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PubMed1991

Capsaicin-sensitive bronchopulmonary receptors with dual sensory-efferent function: mode of action of capsaicin antagonists.

It has been suggested that capsaicin-sensitive interoceptors subserve dual sensory-efferent function in sense of being sites not only for initiating sensory impulses but also for release of mediators. The efferent response of smooth muscle contraction to capsaicin was analyzed in vitro on the trachea and main bronchi of the guinea-pig. Tetrodotoxin-resistant neurogenic contraction of the trachea evoked by capsaicin was inhibited by pretreatment of the tissue with the mast cell depleting agent of compound 48/80. Pretreatment of the preparation with indomethacin or with antagonists of histamine and 5-HT caused no changes in the responses. Electrical field stimulation of the nerve fibres in the main bronchi induced prolonged capsaicin-sensitive bronchoconstriction. Participation of mast cells and particularly leukotrienes in the responses is suggested. Sensory effect and site of action of capsaicin and its antagonists at the pulmonary receptors were tested in vivo by recording the Bezold-Jarisch reflex in the rat. Ruthenium red (0.5-2 mg/kg i.v.) and resiniferatoxin (0.1 micrograms/kg i.v.) did not evoke the vagal reflex triad of bradycardia, fall in blood pressure and apnoea, but antagonized the effect of capsaicin. The cardiorespiratory reflex triad evoked by stimulation of the regenerative region of the receptors by veratridine was not inhibited by ruthenium red. Furthermore, bradycardia evoked by electrical stimulation of the vagal nerve remained unchanged after pretreatment of the rat with either ruthenium red or resiniferatoxin. It is suggested that capsaicin excites the generator region of the receptors. Ruthenium red and resiniferatoxin antagonize its effect at different sites of the capsaicin receptor coupled cation channel.

Animals↗

PubMed1991

Different pathways by which extracellular Ca2+ promotes calcitonin gene-related peptide release from central terminals of capsaicin-sensitive afferents of guinea pigs: effect of capsaicin, high K+ and low pH media.

Different modes by which Ca2+, entering the nerve terminal, promotes transmitter secretion as well as the ability of protons to release neuropeptides, have been shown in peripheral endings of capsaicin-sensitive afferents. We have studied these two aspects in the central endings of these neurons by measuring the release of calcitonin-gene related peptide-like immunoreactivity (CGRP-LI) from slices of the dorsal half of the guinea pig spinal cord. Although capsaicin (1 microM) released both CGRP-LI and substance P-like immunoreactivity (SP-LI), CGRP-LI was chosen as the sole suitable marker of peptides released from central terminals of capsaicin-sensitive afferents, since after in vitro desensitization to capsaicin (1 microM capsaicin for 20 min), high K+ (80 mM) failed to evoke CGRP-LI release, whereas SP-LI release was still observed. The capsaicin (1 microM)-evoked CGRP-LI release was entirely dependent on extracellular Ca2+. It was unaffected by 0.3 microM tetrodotoxin (TTX), slightly reduced by 0.1 microM omega-conotoxin (CTX) and blocked by 10 microM Ruthenium red (RR). The Ca(2+)-dependent K+ (80 mM)-evoked CGRP-LI release was unaffected by TTX, markedly reduced by CTX and only moderately inhibited by RR. Low pH (pH 5) produced a remarkable increase in CGRP-LI outflow that was abolished after exposure to capsaicin, reduced by about 50% in Ca(2+)-free medium and unaffected by TTX (0.3 microM). The Ca(2+)-dependent component of the proton-evoked CGRP-LI release was abolished in the presence of RR (10 microM) and slightly inhibited by CTX (0.1 microM).(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗

PubMed1991

Capsazepine, a novel capsaicin antagonist, selectively antagonises the effects of capsaicin in the mouse spinal cord in vitro.

