Changes in carotid body amine levels and effects of dopamine on respiration in rats treated neonatally with capsaicin

Dopamine levels in rat carotid bodies and the effects of intravenous dopamine injections on respiration in adult rats anaesthetized with pentobarbitone have been studied in animals which were treated with capsaicin neonatally. Levels of dopamine were five fold higher in the carotid bodies of capsaicin-treated rats as compared with vehicle-treated controls, but there was no significant difference between capsaicin-treated and vehicle-treated rats in their ID50 values for dopamine-induced respiratory depression. Domperidone, a dopamine D2-receptor antagonist, substantially reduced the respiratory depression caused by dopamine, both in capsaicin-treated and in control animals, suggesting that a D2-receptor was involved in the response. Cutting the carotid sinus nerves greatly reduced the ventilatory-depressant effect of dopamine, showing that sensory receptors, most probably arterial chemoreceptors, were responsible for most of the response. Substantially less reflex hyperventilation was evoked in capsaicin-treated rats by the peripheral chemoreceptor stimulants hypoxia and sodium cyanide, in comparison with the controls, and domperidone did not increase the responsiveness. About 80% of the reflex ventilatory change originated from carotid body chemoreceptors. The hypoventilation caused by breathing 100% O2 was not significantly different in capsaicin-treated rats when compared with controls. Domperidone substantially reduced this response in capsaicin-treated rats, but not in vehicle-treated animals. Dopamine-induced respiratory depression in capsaicin-treated rats was slightly enhanced, rather than reduced, by oxygen breathing; domperidone remained an effective antagonist of dopamine-induced ventilatory depression. Most of the reduction in respiration caused by dopamine in rats anaesthetized with pentobarbitone can be attributed to actions on a dopamine D2-receptor located in the carotid body. However, despite the increased levels of dopamine found in the carotid bodies, the reduced peripheral chemosensitivity observed in anaesthetized capsaicin-treated rats does not appear to result from a change in sensitivity to dopamine.     

Pressor sensitivity to exogenous vasopressin in conscious, adult rats treated neonatally with capsaicin.

Pressor responses to exogenous arginine vasopressin were assessed in adult rats that had been treated neonatally with capsaicin or its vehicle. Measurements were made under control conditions, after inhibition of baroreflexes (with pentolinium), and after inhibition of baroreflexes (with pentolinium) and the production of angiotensin II (with captopril). Resting arterial blood pressures and pressor sensitivities to exogenous arginine vasopressin were similar in capsaicin-treated and vehicle-injected rats. Sixty minutes after the administration of pentolinium, systolic and diastolic blood pressures were reduced in both groups of rats and the pressor responses to arginine vasopressin were similarly and significantly enhanced. In both groups of rats 60 min after administration of pentolinium and captopril, systolic and diastolic blood pressures were lower than in the presence of pentolinium alone, but pressor responses were not different from those seen in control conditions. The possibility that the present results are explicable in terms of baroreflexes, the renin-angiotensin system and endogenous vasopressin interacting to influence the pressor sensitivity to exogenous vasopressin is discussed. From the present findings, it seems that our previous observation of impaired, vasopressin-mediated blood pressure recovery following acute hypotension in capsaicin-treated rats cannot be attributed to a reduced pressor sensitivity to the hormone.     

Involvement of capsaicin-sensitive neurones in the haemodynamic effects of exogenous vasoactive peptides: studies in conscious, adult Long Evans rats treated neonatally with capsaicin.

