The effects of capsaicin upon electrogenic ion transport in rat descending colon

Summary Preparations of rat descending colon mucosa have been used to record changes in short circuit current (SCC) under voltage clamp conditions. When added to the basolateral compartment capsaicin (8-methyl-N-vanillyl-6-nonenamide, 0.1-3 M) caused an initial transient increase in SCC, followed by a more prolonged reduction in SCC, that lasted for 20–30 min.Repeated applications of 3 M capsaicin caused desensitisation of the initial secretory response. The antisecretory effects (i. e. reduction in SCC from the original baseline) remained, although they were significantly reduced. In some preparations described as non-responders, 3 M capsaicin did not elicit a secretory response. No desensitisation of the remaining antisecretory responses was observed in these tissues; in fact these reductions in SCC were consistently larger than those from tissues which responded with a secretory response.Tetrodotoxin (100 nM), hexamethonium (10 M), and yohimbine (50 M) had no significant effect upon either secretory or antisecretory responses. Ruthenium red (10 M) abolished the secretory response to 3 M capsaicin, but had no effect upon the antisecretory responses. Pretreatment of the tissues with 1 M substance P(SP) resulted in significant desensitisation to the peptide and abolished the secretory response to 3 M capsaicin. The antisecretory responses remained, and were significantly larger compared with responses from control tissues. Send offprint requests to H. M. Cox at present address     

Influence of several peptidase inhibitors on the pro-inflammatory effects of substance P, capsaicin and collagenase

Injection of substance P (SP) in a rat hindpaw induced extravasation of ¹²⁵I-labelled albumin in both hindpaws and salivation. Intravenous injection of SP dose-dependently increased vascular permeability. This latter effect was increased in rat paws by captopril, an inhibitor of angiotensin-converting enzyme (ACE), administered locally in combination with diprotin A, an inhibitor of an dipeptidyl(amino)peptidase IV (DAP IV) or phosphoramidon, an inhibitor of neutral endopeptidase (NEP). The increase in permeability induced by SP was inhibited by RP 67580, a NK₁-receptor antagonist.Intravenous injection of capsaicin induced labelled albumin extravasation in rat paws. This effect was increased by combination of captopril with diprotin A or phosphoramidon, but not by captopril associated with amastatin, an inhibitor of aminopeptidase M (AmM). It was suppressed by RP 67580.Injection of collagenase in rat paws triggered a swelling and a local plasma exudation. These responses were reduced by RP 67580 but not by RP 68651, its inactive enantiomer. They were increased by combination of captopril with diprotin A or phosphoramidon in normal rats. The potentiating effects of captopril and diprotin A were suppressed by RP 67580 in normal rats but did not develop in kininogen-deficient rats. The oedema induced by collagenase was also increased by lisinopril, another ACE inhibitor, administered locally in combination with apstatin, an inhibitor of aminopeptidase P (AmP). In rats pretreated by methysergide, collagenase-induced oedema was reduced and can be increased by captopril, by lisinopril, administered alone or by lisinopril associated with apstatin.It is concluded that SP is mainly inactivated in rat paws by ACE, DAP IV and NEP In collagenase-induced oedema, a low amount of SP would be released from afferent nerve terminals by bradykinin formed in low amounts. Bradykinin is inactivated in rat paws by ACE and AmP. In collagenase-oedema, the pro-inflammatory effects of bradykinin are concealed by the effects of the other mediators.     

