Activation of primary afferents in the rabbit ear by noxious heat.
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Afferent Pathways↗
Biomedical subjects
J Donnerer
Publications and source records attributed to J Donnerer.
Capsaicin desensitization in vivo is inhibited by ruthenium red.
The effect of systemic administration of Ruthenium Red on the excitatory and desensitizing effect of capsaicin was investigated in rats. Ruthenium Red was injected s.c. 30 min before capsaicin was administered. The excitatory effect of capsaicin on corneal, perivascular and visceral afferents was not influenced by treatment with Ruthenium Red. However, determination of the neuropeptide content and evoked neuropeptide release in peripheral organs and dorsal spinal cord 48 h after treatment showed that Ruthenium Red attenuated the 'desensitizing' effect of capsaicin at peripheral, but not at central, endings of primary afferents. On the other hand, a capsaicin-elicited autonomic reflex mediated by visceral afferents was still obtained in 9 of 14 rats that had received Ruthenium Red and capsaicin. The results indicate that a single dose of Ruthenium Red, which does not reduce the acute excitatory effect of capsaicin, reduces the desensitizing effect of capsaicin on peripheral endings of primary afferents in vivo. This long-lasting protective effect of Ruthenium Red suggests that it is possible to pharmacologically differentiate between the acute and chronic effects of capsaicin.
Animals↗
Capsaicin-evoked neuropeptide release is not dependent on membrane potential changes.
In high K(+)-depolarized spinal cord slices, capsaicin evoked the in vitro release of substance P and calcitonin gene-related peptide (CGRP) from central terminals of C-fibre afferents. This shows that capsaicin-induced release of neuropeptides from sensory afferents is not dependent on membrane potential changes, and that capsaicin-induced Ca2(+)-influx into nerve terminals does not require activation of voltage-sensitive calcium channels (VSCC). On the other hand, in the continuous presence of capsaicin, high K+ did not evoke release of CGRP, but only released substance P, which most likely originated from intrinsic substance P- containing neurones in the spinal cord.
Animals↗
Region-specific noradrenaline depletion by neonatal DSP-4: functional consequences and effect on a coexisting neurotransmitter.
Noradrenaline (NA) depletion following neonatal treatment of rats with DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzyl-amine) was not accompanied by any changes in neuropeptide tyrosine (NPY) levels. After 85-95% NA depletion in the spinal cord of DSP-4-treated rats, the reaction time in the tail withdrawal test was shorter than in the controls but the endogenous activation of the sympathetic nervous system in the baroreceptor reflex remained unchanged. These results suggest that the NA neurons in the spinal cord have an inhibitory function the processing of incoming sensory information.
Animals↗
Which mechanisms account for the sensory neuron blocking action of capsaicin on primary afferents in the rat urinary bladder?
In the rat isolated bladder, capsaicin produced a concentration-dependent contraction, shown previously to depend upon transmitter release from peripheral endings of primary afferents. When using low concentrations (30-300 nM) of capsaicin, exposure to a second and third dose of capsaicin produced smaller responses than the first application, although a subsequent challenge with 10 microM capsaicin still elicited a contraction which was not reduced as compared to the response produced by the first exposure to a low dose of capsaicin. Capsaicin also evoked a prompt outflow of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI), taken as a marker for sensory nerve activation. A second or third application of a submaximal concentration of the drug was ineffective, although a subsequent challenge with 1 microM capsaicin was effective. These findings indicate that neuropeptide depletion does not necessarily account for the early stage of capsaicin 'desensitization' of primary afferents.
Animals↗
Absorption and metabolism of capsaicinoids following intragastric administration in rats.
This study was performed to examine the metabolism and absorption of intragastrically administered capsaicinoids in the anaesthetized rat. [3H]-dihydrocapsaicin ([3H]-DHC) and unlabelled capsaicin were readily absorbed from the gastrointestinal tract but were almost completely metabolized before reaching the general circulation. A certain degree of biotransformation already took place in the intestinal lumen. Unchanged compounds (identified by chromatography) were present in portal vein blood. There seems to be a saturable absorption and degradation process in the gastrointestinal tract and a very effective metabolism in the liver. Less than 5% of the total amount of extracted radio-activity consisted of unchanged [3H]-DHC in trunk blood and brain 15 min after gastrointestinal application. On the other hand, approximately 50% unchanged [3H]-DHC was detected in these tissues 3 min after i.v. or 90 min after s.c. application of the capsaicinoids. Dihydrocapsaicin (DHC) or [3H]-DHC were metabolized when incubated in vitro with liver tissue but not with brain tissue. The metabolic product(s) did not show capsaicin-like biological activity. It can be concluded that rapid hepatic metabolization limits systemic pharmacological effects of enterally absorbed capsaicin.