1. The regional haemodynamic effects of i.v. bolus injections of bradykinin (0.05 or 0.5 nmol), cholecystokinin (0.175 or 1.75 nmol), substance P (0.01 or 0.1 nmol) and calcitonin gene-related peptide (0.05 or 0.5 nmol) were assessed in conscious, adult Long Evans rats that had been treated neonatally with either capsaicin (50 mg kg-1, s.c.) or vehicle. 2. In vehicle-treated rats, both doses of bradykinin were without effect on blood pressure, but caused tachycardia and hindquarters vasodilatation. Moreover, after the higher dose there were dilatations in the renal and superior mesenteric vascular beds. In capsaicin-treated rats the hindquarters vasodilator effects elicited by both doses of bradykinin were significantly reduced, while the tachycardia and responses in the renal and superior mesenteric vascular beds were unchanged. 3. In vehicle-treated rats, cholecystokinin caused dose-dependent increases in blood pressure accompanied by renal, superior mesenteric and hindquarters vasoconstriction followed, after the higher dose, by a hindquarters vasodilatation. The lower dose produced a tachycardia, while there was a bradycardia followed by a tachycardia after the higher dose. In capsaicin-treated rats, the pressor response, as well as the renal vasoconstrictor effects of cholecystokinin, were greater than in vehicle-treated rats, while the heart rate, superior mesenteric or hindquarters responses were not different. 4. In vehicle-treated rats, substance P produced a dose-dependent depressor response and tachycardia accompanied by dilatations in the renal and hindquarters vascular beds and constriction in the superior mesenteric vascular bed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of neonatal treatment with capsaicin on carrageenan-induced paw oedema in the rat

Summary The time course of the paw oedema induced by the subplantar injection of carrageenan was studied in rats treated neonatally with capsaicin and in their vehicle-treated controls. In the capsaicin-treated rats, which show a permanent deficit of unmyelinated primary sensory neurones, carrageenan produced an oedema which was larger and lasted longer than in the vehicle-treated rats. Pretreatment with the histamine liberator compound 48/80 reduced the carrageenan-induced paw oedema only in the capsaicin-treated rats whereas pretreatment with indomethacin reduced it in both groups of rats. The increased and prolonged inflammatory response to carrageenan in capsaicin-treated rats may be explained by an enhanced release of histamine from mast cells and may also reflect a trophic disorder of the denervated skin.     

The influence of neonatal treatment with capsaicin on the control of blood pressure in adult rats in water-replete and water-deprived states.

Arterial blood pressures and heart rates were measured in water-replete and in water-deprived (48 h) conscious, adult rats that had received capsaicin (50 mg kg-1) or its vehicle neonatally. Resting arterial blood pressures and heart rates in capsaicin-treated rats were not different from the controls in either the water-replete or the water-deprived state. Inhibition of the vascular actions of vasopressin (with 1-beta-mercapto,-beta, beta-cyclopentamethylenepropionic acid, 8-D-arginine vasopressin, (d(CH2)5DAVP] had no significant effect on blood pressures in the water-replete animals but caused a significant hypotension in water-deprived rats; the magnitude of the hypotension was the same irrespective of whether the animals had received capsaicin or its vehicle. During angiotensin converting enzyme inhibition (with captopril) and ganglion blockade (with pentolinium), the vasopressin-mediated blood pressure recovery was more gradual in the capsaicin-treated animals than in the controls, but after 60 min blood pressures were similar in all groups. Collectively the results indicate that although the full development of vasopressin-dependent mechanisms following acute hypotension takes longer when a large proportion of unmyelinated afferent fibres have been destroyed by neonatal treatment with capsaicin, 48 h of water deprivation results in a normal involvement of vasopressin-dependent mechanisms in the maintenance of blood pressure.     

Capsaicin-sensitive vagal afferent fibers and stimulation of gastric acid secretion in anesthetized rats

The sensory neurotoxin, capsaicin, has been used to study the reflex pathway by which gastric acid secretion increases in response to gastric distension in urethane-anesthetized rats. Capsaicin (1%) or vehicle (10% Tween 80 in olive oil) was applied directly to each cervical vagus 7-14 days prior to experiments. Gastric acid secretion was measured in acute gastric fistula rats by continuous intragastric perfusion and back titration or by flushing the gastric contents with saline every 10 min. Gastric acid secretion was stimulated by distension (5 ml for 6 min) or by injection of secretagogues (histamine 5.0 mg/kg s.c., bethanechol 0.5 mg/kg s.c. or pentagastrin 16 micrograms/kg per h i.v.). Gastric distension increased gastric acid secretion 6.2 times over basal gastric acid secretion in vehicle-treated control rats; capsaicin pretreatment significantly reduced this response by 40%. Bilateral cervical vagotomy significantly reduced the secretory response to gastric distension in the vehicle-treated group to a level not significantly different from capsaicin-treated rats. The secretory response to histamine was reduced by 42% in capsaicin-treated rats compared to vehicle pretreatment whereas the responses to pentagastrin and bethanechol were unaltered. These results indicate that capsaicin-sensitive vagal afferent fibers mediate the vagal portion of the secretory response to gastric distension; in addition these afferents play a role in the gastric acid secretory response to histamine.     

