Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo

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The capsaicin receptor: a heat-activated ion channel in the pain pathway

The neurotrophins are a small group of dimeric proteins that profoundly affect the development of the nervous system of vertebrates. Recent studies have established clear correlations between the survival requirements for different neurotrophins of functionally distinct subsets of sensory neurons. The biological role of the neurotrophins is not limited to the prevention of programmed cell death of specific groups of neurons during development. Neurotrophin-3 in particular seems to act on neurons well before the period of target innervation and of normally occuning cell death. In animals lacking functional neurotrophin or receptor genes, neuronal numbers do not seem to be massively reduced in the CNS, unlike in the PNS. Finally, rapid actions of neurotrophins on synaptic efficacy, as well as the regulation of their mRNAs by electrical activity, suggest that neurotrophins might play important roles in regulating neuronal connectivity in the developing and in the adult central nervous system.

Physiology of the neurotrophins

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The induction of pain: an integrative review

Local effector functions of capsaicin-sensitive sensory nerve endings : involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides

The influence of natural products upon drug discovery.

The pharmacology of morphine and opioid peptides was studied in the guinea-pig ileum by examining their inhibitory effects on propulsive peristaltic activity and on the cooling-induced longitudinal contraction. In these experiments, dose-response curves were recorded. The rank order of potency in inhibiting peristalsis was found to be: dermorphin greater than FK 33-824 greater than dynorphin-(1-17) greater than dynorphin-(1-13) greater than delta-receptor-peptide greater than morphine greater than [Leu] enkephalin, whereas the rank order in inhibiting cooling-induced contractions was found to be: dynorphin-(1-13) congruent to FK 33-824 congruent to dermorphin greater than delta-receptor peptide greater than morphine. Naloxone antagonized the maximally effective dose of each of the opioid agents. In view of the differences between the abilities of these opioids to inhibit propulsive peristaltic activity, these models seem to be valuable for the examination of inhibitory opioid effects in the gut.

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New models for the evaluation of opioid effects in the guinea-pig ileum

Improved neurochemical recovery of 6-hydroxydopamine-lesioned postganglionic sympathetic neurons by nerve growth factor in the adult rat

Primary sensory neurons respond to a vigorous excitation via the capsaicin receptor/TRPV1 cation channel by a phosphorylation of the Jak/STAT pathway as measured by phospho-STAT3, and of the Ras/Raf-M

The NK1 receptor antagonist SR140333 inhibits capsaicin-induced ERK phosphorylation in sensory neurons.

Evidence for opioid-induced release of glutamate in guinea pig longitudinal muscle-myenteric plexus strip.

(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 capsaicin-denervated rats and in their controls. This inhibitory effect of pentobarbital might be involved in the initial fall in blood pressure in intact animals. (4) The blood pressure which had reached a steady level 20 min after induction of the pentobarbital anaesthesia in intact rats responded to various factors as follows: (A) Bilateral adrenalectomy hardly decreased the blood pressure in the controls and not at all in the capsaicin-denervated rats; thus a substantial influence of the adrenals in the maintenance of blood pressure was excluded. (B) a-Adrenoceptor blockade by phentolamine caused a greater fall of blood pressure in the controls than in the capsaicin-denervated rats; the latter seem therefore under a much lower peripheral adrenergic vasoconstrictor tone. (C) Blockade of the angiotensin-converting enzyme by captopril had a more pronounced and persistent depressor effect in the capsaicin-denervated rats than in the controls; this indicates that the capsaicin-denervated rats have an increased dependence on an angiotensin II-mediated blood pressure regulation. (D) Sodium nitroprusside caused an equally pronounced fall in blood pressure in both groups; its vasodilatory potency thus seems to overrun all other compensatory reflex regulations. It is concluded that the continuous blood pressure regulation under pentobarbital anaesthesia depends upon signals conveyed to the central nervous system via capsaicin-sensitive afferent neurons which activate efferent adrenergic mechanisms. These regulations are regarded supplementary or auxiliary to the baro-and chemoreceptor reflexes.

Josef Donnerer

Papers

New models for the evaluation of opioid effects in the guinea-pig ileum

Improved neurochemical recovery of 6-hydroxydopamine-lesioned postganglionic sympathetic neurons by nerve growth factor in the adult rat

The NK1 receptor antagonist SR140333 inhibits capsaicin-induced ERK phosphorylation in sensory neurons.

Evidence for opioid-induced release of glutamate in guinea pig longitudinal muscle-myenteric plexus strip.

Capsaicin-sensitive afferents and blood pressure regulation during pentobarbital anaesthesia in the rat