Cytotoxicity of capsaicin in monkey kidney cells: lack of antagonistic effects of capsazepine and Ruthenium red

Capsaicin is a natural product of Capsicum peppers, excitatory effects of which have been shown to be mediated by the recently cloned vanilloid receptor 1 (VR1). Since previous studies have shown that capsaicin inhibits protein synthesis, experiments were performed to investigate whether this effect is mediated by VR1 receptor on cultured monkey kidney cells (Vero cells). The capsaicin uptake was assessed in cellular homogenate and in medium by high-performance liquid chromatography (HPLC) separation and quantification on C18 reverse-phase column and fluorescence detection. Toxic effects were assessed by incorporation of [³H]L-leucine into cellular proteins in the presence of capsazepine, the VR1 vanilloid receptor antagonist and Ruthenium red or tyrosine or calcium. Capsazepine (1 to 256 μM) did not modify the uptake rate of capsaicin for incubation times up to 24 h and did not antagonize capsaicin-induced protein synthesis inhibition. It rather inhibited protein synthesis per se from 100 to 256 μM. Ruthenium red which blocks mitochondrial calcium uptake, inhibited protein synthesis and did not antagonise or increase synergistically the effects of capsaicin. Interestingly in a medium deprived of calcium and supplemented by calcium chloride (10–50 μM) the protein synthesis inhibition induced by capsaicin is antagonised somehow. There was no prevention of capsaicin diffusion into the cells. Tyrosine, which seems to be the best preventive agent of capsaicin inhibitory effects, prevents its metabolism but not its diffusion. Capsaicin might enter cells by diffusion and interfere with protein synthesis machinery by competition with tyrosine which in turn prevents the metabolism of capsaicin. The results of the present study suggest that cell responses to capsaicin may be transduced through at least two molecular pathways, one involving VR1, since the receptor antagonist capsazepine fails to prevent the inhibitory effect of capsaicin in Vero cells of renal origin. Received: 27 August 1999 / Accepted: 3 November 1999     

HPLC法测定辣椒浸出物中辣椒素的含量

目的:采用HPLC法测定辣椒浸出物中辣椒素的含量.方法:C18色谱柱,以乙腈-水(50:50)为流动相,检测波长为 229 nm.结果:本方法重现性及精密度良好,回收率为99.4%,RSD为1.22%.结论:方法简便,专属性强;可用于辣椒浸出物的质量控制.     

Analgesia induced by neonatal capsaicin treatment in rats

Twenty-seven rats were treated by 475 mg kg^?1 of subcutaneous capsaicin from 2 to 7 days of their life. After treatment, only 11 rats had survived. Their cutaneous heat, pressure, pricking and visceral hyperosmolarity nociceptive thresholds were measured between 50 and 170 days after treatment. The results showed a considerable, or even total, analgesia to cutaneous as well as to visceral stimuli. The conclusion is that same pathways carried all the nociceptive messages independently of nature or localization of noxious stimuli.     

Pupillary constriction by bradykinin and capsaicin: mode of action

The application of bradykinin or capsaicin to the rabbit eye evoked strong miosis. The effect could be prevented by pretreatment of the eye with tetrodotoxin (TTX) or a substance P (SP) antagonist. However, the miotic response could be elicited despite TTX or the SP antagonist if the dose of capsaicin or bradykinin was increased. Bradykinin and capsaicin contracted the isolated rabbit sphincter pupillae muscle. The contraction produced by bradykinin and capsaicin was unaffected by TTX but reduced by specific SP antagonists. This indicates that bradykinin and capsaicin exert their effects on the isolated sphincter muscle through the release of SP but independent of neuronal conduction. In vivo, the situation seems to be different. The finding that TTX is capable of blocking the miotic response to moderate doses of bradykinin and capsaicin suggests that the effect on the eye under these circumstances is dependent upon a normal impulse traffic.     