Effect of capsaicin on PAF-induced bronchial hyperresponsiveness and pulmonary cell accumulation in the rabbit.

1 Platelet activating factor (PAF), but not the carrier molecule bovine serum albumin (BSA) induced bronchoconstriction in the anaesthetized rabbit. This bronchoconstriction was not altered by prior treatment with capsaicin. 2 Rabbits demonstrated increased airways responsiveness to histamine 24h after exposure to PAF but not to BSA. PAF failed to increase airways responsiveness to histamine in animals pretreated with capsaicin (80 mg kg-1). 3 A significant increase in inflammatory cells was obtained in bronchoalveolar lavage (BAL) 24h after PAF exposure in vehicle-treated rabitts. This was associated with an increase in the numbers of neutrophils and eosinophils. Capsaicin treatment inhibited the PAF-induced influx of inflammatory cells found in BAL, although this was not associated with an inhibition of PAF-induced pulmonary eosinophilia. 4 Capsaicin-induced motor effects were modest in epithelium-intact rabbit bronchial preparations, but were significantly enhanced in epithelium-denuded preparations in the presence of thiorphan. The contractile response to capsaicin was significantly inhibited in tissues exposed to a consecutive dose of capsaicin. Furthermore, ruthenium red abolished capsaicin-induced contraction in epithelium-denuded preparations. 5 Tissue content of calcitonin gene-related peptide-like immunoreactivity and substance P-like immunoreactivity was not reduced in bronchus and iris obtained from capsaicin-treated rabbits, although capsaicin-induced contractile responses in rabbit bronchus obtained from animals previously treated with capsaicin were significantly reduced. Furthermore, airway responses to histamine, methacholine and electrical field stimulation in vitro, were not altered by pretreatment of rabbits in vivo for 3 days with capsaicin.(ABSTRACT TRUNCATED AT 250 WORDS)     

Neonatal capsaicin treatment impairs vasopressin-mediated blood pressure recovery following acute hypotension

Rats were treated with a single injection of either capsaicin (50 mg kg-1 s.c.) or vehicle on day 2 after birth. When the animals were adult, they were challenged with osmotic (water deprivation) and haemodynamic (acute hypotension) stimuli that normally evoke vasopressin release. Capsaicin-treated and vehicle-injected rats showed similar body weight losses and plasma osmolalities following 48 h of water deprivation. Thus it appears that neonatal treatment with capsaicin does not impair the antidiuretic response to plasma hyperosmolality. Following acute ganglion blockade in the presence of angiotensin converting enzyme inhibition, there was some recovery of blood pressure in the vehicle-injected rats, but recovery was significantly (P less than 0.001) less in the capsaicin-treated animals. The recovery may be attributed to vasopressin since it was abolished by an antagonist selective for the pressor action of the peptide (d(CH2)5DAVP). These results suggest that neonatal treatment with capsaicin impairs vasopressin-mediated recovery of blood pressure following acute hypotension. The possible involvement of baro- or chemoreceptor afferents is discussed.     

Intrinsic sensory deprivation induced by neonatal capsaicin treatment induces changes in rat brain and behaviour of possible relevance to schizophrenia