The mouse hemisected spinal cord with attached dorsal roots and spinal ganglia in vitro preparation was used to investigate the effects of the capsaicin antagonist, capsazepine (2-[2-(4-chlorophenyl)ethylamino-thiocarbonyl]-7,8-dihydroxy-2,3,4 ,5- tetrahydro-1H-2-benzazepine). The spinal cord and the ganglia were separated by a perspex gap, allowing application of drugs separately to each compartment. Intracellular recordings were made from 37 cells in laminae II-VI of 12 to 20-day-old mice. Brief applications (30 s) of capsaicin (0.8 microM) excited dorsal horn neurones by activating small diameter primary afferent fibres. The response to capsaicin administered to the spinal cord or to the spinal ganglia was antagonised by the capsaicin antagonist, capsazepine (1.5 microM), administered to the same site. Excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of the dorsal root were not affected by capsazepine. Capsazepine itself (5 microM) did not affect the membrane potential of the dorsal horn cells. Capsazepine did not depress the depolarization evoked by substance P. When capsazepine was applied to the spinal cord and capsaicin to the dorsal root ganglion the capsaicin effect was not antagonised. These data suggest that capsaicin-induced depolarization of spinal dorsal horn neurones was mediated via activation of a specific receptor on primary afferent neurones.

Action Potentials↗

PubMed1999

Noxious heat activates all capsaicin-sensitive and also a sub-population of capsaicin-insensitive dorsal root ganglion neurons.

A sub-population of primary afferent fibres comprising mainly Adelta and C polymodal nociceptors specifically detects high intensity heat stimuli. These fibres are also sensitive to high threshold mechanical stimulation and different chemicals including inflammatory mediators. C-polymodal nociceptors are also activated by capsaicin. Recent findings show that noxious heat induces inward currents in a sub-population of cultured dorsal root ganglion neurons by opening nonselective cation-channels. It has been suggested that noxious heat is transduced by the recently cloned capsaicin-gated ion-channel since oocytes and HEK 293 cells expressing this channel respond to heat as well as capsaicin. In agreement with this suggestion Kirschstein et al. found in a small sample of dorsal root ganglion cells that all heat-sensitive neurons were also sensitive to capsaicin. In this study we examine further, by whole-cell voltage-clamp recording from adult rat dorsal root ganglion neurons grown in culture, the relationship between heat- and capsaicin-sensitivity. Our results show the existence of two kinds of heat-sensitive neurons, distinguished by their temperature thresholds. The low-threshold cells, which comprise the small-medium diameter population, are capsaicin-sensitive, whereas the high-threshold (mainly large-diameter) cells are not, and we postulate the existence of a heat transducer distinct from capsaicin receptor in the latter group.

Animals↗

PubMed1987

Cutaneous lesions in capsaicin-pretreated rats. A trophic role of capsaicin-sensitive afferents?

1. The time course and regional distribution of 'spontaneous' cutaneous lesions in rats desensitized to capsaicin as newborns was correlated to behavioural observations and regional distribution of substance P-like immunoreactivity (SP-LI) and tachykinin-like immunoreactivity (TK-LI) in various skin areas. 2. 'Spontaneous' skin lesions in the form of wounds, scabs and areas of alopecia were observed in 80-90% of rats desensitized to capsaicin. No major sex-related differences were observed with regard to incidence and distribution of the lesions with the possible exception of a lesser tendency to bilateral lesions in female rats. 3. 'Spontaneous' skin lesions were almost restricted to the head: the areas most frequently affected were snouts, periocular and retroauricular regions and ventral area of the neck. 4. No major differences were observed between capsaicin- or vehicle-treated animals in spontaneous or novelty-induced grooming as well as in open-field gross behaviour. Likewise, no differences were observed in the mouse-killing behaviour. 5. Both SP-LI and TK-LI in various skin areas were significantly reduced by systemic capsaicin pretreatment. The rank order of various skin areas for SP-LI or TK-LI levels was: snouts greater than thigh greater than neck greater than abdomen approximately equal to retroauricular region. 6. Intradermal injection of Arg-neurokinin B, a potent and water soluble derivative of neurokinin B, produced a similar plasma extravasation (Evans blue leakage technique) in the skin of vehicle- or capsaicin-pretreated rats. 7. In capsaicin-desensitized rats fur regrowth (measured at abdominal level, 28 days after shaving) was significantly less than in vehicle-treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Extrinsic origin of the capsaicin-sensitive innervation of rat duodenum: possible involvement of calcitonin gene-related peptide (CGRP) in the capsaicin-induced activation of intramural non-adrenergic non-cholinergic neurons.

