in acid output induced by gastric distension (20 cmH2O) was abolished by systemic neonatal capsaicin pretreatment. Likewise, vagotomy and acute coeliac ganglionectomy eliminated this secretory response. 5. Acute intragastric infusion with high doses of capsaicin inhibited the acid responses to distension but failed to modify the increase in acid output induced by insulin. 6. Local application (7-14 days before) of capsaicin to the coeliac ganglion abolished the acid response to gastric distension. This lack of secretory response was not the result of a nonspecific destruction of the ganglion, since changes in intragastric pressure after electrical stimulation of the coeliac ganglion were unaffected by such treatment. 7. These observations indicate that peripheral capsaicin-sensitive sensory neurones, located both in the gastric mucosa and in the coeliac ganglion, play a physiological role in the acid secretory responses to gastric distension.

Cholinergic and C-Fibre Mediated Mechanisms in the Stimulation of Mucociliary Activity Induced by Prostaglandins and Histamine

The involvement of cholinergic and C-fibre mediated mechanisms in the stimulation of mucociliary activity induced by prostaglandins and histamine was investigated in vivo in the rabbit maxillary sinus with a photoelectric technique. The prostaglandins E, (PGE,) and F2(2) alpha (PGF2 alpha) in dose of 0.1 microgram/kg and 10 micrograms/kg respectively stimulated the mucociliary activity in a biphasic fashion, with a small initial response during the first 1-2 min and a later maximum response after 3-4 min. These effects were resistant to atropine and to the SP antagonist (D-Pro2, D-Trp7,9)SP. The small initial response was blocked by pretreatment with high doses of capsaicin (13 mg i.a.), while the maximum response was unaffected. This indicates that the mucociliary responses induced by PGE, and PGF2 alpha involve capsaicin-sensitive C-fibres but that neither acetylcholine nor substance P were responsible. Histamine (50 micrograms/kg) stimulated mucociliary activity in the rabbit maxillary sinus and the effect was abolished by pretreatment with high doses of capsaicin and reduced by the SP antagonist (D-Pro2, D-Trp7,9)SP. This indicates that the histamine-induced stimulation of mucociliary activity involves capsaicin-sensitive C-fibres and that the effect might be mediated by substance P.

Inflammatory effects of acute and chronic capsaicin treatment on rat paw

AbstractCapsaicin extracted from natural sources (Capsicum frutescens) and standard capsaicin (Sigma Chemicals) were used in this study. On acute treatment capsaicin produced a dose‐related inflammatory response in rat paw as measured by the volume displacement method. This response was found to be synergestic when injected with carrageenan. Preliminary experiments showed that pretreatment with diphenhydramine‐HCl produced a significant inhibition of this acute capsaicin induced paw oedema, whereas indomethacin and methysergide were ineffective in blocking paw oedema. On the other hand, chronically capsaicin treated rats (for 10 days) showed a significant inhibition of paw oedema when treated with either carregeenan or a single high dose of capsaicin. Both the extracted and the standard capsaicin showed a similar type of response in all experiments.

Role of vagal and sympathetic afferents in reflex respiratory responses to capsaicin in dogs.

The respiratory responses following stimulation of type J (pulmonary C fiber) receptors by right atrial injections of capsaicin were assessed in spontaneously breathing anesthetized dogs. At the reflexly effective threshold dose, the primary respiratory response elicited was tachypnoea. With higher doses of capsaicin, the tachypnoea was replaced by apnoea. Left atrial injections of capsaicin also resulted in apnoea, which was abolished or reduced by injecting Xylocaine into the pericardial sac, and after vagotomy, apnoea was replaced by tachypnoea. The latter findings suggested that the apnoea produced by left atrial injection of capsaicin might be due to stimulation of receptors with vagal afferents coursing through the pericardium. In vagotomized dogs, administration of capsaicin into the abdominal aorta above the origin of the iliac arteries (the iliac arteries were kept occluded) resulted in a hyperpnoeic response. Following the transection of the spinal cord between L4 and L5, capsaicin injection into the abdominal aorta caused apnoea instead of hyperpnoea. The apnoeic response elicited was abolished by transecting the spinal cord between L1 and L2. It is suggested that the respiratory responses observed were due to stimulation of receptors in the splanchnic bed connected to sympathetic afferents.