Animals↗
Effects of carbonyl cyanide p-trichloromethoxyphenylhydrazone (CCCP) and of ruthenium red (RR) on capsaicin-evoked neuropeptide release from peripheral terminals of primary afferent neurones.
In the superfused isolated rat urinary bladder, capsaicin as well as electrical field stimulation evoked the release of calcitonin gene-related peptide-like immunoreactivity (CGRP-IR). Carbonyl cyanide p-trichloromethoxyphenylhydrazone (CCCP, threshold 2 microM) reduced both, the capsaicin- and the electrical field stimulation-evoked release of CGRP-IR while a low concentration of Ruthenium Red (RR, 0.6 microM and 2 microM) selectively attenuated the capsaicin-evoked release of CGRP-IR but did not influence the effect of electrical field stimulation. 20 microM RR nearly abolished the capsaicin-evoked release, but also attenuated the effect of electrical field stimulation. In the isolated guinea-pig bronchus, electrical field stimulation and capsaicin induced non-cholinergic contractions which are known to be caused by tachykinin release from afferent nerve terminals. CCCP (0.6 microM) only reduced the response to field stimulation; a ten-fold higher concentration of CCCP attenuated field stimulation as well as capsaicin-induced contractions. This is in contrast to the reported selective inhibition of capsaicin-induced contractions by RR. The present data demonstrate that CCCP generally inhibits evoked neuropeptide release, regardless of the kind of stimulation used while low concentrations of RR preferentially inhibit capsaicin-evoked neuropeptide release.
Animals↗
Different control of the adrenocorticotropin-corticosterone response and of prolactin secretion during cold stress, anesthesia, surgery, and nicotine injection in the rat: involvement of capsaicin-sensitive sensory neurons.
The release of ACTH, corticosterone, and PRL was compared in capsaicin-pretreated rats, which lack afferent C-fibers, and their controls under somatosensory (cold, surgery) and central (restraint) forms of stress. Cold stress induced the release of ACTH and consequently that of corticosterone in the controls, but not in the capsaicin-pretreated rats. Intravenous injection of ACTH1-24 was equally effective in releasing corticosterone in both groups. Whereas PRL was not released in response to cold stress, restraint stress did induce the release of both ACTH and PRL, in the capsaicin-pretreated as well as in the control group. Pentobarbital anesthesia alone elicited PRL, but no ACTH release. ACTH release was evoked by surgery under pentobarbital anesthesia but was abolished by capsaicin pretreatment. PRL levels were not further increased by surgery. Nicotine in a small dose (5 micrograms intra-arterially) evoked stimulation of afferent C-fibers as observed on a depressor reflex. Intraperitoneal injection of nicotine (250 micrograms/kg) caused a marked rise in plasma ACTH both in the capsaicin-pretreated conscious rats and in their controls, probably resulting from central stimulation as this effect was shown to be inhibited during pentobarbital anesthesia. A moderate rise of PRL by nicotine was seen in conscious rats. The stimuli used, regarded as experimental models of stress, show essential differences in their ability to evoke the release of ACTH, corticosterone, and PRL. Those stimuli which cause the release of ACTH and corticosterone via afferent C-fiber stimulation do not release PRL, whereas emotional and cognitive stress causes the release of both ACTH and PRL.
Adrenocorticotropic Hormone↗
Ruthenium red selectively inhibits capsaicin-induced release of calcitonin gene-related peptide from the isolated perfused guinea pig lung.
In the present study the influence of Ruthenium red on capsaicin- and bradykinin-evoked neuropeptide release from primary afferent neurons was investigated in the guinea pig. Perfusion of the isolated guinea pig lung in vitro with a capsaicin (1 microM)-containing physiological salt solution increased the amount of calcitonin gene-related peptide-like immunoreactivity (CGRP-IR) in the outflow more than 20-fold. Ruthenium red (RR: 1 microM, 10 microM) dose-dependently reduced capsaicin-induced release of CGRP-IR. Addition of bradykinin (1 microM) to the perfusate induced a 3-fold increase of CGRP-IR in the outflow, which was not significantly reduced by 10 microM RR. These results suggest that RR represents a rather specific antagonist of capsaicin's action on sensory neurons.