Behavioral and physiological effects of xanthines in nonhuman primates

 Caffeine and related xanthines can have significant behavioral effects on measures of locomotor activity, schedule-controlled behavior, drug self-administration, and learning and memory. Xanthines also produce numerous physiological effects including positive inotropic and chronotropic effects on the heart, decreased airway resistance in the lung, and respiratory stimulation. Due to the widespread use of xanthines as constituents of food and beverages and as therapeutic drugs, identification of mechanisms that mediate their pharmacological effects has considerable relevance for drug development and therapeutics. Two primary mechanisms involving the cyclic nucleotide system have been implicated as the bases for the effects of xanthines in the CNS. Many xanthines bind to specific adenosine recognition sites and block the actions of adenosine. Xanthines also inhibit cyclic nucleotide phosphodiesterases, the enzymes responsible for the hydrolytic inactivation of cyclic AMP and cyclic GMP. Recent research in nonhuman primates has characterized the behavioral, respiratory and cardiovascular effects of a number of xanthines and related drugs differing in affinity at different subtypes of adenosine receptors and in capacity to inhibit different molecular forms of PDE. The behavioral-stimulant effects of xanthines appear to be mediated principally by their adenosine-antagonist actions and may be limited by PDE inhibition. The respiratory-stimulant and cardiac effects of xanthines, on the other hand, appear to be linked more closely to their PDE- inhibiting actions than to adenosine antagonism. Converging lines of evidence suggest that adenosine A₂ and cAMP-specific (possibly type IV) PDE mechanisms play especially prominent roles in mediating the behavioral and physiological effects of xanthines in nonhuman primates. Received: 6 March 1996 / Final version: 11 September 1996     

HPLC测定辣椒风湿贴中辣椒碱的含量

目的 建立测定辣椒风湿贴中辣椒碱含量的方法.方法 采用HPLC法,Luna C18色谱柱(250 mm×4.6 mm,10 μm),甲醇-水(65:35)为流动相,检测波长281 nm.结果 在6.04～241.60 μg·ml-1范围内,辣椒碱浓度与峰面积的线性关系良好(r=0.9997),RSD=0.95%(n=6),平均回收率为100.6%(n=5).结论 所建方法准确、简便、快速,适用于辣椒风湿贴的质量控制.     

Differential effects of locally-applied capsaicin on distension-stimulated gastric acid secretion in the anesthetized rat

Summary The effects induced by the local administration of capsaicin on acid production have been investigated in the continuously perfused stomach of the anesthetized rat. Basal acid secretion was not influenced by 10 min intragastric perfusion with capsaicin (300 g min^–1). Acid responses elicited by distension of the stomach with increases in intragastric pressure of 5 and 10 cm H₂O were not modified after a 10 min intraluminal infusion with 80 or 300 g min^–1 of capsaicin. H⁺ output stimulated by higher intraluminal pressure (20 cm H₂O) were significantly decreased by intraluminal infusion of capsaicin (20, 80, 300 and 600 g min^–1). Acid responses to carbachol (4 g kg^–1, i.p.) were not influenced by intragastric (300 g min^–1), or systemic neonatal, treatment with capsaicin.Intraluminal infusion of the neurotoxin tetrodotoxin (0.12 g min^–1, 10 min) decreased acid responses to an increase in intragastric pressure of 20 cm H₂O but not those elicited by distention with a pressure of 10 cm H₂O. Neonatal systemic treatment (s. c.) with capsaicin or local gastric serosal application of either capsaicin or tetrodotoxin abolished acid responses to gastric distension (+ 20 cm H₂O). Capsaicin (80 g min^–1) and tetrodotoxin (0.12 g min^–1) infused concurrently into the lumen did not inhibit gastric acid secretion stimulated by an increase of 20 cm H₂O in intragastric pressure to any greater extent than did either drug given alone. The inhibition of acid secretion cannot be attributed to an increase in H⁺ loss, since intragastric infusion of capsaicin (300 g min^–1) did not cause any significant acid loss in rats pretreated with omeprazole and undergoing luminal perfusion with acid saline during gastric distension (+ 20 cm H₂O). Neither the intragastric perfusion nor the serosal application of capsaicin modified the H⁺ production induced by electrical stimulation of the vagus. This acid response was, however, abolished following 10 min intraluminal perfusion with tetrodotoxin (0.12 g min^–1).These observations confirm that capsaicin-sensitive sensory fibers located in the stomach wall mediate the acid secretory responses to intragastric distension. Such fibers are susceptible to the effects of capsaicin when administered systemically or through the gastric serosa, but only partially if capsaicin is infused intraluminally.Correspondence to: J. V. Esplugues     