Schizophrenia is considered to be a neurodevelopmental disorder with origins in the prenatal or neonatal period. Brains from subjects with schizophrenia have enlarged ventricles, reduced cortical thickness (CT) and increased neuronal density in the prefrontal cortex compared with those from normal subjects. Subjects with schizophrenia have reduced pain sensitivity and niacin skin flare responses, suggesting that capsaicin-sensitive primary afferent neurons might be abnormal in schizophrenia. This study tested the hypothesis that intrinsic somatosensory deprivation, induced by neonatal capsaicin treatment, causes changes in the brains of rats similar to those found in schizophrenia. Wistar rats were treated with capsaicin, 50 mg kg(-1) subcutaneously, or vehicle (control) at 24-36 h of life. At 5-7 weeks behavioural observations were made, and brains removed, fixed and sectioned. The mean body weight of capsaicin-treated rats was not significantly different from control, but the mean brain weight of male, but not female, rats, was significantly lower than control. Capsaicin-treated rats were hyperactive compared with controls. The hyperactivity was abolished by haloperidol. Coronal brain sections of capsaicin-treated rats had smaller cross-sectional areas, reduced CT, larger ventricles and aqueduct, smaller hippocampal area and reduced corpus callosum thickness, than brain sections from control rats. Neuronal density was increased in several cortical areas and the caudate putamen, but not in the visual cortex. It is concluded that neonatal capsaicin treatment of rats produces brain changes that are similar to those found in brains of subjects with schizophrenia.     

Capsaicin treatment in adult Wistar-Kyoto and spontaneously hypertensive rats: effects on nociceptive behavior and cardiovascular regulation

Effects of s.c. capsaicin pretreatment on nociception, mean systemic arterial blood pressure, and dose-response curves for depressor effects of substance P (SP) and pressor effects of angiotension II (AII) and norepinephrine (NE) were examined in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Capsaicin pretreatment significantly elevated hot plate and tail flick latencies in SHR subjects but was without effect in WKY rats. Capsaicin pretreatment significantly reduced mean systemic arterial blood pressure in rats of both strains. Both vehicle- and capsaicin-treated WKY subjects exhibited greater depressor responses than did subjects of the corresponding SHR groups after i.v. SP administration. Vehicle-treated SHR subjects exhibited greater pressor responses to both AII and NE than did rats of the vehicle-treated WKY group. Capsaicin treatment decreased the sensitivity of WKY rats to the pressor effects of both AII and NE. Strain differences involving nociception, cardiovascular regulation, and responses to capsaicin may underly the results reported.     

Capsaicin decreases B-endorphin hypothalamic concentrations in the rat

Capsaicin has been administered intraventricularly to adult rats and subcutaneously to neonatal rats. Adult rats were killed three, five, seven and fifteen days after capsaicin administration, while rats treated neonatally were killed when six months old. In the adult rats capsaicin induced a decrease in hypothalamic B-endorphin concentrations three, five and seven days after treatment, while they returned to normal values by day fifteen. A decrease in B-endorphin hypothalamic concentrations was also present in rats treated neonatally, while substance P, somatostatin and met-enkephalin concentrations were never affected by capsaicin treatment.     

Substance P immunoreactivity in the rat mammary nipple and the effects of capsaicin treatment on lactation

Tissue concentrations of substance P immunoreactivity (SP-I) were measured in rat mammary nipples and were significantly greater than in ventral abdominal skin in nonpregnant and pregnant rats. In contrast, the concentration of nipple SP-I was lower than that of skin in twelve day lactating animals. The mean total SP-I content of the pooled twelve nipples from each rat was not significantly different in nonpregnant, pregnant or lactating rats. However, the mean weight of the pooled twelve nipples from each rat was significantly higher in the lactating rats than in pregnant rats. Immunohistochemistry revealed SP-I nerve trunks and single fibers throughout the nipples of lactating rats. Nerve fibers were observed among smooth muscle and along blood vessels throughout the dermis and in association with epidermal structures. Some SP-I fibers were also observed in association with the main lactiferous duct and mammary gland secretory parenchyma. Radioimmunoassay and immunohistochemistry of nipples from lactating rats treated with capsaicin as neonates revealed a marked depletion of SP-I. Rats treated with capsaicin as neonates had a normal gestation period and produced litters of normal size and birth weight. However, the litters of these lactating rats grew at a significantly slower rate than litters from controls. The quantity of milk obtained from capsaicin-treated lactating dams, following a one hour suckling period on the twelfth day of lactation, was significantly less than that obtained by litters of control dams. It is concluded that capsaicin-sensitive primary sensory nerves of the mammary nipple play a role in the afferent limb of the suckling reflex. One transmitter candidate for these nerves is substance P.     