Animals↗
Capsaicin-sensitive afferents and blood pressure regulation during pentobarbital anaesthesia in the rat.
(1) Maintenance of blood pressure was investigated during induction of pentobarbital anaesthesia in rats after elimination of capsaicin-sensitive afferent neurons (capsaicin-denervated rats) as compared to vehicle-treated controls. The catecholamine content of heart and adrenals and the rise in blood pressure following electrical excitation of the spinal adrenergic nerves (pithed rat preparation) was also compared between both groups. (2) Capsaicin-denervated rats and their controls had equal amounts of catecholamines in heart and adrenals as well as equal pressor responses to electrical stimulation of spinal sympathetic nerves, thus excluding an influence of capsaicin on efferent pathways. In the state of consciousness, both groups showed the same blood pressure. (3) In capsaicin-denervated rats and in their controls, pentobarbital-induced anaesthesia (50 mg/kg i.p.) was characterized by a decline in blood pressure during the first 6 min. In the controls, this fall in blood pressure was followed by a slow compensatory rise to a level slightly higher than before anaesthesia, and this level was maintained during the following 60 min. This compensation was completely absent in capsaicin-denervated rats, indicating a role for capsaicin-sensitive nerves in this mechanism. An injection of pentobarbital (50 mg/kg i.p.) in pithed rats reduced the pressor response to electrical stimulation of spinal sympathetic nerves by about 40% in capsaicindenervated rats and in their controls. This inhibitory effect of pentobarbital might be involved in the initial fall in blood pressure in intact animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenal Glands↗
Evidence for an excitatory action of the benzodiazepine receptor inverse agonist FG 7142 on C-fibre afferents.
(1) The stimulation of adrenocorticotrophic hormone (ACTH) release by FG 7142 was found to be 50% inhibited in capsaicin-desensitized rats indicating that the excitatory effect of this inverse benzodiazepine agonist is partly mediated through capsaicin-sensitive afferents. (2) The in vitro release of substance P from spinal cord slices was stimulated in a tetrodotoxin-resistant manner by FG 7142. No stimulation of the substance R release by FG 7142 was observed when spinal cord slices were taken from capsaicin-pretreated rats which lack afferent C-fibres. (3) Ro 15-1788 antagonized the in vivo as well as the in vitro stimulatory effects of FG 7142 indicating that they were brought about by interaction with benzodiazepine receptors. (4) It is concluded that FG 7142 has a direct excitatory effect on central terminals of capsaicin-sensitive afferents and that neurotransmitters released from primary afferents are involved in inducing ACTH release following administration of FG 7142 in vivo.
Adrenocorticotropic Hormone↗
Influence of capsaicin-induced denervation on neurogenic and humoral control of arterial pressure.
(1) The influence of capsaicin-sensitive afferent neurones on the regulation of blood pressure by reflex noradrenergic responses and by activation of the renin-angiotensin system was investigated in the rat anaesthetized with pentobarbital. (2) Lowering the pressure in the carotid sinus through unilateral carotid occlusion caused a reflex rise in mean systemic blood pressure which was less marked in capsaicin-pretreated rats than in controls, although an equal drop in mean pressure in the carotid sinus region was observed in both groups. Occlusion of the second carotid artery caused an additional increase in mean systemic blood pressure which was identical in the two groups. (3) Pharmacological blockade of the renin-angiotensin-system with captopril induced a more pronounced hypotonia in capsaicin-pretreated than in control rats. Yet, this difference was based on the impaired noradrenergic counterregulation in capsaicin-pretreated rats, because both groups showed identical responses to captopril following guanethidine-induced adrenergic blockade. (4) Plasma renin activity was increased by a factor of 2 following guanethidine treatment of awake animals. It reached levels 5-7 times higher than those observed in awake animals during pentobarbital anaesthesia. This anaesthesia-induced increase in plasma renin activity was not altered by guanethidine pretreatment. There was no difference in plasma renin activity between controls and capsaicin-pretreated rats under all the conditions tested. (5) These results show that the immediate reflex adjustment of blood pressure is impaired in the capsaicin-pretreated rat, possibly because of an impairment of sensors for low perfusion pressure in the carotid sinus. On the other hand, the renin-angiotension-system remains unimpaired after neonatal capsaicin-pretreatment.