Behavioral and physiological effects of cocaine in humans following triazolam

RATIONALE: Cocaine abuse represents a significant public health problem. Gamma-aminobutyric acid (GABA) agonists may attenuate the behavioral effects of cocaine and may be effective pharmacotherapies for cocaine abuse and dependence. OBJECTIVES: The aim of this experiment was to determine the combined effects of oral cocaine (0 and 300 mg) and triazolam (0 and 0.5 mg), a GABA(A) modulator, in 10 individuals with recent histories of cocaine use. METHODS: Volunteers received each of the four possible drug combinations in mixed order. Drug effects were assessed using a battery of subject-rated drug-effect questionnaires and physiological indices. RESULTS: Cocaine alone produced prototypical stimulant-like subject-rated drug effects (e.g., increased ratings of High, Like Drug, and Willing to Take Drug Again). Triazolam alone produced sedative-like effects (e.g., increased scores on the Pentobarbital, Chlorpromazine, Alcohol Group [PCAG] scale of the Addiction Research Center Inventory [ARCI]). Triazolam pretreatment did not significantly attenuate the subject-rated effects of cocaine. CONCLUSIONS: While the results of this study do not support the utility of GABA(A) modulators as pharmacotherapies for cocaine abuse, future research should test other benzodiazepines (e.g., alprazolam) using more sophisticated methods (e.g., dose-response curves for the drugs alone and in combination) and behavioral arrangements (e.g., drug discrimination).     

Corneal lesions induced by the systemic administration of capsaicin in neonatal mice and rats

Summary Following a single subeutaneous injection of capsaicin to neonatal mice, a high incidence of corneal lesions with opacity developed after a long latency. The intensity of the lesions progressed for about 1 month in animals which had received a high dose (50 or 100 mg/kg) of capsaicin. Although the intensity gradually decreased thereafter, 50% of animals still exhibited a visible opacity 6 months after treatment. Similar corneal lesions were also produced in neonatal rats which had been injected with capsaicin. It is suggested that the corneal lesions induced by capsaicin may be due to destruction of the trigeminal nerve.     

Cytotoxicity and genotoxicity of capsaicin in human neuroblastoma cells SHSY-5Y

Capsaicin, a natural product of Capsicum species, induces excitation of pain perception at nociceptive terminals. Our previous studies have shown that capsaicin inhibits protein synthesis in cultured monkey kidneys cells (Vero cells) and in primoculture of rat astrocytes. We have now investigated the effect of capsaicin on human neuroblastoma cells SHSY-5Y. The cytotoxicity has been assessed by incorporation of [³H]L-leucine into cellular protein in the presence of capsaicin and the genotoxicity has been evaluated using the comet assay and the fragmentation assay after incubation of neuroblastoma cells with 25–100 μM capsaicin. The concentration required to inhibit 50% of the protein synthesis (IC₅₀) was found to be 60 μM after incubation with the toxin during one cellular cycle (5 days) of SHSY-5Y. The results of the comet test and DNA fragmentation assay clearly suggest that capsaicin is able to induce DNA strand breaks already with concentrations in the range of 50 μM, corresponding to 29.3 μM of capsaicin not bound to alpha-1 acid glycoprotein. Several daily topical applications of preparations containing 0.075% of capsaicin could lead to blood capsaicin concentration of this order of magnitude following transdermal passage (5% of the total quantity applied). Because DNA strand breaks or DNA lesions may affect cellular functions, lead to cell death and/or mutagenesis, our data in case of inappropriate DNA repair may have important implications for the possible health threats of capsaicin, specially in the case of misuse of capsaicin preparations in pathological situations. Received: 30 November 1998 / Accepted: 16 June 1999     