Capsaicin produces a concentration-related relaxation of the longitudinal muscle of the rat isolated duodenum in the presence of atropine (3 microM) plus guanethidine (3 microM). This effect of capsaicin is partly (about 40%) antagonized by tetrodotoxin (1.0 microM) suggesting the involvement of intramural non-adrenergic non-cholinergic (NANC) neurons. The capsaicin-induced relaxations are unaffected by previous bilateral vagotomy or removal of the inferior mesenteric ganglion but are completely prevented by removal of the coeliac ganglia plus the superior mesenteric ganglion (72 h before). Acute duodenal denervation did not modify the response to capsaicin. Unlike various neuropeptides (substance P, kassinin, neurokinin A, cholecystokinin octapeptide, somatostatin, vasoactive intestinal polypeptide) only the calcitonin gene-related peptide (CGRP) closely mimicked, both qualitatively and quantitatively, the capsaicin-induced relaxations. The CGRP-induced relaxations were unaffected by hexamethonium and partly reduced (about 40%) by tetrodotoxin. In preparations desensitized to adenosine-triphosphate (ATP) a putative NANC inhibitory neurotransmitter of the rat duodenum, the effects of CGRP were reduced (about 30%) as compared to controls. After ATP-desensitization tetrodotoxin did not produce any further reduction of the CGRP-induced relaxations suggesting the involvement of endogenous ATP in the neuronal (tetrodotoxin-sensitive) component of the CGRP-induced relaxations. Either ATP- or CGRP-desensitization reduced (about 50 and 65% respectively) the amplitude of the capsaicin-induced relaxations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed2003

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.

Acetic Acid↗

PubMed2002

The addition of glyceryltrinitrate to capsaicin cream reduces the thermal allodynia associated with the application of capsaicin alone in humans.

The aim of this study was to determine whether topical application of capsaicin cream causes thermal allodynia and the extent to which this is attenuated by the addition of glyceryltrinitrate (GTN). This was a double blind placebo controlled study of 40 consenting adult subjects. Each of four cream combinations (GTN, capsaicin, GTN/capsaicin and vehicle) were applied to the subjects with at least a 1 day interval between each application. Water at a known temperature was applied to the standard area of skin where cream had been applied. Subjects rated the resulting thermal allodynia using a 0-10 Likhert score. Thermal allodynia is usually apparent when warm water is applied to skin containing capsaicin. The thermal allodynia caused by the topical application of capsaicin was significantly reduced by the addition of GTN. The addition of GTN to capsaicin cream significantly reduces the thermal allodynia associated with the application of capsaicin cream alone.

Capsaicin↗

PubMed1998

Capsaicin sensitivity is associated with the expression of the vanilloid (capsaicin) receptor (VR1) mRNA in adult rat sensory ganglia.

A vanilloid receptor (VR1) has recently been cloned and shown to be a target for capsaicin, the excitotoxic component of capsicum peppers (Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D. and Julius, D., Nature, 389 (1997) 816-824). The effects of capsaicin appear to be selective for a subset of sensory neurones which includes polymodal nociceptors. The present study describes the distribution of VR1 mRNA, together with measurements of capsaicin sensitivity, in sensory nerve ganglia of different embryological origins and a single sympathetic ganglion, the superior cervical ganglion (SCG). In situ hybridisation revealed the expression of VR1 mRNA in small-to-medium-sized neurones of the dorsal root, trigeminal and vagal ganglia. No hybridisation signal was observed in the SCG neurones. This pattern of expression correlated with capsaicin sensitivity measured by whole-cell voltage clamp where, in similar sized cells, over 80% of neurones from dorsal root and vagal ganglia were capsaicin sensitive, but all SCG neurones were insensitive to capsaicin.

Animals↗

PubMed2002

The orofacial capsaicin test in rats: effects of different capsaicin concentrations and morphine.

The aim of this study was to develop a rat model of capsaicin-induced pain in the orofacial region. We examined the effects of subcutaneous injection of different doses of capsaicin (0.25, 0.4, 0.8, 1.5, 2.5, 25, 50, 100, 500 microg) on the face-grooming response. Injection of capsaicin into the vibrissa pad produced an immediate grooming of the injected area with ipsilateral fore- or hindpaw. A positive relationship between the amplitude of the grooming response and the capsaicin dose was observed until 1.5 microg, but with the highest concentrations (ranging from 25 to 500 microg) the amplitude of the response decreased. Morphine administered either systemically (in the neck, 0.5-4.0 mg/kg) or locally (0.25-1.0 mg/kg) reduced in a dose-dependent fashion the face grooming provoked by subcutaneous capsaicin (1.5 microg). The systemic and local morphine effects could be reversed by systemic (0.1 mg/kg) and local (0.05 mg/kg) administration of naloxone, respectively. The local administration of morphine (ED(50): 0.65 mg/kg) was more potent than systemic injection (ED50: 2.54 mg/kg) in reducing the grooming behavior. In conclusion, the orofacial capsaicin test appears to be a valid and reliable method for studying trigeminal pain mechanisms and testing analgesic drugs. The results of the present study also support the clinical use of peripheral opioid administration for the treatment of orofacial painful conditions.