Reversal of the relation between respiratory drive and airway tone in cats

To examine the relationship between respiratory drive and airway tone in the exercise pressor reflex in the cat, we recorded tension in a tracheal segment and activity in the phrenic nerve, before and after injecting capsaicin in various doses (0.3–20 μg/kg) into the femoral artery. Injection of all doses of capsaicin relaxed the tracheal segment. However, high doses of capsaicin evoked neural apnea followed by increased phrenic nerve activity whereas low doses evoked only increased phrenic nerve activity. All responses wre abolished by cutting hindleg nerves. We were certain that relaxation was due to decreases of parasympathetic bronchoconstrictor activity and not to increases in activity of other inhibitory pathways, because we found no change in capsaicin-evoked relaxation after β-adrenergic blockade with propranolol and no capsaicin-evoked relaxation after muscarinic blockade with atropine and restoration of tone with 5-hydroxytryptamine. These results provide good evidence that injecting capsaicin into the femoral artery reverses the direct relation between respiratory drive and airway tone and does so by decreasing parasympathetic bronchoconstrictor activity.

Capsaicin-induced excitation of locus coeruleus neurons.

The noradrenergic pontine nucleus locus coeruleus (LC) seems to be involved in sensory processing. In the present study, the effect of capsaicin, a drug which specifically interferes with chemosensitive primary afferents, on LC firing rate was analysed, utilizing electrophysiological techniques. In control rats, low doses of capsaicin (1-8 micrograms kg-1 i.v.) caused a marked excitation of LC units. The effect was instantaneous in onset but short-lasting and no signs of tachyphylaxis were observed. The excitation was maintained in adult rats treated as neonates with high doses of capsaicin (50 mg kg-1 s.c.) but almost totally prevented by pretreatment of adult rats with high doses of capsaicin (300 mg kg-1 s.c.). According to our histological data, using selective silver impregnation techniques, the LC seems not to receive innervation by sensory primary afferents. It is proposed that the capsaicin-induced excitation of LC neurons is a centrally mediated effect and might, in part, be involved in the analgetic effect induced by the drug.

Characterization of the peptide and sensory neurotoxic effects of capsaicin in the guinea pig

The effects of capsaicin, the major pungent ingredient of hot peppers, were assessed on sensory neuron neuropeptide levels and on sensory function in the adult guinea pig. Systemic doses of capsaicin as low as 2.5 mg/kg depleted substance P (SP) in dorsal roots plus ganglia (DRG) whereas a 10-mg/kg dose depleted the peptide maximally in DRG and in the dorsal spinal cord. High doses of capsaicin had no consistent effects on levels of cholecystokinin (CCK), vasoactive intestinal polypeptide, or somatostatin, although a transient decrease in CCK levels was observed 4 days after dosing. A single 5-mg/kg dose of capsaicin rendered animals completely insensitive to chemical irritation of the cornea without affecting sensitivity to noxious heat. Higher doses of capsaicin produced a marked insensitivity to nociceptive and non-nociceptive heat as well as to chemical irritation without affecting other sensory modalities. The SP depletion and sensory deficits produced by a single 50-mg/kg dose of capsaicin were still evident 10 weeks later. The pattern of selectivity of the sensory deficits produced by capsaicin differed from that produced by morphine which was active against all forms of nociceptive stimuli. The results indicate that in the guinea pig capsaicin is potent at producing a unique, long-lasting syndrome of peripheral sensory deficits that may result from an effect of the agent on SP-containing primary afferent neurons.