辣椒素治疗变应性鼻炎的临床疗效及作用机制

目的评价辣椒素治疗变应性鼻炎的临床疗效,并对其作用机制进行初步研究。方法选择我院收治的47例变应性鼻炎患者,采用辣椒素进行治疗,观察患者的临床疗效,并对治疗前后患者SP含量、血清TIgE、SIgE、ECP水平进行分析。结果经过3个疗程的治疗,47例患者中,显效33例(70.21%),有效11例(23.41%),无效3例(6.38%)。其中17例治疗后患者体征恢复正常,临床症状完全消失。治疗后,患者鼻分泌量及SP含量均显著下降,与治疗前相比,差异有统计学意义(P<0.05);治疗后患者血清TIgE、SIgE、ECP水平均明显降低,与治疗前相比,差异有统计学意义(P<0.05)。结论辣椒素治疗变应性鼻炎临床疗效显著,其作用机理可能与抑制P物质释放、降低IgE介导的Ⅰ型变态反应有关。     

Effects of intracerebroventricular capsaicin on thermoregulatory behavior in the rat

To clarify the action of capsaicin on the thermoregulatory system of rat, behavioral and autonomic responses were studied following intracerebroventricular (ICV) injection. Rats were chronically implanted with a lateral cerebral ventricular guide cannula. After the recovery period they were placed in a climatic chamber at ambient temperature (T_a) of 20, 30 or 35°C. In the first series of experiments, they had access to a lever which activated a fan that drew cool outside air into the chamber. After ICV capsaicin (23 μg), the rats increased bar-pressing behavior for fresh air at T_a ranging from 20°C to 35°C. In the second series of experiment, the rats had no access to fanning. ICV capsaicin produced a fall in rectal and hypothalamic temperature (T_hy) and increased n cutaneous temperature. These changes depended on T_a. At a T_a of 30°C T_hy fell slightly (mean of 0.2±0.16°C. At a T_a of 20°C T_hy fell to a mean of 1°C±0. 17°C. The conclusion drawn is ICV capsaicin activated behavioral as well as autonomic thermoregulatory heat-loss responses. The effect of capsaicin resembles the effect of local heating of the hypothalamus. However, since hypothalamic temperature decreased the drug may have lowered the thermal set point, or excited directly hypothalamic warm-sensitive neurons.     

Behavioral and physiological effects of acute ketamine exposure in adult zebrafish

Ketamine is a non-competitive glutamatergic antagonist used to induce sedation and analgesia. In sub-anesthetic doses, it induces hyperlocomotion, impairs memory and evokes stereotypic circling in rodents. Zebrafish (Danio rerio) emerged as a promising new animal model to screen the effects of psychotropic compounds. Here, we investigated the effects of sub-anesthetic doses of ketamine on anxiety, locomotion, habituation and social behavior of adult zebrafish. Acute 20-min exposure to 20 and 40 mg/L (but not 2 mg/L) of ketamine reduced anxiety, impaired intra-session habituation, evoked circular swimming and disrupted zebrafish shoaling. Additionally, ketamine reduced whole-body cortisol levels and elevated brain c-fos expression in zebrafish. Our findings demonstrate the sensitivity of zebrafish to behavioral and physiological effects of sub-anesthetic doses of ketamine, further supporting the utility of this species as a model for neuropharmacological research, including testing ketamine and related drugs.     

Actions of calcitonin gene-related peptide and tachykinins in relation to the contractile effects of capsaicin in the guinea-pig and rat heart in vitro