Analgesics, Opioid↗

PubMed1998

The addition of GTN to capsaicin cream reduces the discomfort associated with application of capsaicin alone. A volunteer study.

In a double blind, placebo controlled trial of 40 volunteers, the burning discomfort associated with application of capsaicin cream (0.025%) was compared to placebo, GTN cream (1.33%) and to the combination of capsaicin cream (0.025%) plus GTN cream 1.33%. Median VAS for burning pain were 0 for the placebo, GTN and GTN + capsaicin groups and 3 for the capsaicin group after single application of each cream at daily intervals. This study demonstrates that after single application the addition of GTN to capsaicin significantly reduces the burning discomfort associated with application of capsaicin alone.

Capsaicin↗

PubMed2001

Axonal transport of VR1 capsaicin receptor mRNA in primary afferents and its participation in inflammation-induced increase in capsaicin sensitivity.

Capsaicin receptors are expressed in primary sensory neurons and excited by heat and protons. We examined the inflammation-induced changes of the level of VR1 capsaicin receptor mRNA in sensory neurons and the sensitivity of primary afferents to capsaicin. Carrageenan treatment induced axonal transport of VR1 mRNA, but not that of preprotachykinin mRNA, from the dorsal root ganglia to central and peripheral axon terminals. The sensitivity of central terminals to capsaicin, which was estimated by measuring the capsaicin-evoked release of glutamate from the dorsal horn, was increased by peripheral inflammation, and such an increase was suppressed by inhibiting the RNA translation in the dorsal horn with cycloheximide and an intrathecal injection of VR1 antisense oligonucleotides. Thus, peripheral inflammation induces the axonal transport of VR1 mRNA, which may be involved in the hypersensitivity of primary afferents to capsaicin and the production of inflammatory hyperalgesia.

Afferent Pathways↗

PubMed1989

Morphine, capsaicin and K+ release purines from capsaicin-sensitive primary afferent nerve terminals in the spinal cord.

In the present study the neuronal source of adenosine released by K+, morphine and norepinephrine (NE) from the spinal cord was investigated. Intrathecal pretreatment with 5,7-dihydroxytryptamine and 6-hydroxydopamine reduced spinal 5-hydroxytryptamine and NE levels, respectively, but had no effect on adenosine release from dorsal spinal cord synaptosomes evoked by K+ or morphine. NE-evoked release of adenosine was unaffected by 5,7-dihydroxytryptamine but increased by 6-hydroxydopamine. Subcutaneous pretreatment of neonatal or intrathecal pretreatment of adult rats with capsaicin increased nociceptive thresholds and reduced the release of adenosine evoked by K+ and morphine but not NE from dorsal spinal cord synaptosomes. Intrathecal capsaicin also inhibited morphine-evoked release of adenosine in vivo. K+ and morphine released only small amounts of adenosine from ventral spinal cord synaptosomes whereas NE released significant amounts. Exposure of dorsal, but not ventral, spinal cord synaptosomes to capsaicin produced a dose- and Ca++-dependent release of adenosine, which was reduced by capsaicin pretreatment (neonatal and adult) and inhibition of ecto-5'-nucleotidase. Capsaicin also released endogenous ATP from dorsal spinal cord synaptosomes. These results suggest that primary afferent nerve terminals in the dorsal horn of the spinal cord release adenosine in response to morphine and K+, and a nucleotide (possibly ATP) in response to capsaicin. Adenosine does not appear to be released from the terminals of descending aminergic pathways. The source of purines released by NE is less certain.

Adenosine↗

PubMed1991

Treatment of painful diabetic neuropathy with topical capsaicin. A multicenter, double-blind, vehicle-controlled study. The Capsaicin Study Group.