Evidence for the involvement of vanilloid receptor in the antinociception produced by the dialdeydes unsaturated sesquiterpenes polygodial and drimanial in rats

This study investigated whether or not the neonatal treatment of rats with the sesquiterpenes polygodial or drimanial could cause persistent antinociception similar to that induced by capsaicin. Rats were injected subcutaneously 48 h after birth with capsaicin (50 mg/kg), polygodial (150 mg/kg), drimanial (150 mg/kg) or vehicle (1ml/kg). Six to eight weeks later, rats were tested in models of nociception. Treatment of rats with capsaicin, polygodial or drimanial produced significant inhibition of the first phase and, to a lesser extent, the second phase of formalin-induced nociception. A significant reduction in Complete Freund's Adjuvant and capsaicin-induced hyperalgesia was observed in the animals neonatally treated with capsaicin, polygodial or drimanial compared with vehicle-treated rats. Moreover, both sesquiterpenes caused inhibition of plasma extravasation induced by injection of capsaicin. The neonatal treatment with capsaicin, polygodial or drimanial significantly decreased [3H]-resiniferatoxin binding sites in the rat spinal cord, but only capsaicin neonatal treatment significantly reduced the expression of TRPV1 in dorsal root ganglia (DRG) when assessed by Western blot. These results extend our previous findings demonstrating that the neonatal treatment of rats with polygodial or drimanial, similar to that reported for capsaicin, produced persistent antinociception in adult animals associated with TRPV1 down-regulation in the spinal cord, but not TRPV1 expression in DRG.     

Systemic capsaicin treatment impairs the micturition reflex in the rat.

Filling the urinary bladder via a urethral cannula and preventing its voiding in anaesthetized rats led to rhythmic contractions of the detrusor muscle, which lasted for more than 1 h. This rhythmic activity ceased about 30 min after a s.c. injection of 50 mg kg-1 capsaicin. The contractile response of the detrusor to topically applied capsaicin was lost after systemic administration of the toxin, whereas no change in the sensitivity to acetylcholine was observed. Urinary bladders of normal rats had a capacity of about 1 ml. Bladders of rats treated with capsaicin as neonates held a volume of more than 5 ml without contracting. Such bladders were insensitive to topically applied capsaicin but they contracted to acetylcholine as strongly as the bladders of control rats. During an observation period of 3 days control rats gained weight at night and lost weight by day. Rats treated with capsaicin as neonates showed little fluctuation in body weight. Such rats hardly excreted any urine by day although at night they excreted as much as controls. A water load of 5 ml 100 g-1 was excreted by control rats within 3 h. Rats treated with capsaicin as neonates excreted only half as much. In addition, 50% of the water load was excreted far later by capsaicin treated rats than by controls. Few changes were observed in rats treated with capsaicin as adults. It is concluded that all primary afferent fibres mediating the sensation of a full bladder are capsaicin-sensitive. An additional effect of capsaicin on renal mechanisms cannot be excluded.     

Capsaicin-sensitive nerves modulate resting blood flow and vascular tone in rat gut