Anesthesia↗
Effects of endothelin on the cardiovascular system and on smooth muscle preparations in different species.
(1) The actions of porcine endothelin (ET), an endothelium-derived vasoconstrictor peptide, have been investigated in several in vitro smooth and cardiac muscle preparation as well as on the blood pressure of anaesthetized rats and rabbits. (2) In isolated visceral smooth muscles (guinea pig ileum, rat colon and uterus, rabbit jejunum) ET caused a long-lasting contraction which persisted after repeated rinsing. ET did not interfere with the spontaneous phasic activity of the rabbit jejunum or with contractions evoked by histamine or carbachol. (3) ET contracted isolated blood vessels (portal vein of guinea-pig and rat). In isolated perfused organs (rabbit ear, guinea-pig lung, rat mesentery and hindpaw) ET led to a long-lasting vasoconstriction. In the isolated perfused guinea-pig lung ET caused vaso- and bronchoconstriction. (4) ET produced a long-lasting positive inotropic effect in spontaneously beating isolated guinea-pig atria. The positive inotropic action of strophanthin was augmented in the presence of ET. (5) In the isolated perfused guinea-pig and rat hearts the prominent effect of ET was a long-lasting coronary vasoconstriction. (6) Pithed rats responded to i.v. injection of ET with a long-lasting increase in blood pressure. In pentobarbitone anaesthetized rats pretreated either with atropine, with guanethidine plus atropine, or with guanethidine plus atropine plus indomethacin, the long-lasting increase in blood pressure was smaller than in pithed rats whereas the initial short-lasting decrease in blood pressure was more pronounced; in pentobarbitone anaesthetized rabbits endothelin caused bronchoconstriction, a decrease in blood pressure and a pronounced increase in central venous pressure possibly resulting from pulmonary or coronary artery constriction or a combination of both effects.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Capsaicin-induced stimulation of polymodal nociceptors is antagonized by ruthenium red independently of extracellular calcium.
The dual effect of capsaicin on primary afferent neurons, excitation and stimulation of transmitter release, its dependence on extracellular calcium and its modulation by Ruthenium Red have been investigated in the rabbit ear. Injection of capsaicin into the central artery of the isolated perfused ear with intact neuronal connection induced a reflex fall in systemic arterial blood pressure of the anaesthetized rabbit. Addition of Ruthenium Red (0.6-20 microM) to the perfusate of the ear reversibly attenuated this response in a dose-dependent manner. Perfusion of the ear with a Ca2+-free, 3 mM EGTA-containing physiological salt solution enhanced the capsaicin-evoked depressor reflex but did not prevent the inhibitory action of Ruthenium Red. Perfusion of the isolated rabbit ear with capsaicin (10 microM)-containing physiological salt solution induced the release of substance P-like immunoreactivity which was inhibited by Ruthenium Red (0.6-20 microM) and by omission of extracellular Ca2+. The results demonstrate that capsaicin-evoked transmitter release is dependent on extracellular calcium while capsaicin-evoked excitation is not reduced in a Ca2+-free perfusate. Both effects of capsaicin are potently inhibited by Ruthenium Red. The fact that capsaicin-induced excitation of primary afferents is antagonized by Ruthenium Red also in the absence of extracellular Ca2+ suggests this inhibitory action of Ruthenium Red is not only mediated by inhibition of transmembrane Ca2+ fluxes.
Animals↗
Primary sensory neurones and naloxone-precipitated morphine withdrawal.
1. The C-fibre-evoked depressor reflex following i.a. injection of capsaicin and the wiping movements following chemical irritation of the cornea by capsaicin were both found to be augmented in the naloxone-precipitated morphine withdrawal phase. 2. The in vitro capsaicin-evoked release of substance P from central terminals of C-fibre afferents in the spinal cord was decreased in morphine-treated rats. Following naloxone, the release in the morphine-treated group was as large as in the control group. 3. The C-fibre mediated plasma extravasation in the rat paw after naloxone was found to be the same in morphine-treated and control rats. 4. It is concluded that C-fibre-evoked reflex reactions are augmented during morphine withdrawal, but that the mechanisms responsible are either located postsynaptically to the primary sensory neurone or further centrally.