A multicenter study was conducted to establish the efficacy of topical 0.075% capsaicin cream in relieving the pain associated with diabetic neuropathy. Capsaicin or vehicle cream was applied to painful areas four times per day for 8 weeks in patients randomly assigned to one of two groups. Pain intensity and relief were recorded at 2-week intervals using physician's global evaluation and visual analog scales. Analysis at final visit for 252 patients showed statistical significance favoring capsaicin compared with vehicle for the following: 69.5% vs 53.4% pain improvement by the physician's global evaluation scale, 38.1% vs 27.4% decrease in pain intensity, and 58.4% vs 45.3% improvement in pain relief. With the exception of transient burning, sneezing, and coughing, capsaicin was well tolerated. Study results suggest that topical capsaicin cream is safe and effective in treating painful diabetic neuropathy.

Administration, Topical↗

PubMed1998

Desensitization of bladder sensory fibers by intravesical capsaicin or capsaicin analogs. A new strategy for treatment of urge incontinence in patients with spinal detrusor hyperreflexia or bladder hypersensitivity disorders.

Recent experimental studies have identified a category of unmyelinated type C bladder afferent fibers in the pelvic nerves which are extremely sensitive to capsaicin. Sensory input conveyed by these fibers triggers a spinal reflex which, in chronic spinalized animals, facilitates and controls micturition. In addition, bladder C fibers were also shown to have a role in bladder pain perception. In humans capsaicin-sensitive afferent fibers also innervate the bladder and contribute to the reflexogenic control of the detrusor muscle and to bladder pain perception. Desensitization of such fibers by intravesical administration of capsaicin, presumably by blocking sensory transmission, has been shown to reduce involuntary micturition and to increase bladder capacity in patients with detrusor hyperreflexia of spinal origin, and to reduce the intensity of bladder pain in patients with bladder hypersensitivity. Very recently, resiniferatoxin, an ultrapotent capsaicin analog, was shown to have a similar clinical effect in this subset of patients. However, unlike capsaicin, resiniferatoxin did not evoke acute irritative urinary symptoms during bladder instillation.

Administration, Intravesical↗

PubMed1991

Ruthenium red as a selective capsaicin antagonist of the motor response to capsaicin in the human isolated ileum.

We have investigated the effect of ruthenium red, omega-conotoxin fraction GVIA (CTX) and tetrodotoxin (TTX) on the relaxation produced in the circular muscle of the human isolated ileum by capsaicin, electrical field stimulation (EFS) or vasoactive intestinal polypeptide (VIP). Ruthenium red (10 microM) selectively blocked the capsaicin-evoked relaxation while leaving the response to EFS or VIP unaffected. CTX had no significant effect on the various stimuli. TTX blocked the relaxation due to EFS but not that due to capsaicin or VIP. It is concluded that capsaicin excitation of primary afferents in the human ileum, leading to VIP release and muscle relaxation, occurs with mechanisms similar to those operating in animal tissues and that ruthenium red acts as a selective capsaicin antagonist in the human ileum.

Aged↗

PubMed1998

Mecamylamine inhibits nicotine but not capsaicin irritation on the tongue: psychophysical evidence that nicotine and capsaicin activate separate molecular receptors.

Using a two-alternative forced-choice (2-AFC) discrimination test coupled with category intensity ratings, we investigated the effect of mecamylamine, an antagonist of neuronal nicotinic acetylcholine receptors (nAchRs), on oral irritation elicited by nicotine or capsaicin. Mecamylamine (0.075%) was first delivered to one side of the tongue with distilled H2O delivered to the other side. After 10 min either capsaicin (1 ppm) or nicotine (0.12%) was applied bilaterally to the tongue, and subjects were asked to choose which side yielded a stronger sensation (2-AFC) as well as to provide a rating of the irritation intensity difference between the two sides of the tongue. When nicotine was given after mecamylamine, a significant proportion of subjects chose the mecamylamine-untreated side as yielding stronger irritation. When capsaicin was given after mecamylamine, both sides of the tongue were chosen in equal numbers. These data indicate that mecamylamine reduced irritation elicited by nicotine but not capsaicin, and provide further evidence that nicotine oral irritation is mediated via a neuronal nAchR while capsaicin activates trigeminal fibers via a separate molecular receptor.

Adult↗

PubMed1998

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.

Alanine↗