Summary Acute and chronic treatments with capsaicin were used to evaluate the role of afferent neurons in the regulation of intestinal blood flow. Experiments were performed on anesthetized rats, in which mean intestinal blood flow was determined with a pulsed Doppler flowmeter mean systemic arterial pressure was determined with a transducer, and intenstinal vascular conductance (C) was calculated from these measurements. Acute administration of periarterial capsaicin (0.5 mg) induced biphasic intestinal vascular responses. An early hyperemic response occurred with a maximal increase in blood flow of 31 % at 5 min, followed by a decrease in blood flow of 17% at 30 min. Arterial pressure was decreased by the application of capsaicin, initially by 10%. There was an early increase of 49% in conductance, followed by a 15% decrease, compared with control values. When 1 or 4 mg capsaicin was instilled into the lumen of the jejunum there was a response pattern similar to that observed after periarterial application of capsaicin. Intrajejunal capsaicin (4 mg) increased blood flow by 51%, followed by a decrease of 16%. Mean mesenteric artery conductance was increased by 32% initially and subsequently was decreased by 21%, in response to acute intrajejunal administration of capsaicin. Both mean blood flow and conductance were increased (44% and 76%, respectively) in adult rats chronically pretreated with capsaicin (170 mg total dose) when compared with vehicle-treated controls.However, in rats pretreated neonatally with capsaicin (50 mg/kg) and allowed to mature, basal flood flow was lower than in control animals but C was not different from control littermates. These findings suggest that the hyperemic effect of acute administration of capsaicin may be related to the stimulation of afferent sensory nerves and release of vasodilatory peptides. The late vasoconstrictor effect could be due to neuronal depletion of vasodilator peptides in perivascular nerves. However, changes observed in the intestinal circulation after chronic pretreatment with capsaicin in the adult rat, in contrast to the observations in the neonatally treated rat, cannot be explained entirely by simple depletion of peptides from the sensory nerves. We conclude that capsaicin-sensitive, afferent nerves in the small intestine modulate the resting vascular tone in rat gut. Send offprint requests to O. D. Hottenstein at the above address     

Effect of capsaicin neonatal treatment on the salt intake of the adult rat.

The present study investigated the involvement of capsaicin-sensitive sensory neurons on salt intake control in the rat, following capsaicin neonatal treatment. Capsaicin did not affect salt appetite induced by intramuscular injection of deoxycorticosterone enantate, or by intracranial injection of renin. Moreover, it did not alter salt preference of rats given access to a variety of NaCl concentrations, or the need-free salt intake of multidepleted male rats. On the other hand, in response to furosemide-induced sodium depletion, the salt intake of capsaicin-treated rats was lower than that of controls. However, furosemide-induced Na+ excretion of capsaicin-treated rats proved to be lower than that of controls, thus suggesting that difference in salt intake might be secondary to lower sensitivity of capsaicin-treated rats to the natriuretic action of furosemide. Salt intake is known to be influenced by sensory information from the oral cavity, from the liver and from the intravascular compartment. The absence of effect of capsaicin neonatal treatment suggests that sensory fibers relevant to salt intake control may not be capsaicin sensitive. On the other hand, our findings indicate that capsaicin treatment alters the renal response to furosemide and stimulate further studies on the effects of capsaicin on renal function.     

Effects of neurotensin microinjected into ventral tegmental area on spontaneous motor activity in neonatal 6-hydroxydopamine-treated rats]

Intracerebroventricular treatment of the catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA) after desmethylimipramine pretreatment results in semipermanent brain dopamine (DA) depletion. It has been shown that rats neonatally treated with 6-OHDA show hyperactivity in an open-field test. The purpose of this study was to investigate the spontaneous motor activity in neonatal 6-OHDA-treated rats following bilateral saline (SAL; 0.25 microliter) or neurotensin (NT; 1.25, 2.50, 5.00 micrograms/0.25 microliter/side) microinjection into the ventral tegmental area. Each dose of NT significantly augmented locomotor activity in 6-OHDA-treated rats. On the other hand, controls did not show significant increase in lower dose of NT. Effect of NT microinjection on number of rearings in the 6-OHDA-treated group was not significantly altered compared to the vehicle-treated group. These results suggest that the responses in locomotor activity to NT the ventral tegmental area increase in neonatal 6-OHDA-treated rats, and imply that residual activity in mesolimbic DA neurons which is mediated by NT receptors contributes to a part of the hyperactivity seen after neonatal 6-OHDA lesion.     