Summary 1. The effects of calcitonin gene-related peptide (CGRP), neurokinin A (NKA), neuropeptide K (NPK) and substance P (SP) on contractility of the guinea-pig and rat heart were studied in vitro in relation to the response to capsaicin. 2. Human (h) CGRP alpha (a) and beta () were equipotent in stimulating the contractile force and rate of the spontaneously beating guinea-pig right atrium. 3. Both NKA and NPK inhibited contractile force and rate in the guinea-pig atrium whilst a mainly negative chronotropic effect was observed in the whole heart. SP did not influence cardiac contractility. 4. Human CGRP and mimicked the contractile effects of capsaicin in the guinea-pig atrium. In the whole heart preparation, hCGRP and capsaicin increased heart rate whereas capsaicin also evoked an atropine-resistant inhibition of contractile force. The stimulatory effect of capsaicin on heart rate was absent after systemic capsaicin pretreatment, while the inhibition of ventricular contractile tension remained unchanged. 5. Extended incubation with hCGRP or was associated with development of cross-tachyphylaxis between these two agents in the guinea-pig atrium. However, CGRP tachyphylaxis did not change the atrial response to noradrenaline, forskolin or NKA. The stimulatory effects of capsaicin on atrial contractility were absent after tachyphylaxis to hCGRP or . 6. There was no detectable supersensitivity to the stimulatory effects of rat (r) CGRP on the spontaneously beating atrium after capsaicin pretreatment of adult or neonatal rats. In conclusion the present data provide further evidence that the capsaicin-induced stimulation of atrial contractility is due to local release of CGRP. CGRP tachyphylaxis seems to be a specific, receptor-mediated event and is not related to down-regulation of the adenylate cyclase system. The inhibition of the contractile force in whole heart preparations by capsaicin is most likely due to a non-cholinergic effect independent of tachykinin release. Send offprint requests to A. Franco-Cereceda at the above address     

Relationship of pulmonary function response to ozone exposure and capsaicin cough sensitivity

Abstract

Context: Challenge studies in humans have shown considerable interindividual variability in pulmonary impairment across ozone exposure.

Objective: Since previous results suggested effect modulation by neural mechanism, we investigated sensory C-fiber reactivity in relationship to ozone-triggered response pattern.

Methods: Cough reflex thresholds reflecting C-fiber sensitivity were evaluated by capsaicin single breath dose–response method. Capsaicin concentrations triggering, respectively, two and five or more coughs (C2, C5) were recorded. Sixteen healthy subjects were randomly exposed in an intermittent exercise protocol to ozone concentrations of 240 and 40?ppb (sham exposure). Ozone responsiveness was defined by a decrease in forced expiratory volume in 1?s (FEV₁) of more than 5%.

Results: Based on a dichotomous classification, subjects with enhanced reactivity to ozone had lower cough thresholds than non-responders (C2, p?=?0.035; C5, p?=?0.086). Over all, we could demonstrate relationships between capsaicin sensitivity and ozone-triggered changes in FEV₁, peak expiratory flow and maximal expiratory flow at 50% vital capacity but not in specific airway resistance.

Conclusion: Our results suggest that capsaicin challenge tests might be useful to characterize subjects with enhanced pulmonary function response towards inhalant irritants.     

Synthesis and elucidation of deuterated vanillylamine hydrochloride and capsaicin

Capsaicin is the major pungent component of hot peppers, which belong to the plant genus Capsicum. Although the biosynthesis of capsaicin is known to involve the condensation of vanillylamine and 8‐methylnonenoic acid by capsaicin synthase, the mechanism of biosynthesis is still not fully understood. In this study, deuterium labelled versions of capsaicin and the precursor vanillylamine were synthesized in order to investigate the biosynthesis of capsaicin in hot peppers. Copyright © 2009 John Wiley & Sons, Ltd.     

Species-related variations in the effects of capsaicin on urinary bladder functions: relation to bladder content of substance P-like immunoreactivity