Animals↗
Reflex activation of the adrenal medulla during hypoglycemia and circulatory dysregulations is regulated by capsaicin-sensitive afferents.
1. Catecholamines were measured in the adrenal venous outflow during hypoglycemia, hypotension, hypovolaemia and efferent splanchnic nerve stimulation in anaesthetized capsaicin-pretreated rats and their vehicle controls. In control rats, efferent splanchnic nerve stimulation caused a marked rise in adrenaline and noradrenaline levels. In contrast, the other stimuli mainly elicited adrenaline release. 2. The release of adrenaline and nor-adrenaline evoked by splanchnic nerve stimulation was of the same magnitude in capsaicin-pretreated rats (whose afferent C-fibres were destroyed by this pretreatment) as in their untreated controls. 3. Capsaicin-pretreatment of rats resulted, however, in a reduced adrenaline release during insulin-induced hypoglycemia for up to 30 min and, as a consequence, generated a greater fall in blood glucose. The adrenal response to hypoglycemia in the first 30 min was also reduced by bilateral vagotomy indicating the existence of glucoreceptors on peripheral vagal terminals. 4. Adrenaline secretion following central glucopenia induced by 2-deoxy-D-glucose remained unaffected by capsaicin-pretreatment, indicating an intact function of the central regulation of adrenaline release. 5. Hypotension evoked either by sodium nitroprusside or by haemorrhage resulted in a pronounced increase in adrenaline release which was almost absent in the capsaicin-pretreated rats. 6. It is concluded that the stimulation of the adrenal medulla during hypoglycemia, hypotension, and hypovolaemia is based on a reflex mechanism initiated by capsaicin sensitive afferents.
Adrenal Medulla↗
Neonatal capsaicin treatment of rats reduces ACTH secretion in response to peripheral neuronal stimuli but not to centrally acting stressors.
1. Plasma adrenocorticotrophic hormone (ACTH) concentrations were measured in rats following exposure to anaesthetic agents, after stimulation of peripheral sensory nerves, and during psychological stress. 2. In rats, kept in their home cages, the i.p. injection of sodium pentobarbitone did not cause an increase in plasma ACTH, whereas injection of urethane increased plasma ACTH several times. In rats transferred to a glass dessicator and inhaling oxygen, plasma ACTH was more than 3 fold higher than in rats in their home cage. Exposure to nitrous oxide, halothane or ether in a glass dessicator produced significantly higher plasma ACTH concentrations when compared to exposure in the home cage. 3. In rats anaesthetized with pentobarbitone, the electrical stimulation of large myelinated afferents in the sciatic nerve did not trigger a measurable increase in ACTH secretion, whereas stimulation of afferent A delta- and C-fibres significantly elevated plasma ACTH concentrations. Rats treated as neonates with capsaicin showed an attenuated ACTH response to A and C-fibre stimulation. 4. Similarly, capsaicin pretreatment reduced the increase in ACTH secretion during morphine withdrawal; a similar effect was produced by clonidine. 5. ACTH secretion following open field exposure, ether stress or hypoglycaemia was not changed by capsaicin pretreatment. 6. It was concluded that capsaicin-sensitive afferents are involved in the secretion of ACTH elicited by somatosensory forms of stress. Centrally evoked ACTH release is not affected by capsaicin pretreatment.
Adrenocorticotropic Hormone↗
Effects of clonidine and yohimbine on a C-fibre-evoked blood pressure reflex in the rat.
1. The involvement of alpha 2-adrenoceptors in a capsaicin-induced depressor reflex in the rat has been investigated. 2. The reflex fall in blood pressure following an intra-arterial injection of capsaicin was partially blocked by an intrathecal infusion of clonidine (1 microgram) at the spinal cord level L4-L5, an effect which was abolished by the prior intrathecal infusion of yohimbine (5 micrograms). 3. Clonidine (1 microgram) given intracisternally blocked the depressor reflex almost completely; however, it also produced a gradual, prolonged fall in mean carotid pressure. 4. Yohimbine (20 micrograms) given intracisternally did not change mean blood pressure but had a dual effect on the depressor reflex in response to the capsaicin injection: a short period of enhanced reflex response was followed by a long lasting inhibition of the response. 5. It was concluded that alpha 2-adrenoceptors in the spinal cord inhibit the capsaicin-evoked depressor reflex and that pre- and postsynaptic alpha 2-adrenoceptors in the brain stem modulate this reflex.
Animals↗