Anandamide induces cardiovascular and respiratory reflexes via vasosensory nerves in the anaesthetized rat

1. We tested the hypothesis that sensory nerves innervating blood vessels play a role in the local and systemic regulation of the cardiovascular and respiratory (CVR) systems. We measured CVR reflexes evoked by administration of anandamide (86 - 863 nmoles) and capsaicin (0.3 - 10 nmoles) into the hindlimb vasculature of anaesthetized rats. 2. Anandamide and capsaicin each caused a rapid dose-dependent reflex fall in blood pressure and an increase in ventilation when injected intra-arterially into the hindlimb. 3. Action of both agonists at the vanilloid receptor (VR1) on perivascular sensory nerves was investigated using capsazepine (1 mg kg(-1) i.a.) a competitive VR1 antagonist, ruthenium red (1 mg kg(-1) i.a.), a non-competitive antagonist at VR1, or a desensitizing dose of capsaicin (200 nmoles i.a.). The cannabinoid receptor antagonist SR141716 (1 mg kg(-1) i.a.) was used to determine agonist activity at the CB(1) receptor. 4. Capsazepine, ruthenium red, or acute VR1 desensitization by capsaicin-pretreatment, markedly attenuated the reflex CVR responses evoked by anandamide and capsaicin (P< 0.05; paired Student's t-test). Blockade of CB(1) had no significant effect on the responses to anandamide. 5. Local sectioning of the femoral and sciatic nerves attenuated CVR responses to anandamide and capsaicin (P< 0.05). Vagotomy or carotid sinus sectioning had no significant effect on anandamide- or capsaicin-induced responses. 6. These data demonstrate that both the endogenous cannabinoid, anandamide, and the vanilloid, capsaicin, evoke CVR reflexes when injected intra-arterially into the rat hindlimb. These responses appear to be mediated reflexly via VR1 located on sensory nerve endings within the hindlimb vasculature.     

Capsaicin-sensitive afferent neurones and gastrointestinal propulsion in the rat

Gastrointestinal propulsion (gastric emptying and gastrointestinal transit) of a test meal containing charcoal and 51Cr as well as defaecation in relation to food intake were studied in adult rats pretreated with capsaicin (0.40 mmol kg-1 S.C.) or its solvent one week before experimentation. In solvent-treated rats, gastrointestinal propulsion did not differ when the test meal was given to conscious animals or when the meal was administered under ether anaesthesia. In rats treated with capsaicin, gastrointestinal propulsion was unchanged as compared with solvent-treated rats when the test meal was administered to conscious animals. When, however, the meal was given under ether anaesthesia capsaicin-treated rats showed a delayed gastrointestinal propulsion as compared with solvent-treated rats. This delay in gastrointestinal propulsion was abolished by pretreatment of the animals with guanethidine (67 mumol kg-1 S.C.). Rats treated with capsaicin exhibited a prolonged sleeping time in response to ether as compared with solvent-treated rats. Defaecation in relation to food intake was not changed in rats treated with capsaicin as compared with solvent-treated animals. These results indicate that capsaicin-sensitive afferent neurones do not participate in the physiologic control of gastrointestinal propulsion. The delay in gastrointestinal propulsion observed in capsaicin-treated rats when fed under ether anaesthesia seems to involve the sympathetic nervous system. This finding suggests that secondary functional changes in the autonomic nervous system following capsaicin treatment can influence physiologic processes in which capsaicin-sensitive afferent neurones are not primarily implicated.     

Captopril and capsaicin modify opioid withdrawal in the morphine-dependent rat

The involvement of neurokinins, especially substance P, in the opiate withdrawal syndrome was studied by treating rats with drugs that have been reported to increase (captopril) or decrease (capsaicin) tissue levels of substance P. Preliminary experiments with captopril (0.1, 0.3, 1 or 3 mg/kg, SC) showed that the 0.3 mg/kg dose enhanced some of the naloxone-precipitated withdrawal signs. Captopril alone had no effect in the morphine-dependent rat. On experimental days, either saline or captopril (0.3 mg/kg) was injected (SC) immediately before naloxone in morphine-dependent rats that were pretreated (4 to 10 days before the morphine pellet implantation) with either capsaicin (125 mg/kg, SC) or the capsaicin vehicle (N = 8 for each of 4 groups). Capsaicin treatment inhibited the following withdrawal signs: rhinorrhea, lacrimation and salivation. Captopril increased the occurrence of these secretory responses in vehicle-treated but not in capsaicin-treated animals. Other withdrawal signs were not altered by either captopril or capsaicin treatment. The results support the conclusion that substance P and related neurokinins may be involved in the expression of some signs of opioid withdrawal.