Summary 1. The effect of capsaicin on bladder motility in vivo (urethane anaesthesia) and in vitro, plasma extravasation (Evans blue leakage technique) and content of substance P-like immunoreactivity (SP-LI) of the urinary bladder was investigated in various mammalian species. 2. Systemic capsaicin desensitization (rat and hamster, 50 mg/kg s.c. 4 days before; guinea-pig 55 mg/kg s. c. 4–7 days before) increased bladder capacity in rats and guinea-pigs and reduced voiding efficiency in guinea-pigs. All other urodynamic parameters were unaffected in both rats, guinea-pigs and hamsters. 3. Reflex bladder voiding was abolished by spinal cord transection in anaesthetized rats and hamsters. On the other hand, hexamethonium-(20 mg/kg i.v.)sensitive voiding contractions were obtained in response to saline filling 45 min from cord transection in guinea-pigs, indicating a profound interspecies variation in the basic organization of micturition. 4. Exposure to capsaicin (1 M) produced a contraction of the isolated bladder from rats, guinea-pigs (dome) and mice. Capsaicin produced only a slight contractile response in the guinea-pig bladder base. The motor response to capsaicin of the rat, guinea-pig and mouse bladder exhibited marked desensitization, suggesting a specific effect on sensory nerves. On the other hand, capsaicin (1 M) produced a slight relaxation of the hamster isolated bladder but this effect was reproducible at 1–2 h intervals, suggesting an unspecific effect. Capsaicin (1–10 M) did not affect motility of strips from the dome or the base of the rabbit bladder. 5. Intravenously administered capsaicin produced a marked plasma extravasation (Evans blue leakage) in the lower urinary tract of rats, mice and guinea pigs. In rats but not guinea-pigs the reaction in the bladder base was greater than in the dome. In hamsters intravenous capsaicin failed to induce any significant Evans blue leakage in the lower urinary tract. 6. SP-LI was detected in the lower urinary tract of rats, guinea-pigs, rabbits and mice but not hamsters. Bladder SP-LI was depleted by systemic capsaicin desensitization in rats, guinea-pigs and mice. Reverse phase HPLC indicated that all the immunoreactive material co-eluted with authentic substance P or its oxidized form. 7. These findings indicate that noticeable species-related differences exist with regard to the functions mediated by the Capsaicin-sensitive neurons in the urinary bladder. Send offprint requests to C. A. Maggi     

Differential effects of capsaicin on the content of somatostatin,substance P,and neurotensin in the nervous system of the rat

Summary The distribution of immunoreactive substance P (I-SP), somatostatin (I-SRIF), and neurotensin (I-NT) and the effect of capsaicin treatment on the concentration of these peptides was studied in the peripheral and central nervous system of the rat.Neonatal capsaicin treatment (50 mg/kg s.c.) caused a depletion of I-SRIF as well as of I-SP in sensory nerves and in the dorsal half of the spinal cord. No recovery of the peptide content was found when examined 4 months later suggesting an irrerersible effect. I-NT, not a constituent of primary sensory neurons, was not changed in the spinal cord. None of the peptides studied was depleted in the hypothalamus or preoptic area.Capsaicin treatment of adult rats also led to a decrease of I-SRIF and I-SP in primarh sensory neurons. The highest dose used (950 mg/kg s.c.) induced no greater depletion than the lowest one (50 mg/kg), except for I-SP in dorsal root ganglia. Intraperitoneal injection of capsaicin led to a higher degree of depletion than subcutaneous administration as examined 1 week after treatment. In contrast to neonatal treatment, the I-SRIF content was completely restored within 4 months after treatment of adult rats. The I-SP content, however, did not completely recover in all areas but remained reduced in cornea, vagus nerve, dorsal spinal cord, and medulla oblongata for up to 9 months.Intraventricular administration of capsaicin (200 g) caused a depletion of I-SP in the medulla oblongata but had no effect on the content of all 3 peptides in hypothalamus or preoptic area. In contrast to systemic treatment, no depletion of I-SP or I-SRIF was found in the trigeminal ganglion. Chemosensitivity of the eye was abolished after intraventricular or systemic treatment. Repeated topical application of a capsaicin solution (10 mg/ml) to the eye led within 4 h to a nearly complete depletion of I-SP in the cornea.These experiments show that capsaicin treatment of rats caused a depletion of both I-SRIF and I-SP in primary sensory neurons. While topical or systemic capsaicin administration causes depletion in terminals, the failure of intraventricular injections of capsaicin to deplete the peptides in the trigeminal ganglion suggests that depletion of the entire neuron requires an action of capsaicin on the peripheral branch and/or the cell body.