Effects of neonatal capsaicin treatment on nociceptive thresholds in the rat

The responsiveness to noxious thermal, mechanical, and chemical stimuli was examined in adult rats that had been treated neonatally with capsaicin. A range of capsaicin doses was employed to determine whether the neurotoxicity of capsaicin to primary afferent fibers would be manifested behaviorally in a selective effect on nociceptive thresholds to specific stimuli. Animals were given 5 to 100 mg/kg of capsaicin at 2 days of age and were examined 2 to 4 months later using the tail flick and hot plate tests to determine thermal thresholds, the paw pressure test to determine mechanical thresholds, and the formalin test to determine chemical thresholds. Significant impairments of treated animals' responses to all three types of stimuli were found at high doses of capsaicin and at doses which seem to lead to the depletion of only unmyelinated primary afferent fibers. Slightly higher doses of capsaicin were required to increase thermal nociceptive thresholds in the tail flick test as compared with the other tests, and mechanical nociception seemed to be the most sensitive to the effects of capsaicin. At any particular dose of capsaicin, considerable variability was found in the responsiveness of animals to noxious stimuli. This may partly explain the inconsistencies in studies of nociceptive thresholds in capsaicin-treated animals. The results also demonstrate the difficulty of correlating the degree of analgesia exhibited by these animals with the extent of loss of primary afferent fibers or with the depletion of afferent putative peptide transmitters.

Dose-dependent effects of capsaicin on primary sensory neurons in the neonatal rat

The numbers of myelinated and unmyelinated fibers were counted in dorsal roots of adult rats treated neonatally with capsaicin in doses ranging from 5 to 100 mg/kg. Substance P and somatostatin levels in the spinal cord, dorsal roots, and sensory ganglia also were determined in control and treated animals. Capsaicin administration lead to the loss of both small myelinated and unmyelinated fibers from dorsal roots. However, whereas a near total loss, up to 94%, of unmyelinated fibers was achieved after high doses of capsaicin, the reduction of myelinated fibers, even of the smallest caliber, did not exceed 40%. The degree of fiber loss showed a clear dose dependency, with little detectable damage to myelinated fibers at doses of less than 50 mg/kg and with an ED50 for damage to unmyelinated fibers of 5 to 10 mg/kg. In all of the structures examined, particularly the dorsal roots, a roughly parallel decrease of substance P and somatostatin was found with capsaicin dose. The depletions of spinal cord substance P (55%) and somatostatin (20%) produced by neonatal capsaicin treatment were similar to those produced by dorsal rhizotomy. Capsaicin does not appear to be specific for primary afferents containing either substance P or somatostatin.

Nociceptor stimulation and PGE release by capsaicin.

1. Intraarterial injection of capsaicin (threshold dose 0.3 μg) into the isolated perfused rabbit ear causes a dose-dependent reflex fall in blood pressure by stimulation of chemosensitive nociceptors. 2. Infusion of capsaicin (1 and 10 μg/ml) into the isolated rabbit ear dose-dependently stimulates prostaglandin biosynthesis, equally in innervated and chronically denervated preparations, therefore mainly in extraneuronal tissue. The capsaicin-induced prostaglandin E release is dependent on the presence of extracellular Ca2+. 3. The nociceptive reflex fall in blood pressure induced by i.a. injection of bradykinin is progressively enhanced under infusion of 1 μg/ml capsaicin whereas that induced by acetylcholine is not. Its enhancement is explained by the capsaicin-induced increased amount of prostaglandin E at the nociceptor sites. 4. Infusion of 10 μg/ml capsaicin renders the nociceptors insensitive to effects of bradykinin and acetylcholine. 5. Although the stimulation of nociceptors by capsaicin in a small dose includes the release of prostaglandin E from the surrounding tissue, it cannot be said whether a prostaglandin-mediated mechanism is also involved in the long lasting functional impairment of chemosensitive fibres induced by high doses of capsaicin.