We tested the hypothesis that activation of P2X receptors associated with vagal afferent nerves can evoke a Bezold‐Jarisch (B‐J) depressor reflex in anaesthetized rats. Injection of αβ‐methylene ATP (αβ‐MeATP; 0.6‐600 nmol i.v.) evoked a dose‐dependent B‐J reflex comprising bradycardia, hypotension and apnoea in rats anaesthetized with pentobarbitone. Apnoea was commonly preceded by hyperventilation. Bilateral vagotomy significantly reduced the bradycardia and most of the apnoeic response without affecting hyperventilation, and unmasked a vasopressor response. Hypotension and apnoea were subject to desensitization, and ATP was about 100 times less potent than αβ‐MeATP in evoking the B‐J reflex. ED50 values for responses to αβ‐MeATP were: bradycardia 14.6 ± 3.8 nmol; apnoea 47.1 ± 8.5 nmol; hyperventilation 23.3 ± 6.0 nmol, n= 14. The ED50 for apnoea was significantly greater than that for bradycardia or hyperventilation (P < 0.05). Atropine (2.8 μmol (kg body wt)−1 i.v.) antagonized the reflex bradycardia and hypotension. The P2 antagonists suramin (14 μmol (kg body wt)−1 i.v.) and PPADS (17 μmol (kg body wt)−1 i.v.) antagonized the bradycardic and apnoeic components of the reflex response to αβ‐MeATP, without reducing the vasopressor or hyperventilatory responses to the agonist. Recordings from vagal afferents showed that pulmonary inflation receptors were activated by αβ‐MeATP in 62 % of units recorded (ED50 22 ± 5 nmol) and this was blocked by PPADS (17 μmol (kg body wt)−1 i.v.); unidentified vagal afferents were also activated. αβ‐MeATP activated carotid chemoreceptor afferents (ED50 23 ± 9 nmol), an action that was unaffected by PPADS or suramin. The results support the hypothesis that P2X receptor subtypes for ATP are associated with specific sensory nerves that form part of the homeostatic mechanism for cardiovascular and respiratory regulation and these receptors therefore have physiological, pathological and therapeutic significance.

Background and purpose: Endothelin-1 (ET-1) is present in murine and human skin and causes itch (pruritus) when injected in humans. This behavioural study examined the scratch reflex evoked by ET-1 in mice. Experimental approach: An automated detector was used to determine whether ET-1 causes reflex scratching, the behavioural correlate of itching, in BALB/c mice. Selective agonists and antagonists were used to probe the ET receptor(s) involved.Key results: ET-1 evoked dose-related reflex scratching lasting up to 20 min following intradermal injection (0.1-100 ng; 0.04-40 pmol). The ED 50 for ET-1 induced scratching was 2.1 ng and desensitization occurred with cumulative dosing. High doses of the ET B receptor agonist IRL1620 (10 mg; 5.5 nmol), also caused scratching (ED 50 1.3 mg, 0.7 nmol). The ET A receptor antagonist BQ123 significantly reduced scratching evoked by ET-1 and IRL 1620, suggesting that both agonists caused scratching via an ET A receptor-dependent mechanism. The ET B receptor antagonist BQ788 significantly reduced scratching evoked by IRL1620 but had no effect on scratching evoked by ET-1. This indicated that activation of ET B receptors by high doses of ET B agonist, but not ET-1, can trigger scratching. Conclusion and implications: ET-1 is a potent endogenous activator of reflex scratching (itch). Mechanisms for ET-induced scratching are considered, including direct action of ET-1 on pruriceptive nerve endings and indirect actions via release of endogenous mediators such as histamine from mast cells. ET-1 and ET A receptors, possibly also ET B receptors, are potential targets for developing specific anti-pruritic drugs to treat pruritic skin disorders such as atopic dermatitis.

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Neuropeptides synthesized in dorsal root ganglia (DRG) have been implicated in neurogenic in¯ammation and nociception in experimental and clinical in¯ammatory arthritis. We examined the very early changes in response to adjuvant injection in a rat model of unilateral tibio-tarsal joint in¯amma-tion and subsequent monoarthritis. Within 30 min of adjuvant injection ipsilateral swelling and hyperalgesia were apparent, and marked increases in b-preprotachykinin-A (b-PPT-A) and a-calcitonin gene-related peptide (CGRP)-encoding mRNAs were observed in small-diameter L5 DRG neurones innervating the affected joint. This response was augmented by recruitment of additional small-diameter DRG neurones expressing b-PPT-A and CGRP transcripts. The increased mRNA was paralleled by initial increases in L5 DRG content of the protein products, substance P and calcitonin gene-related peptide. Within 15 min of adjuvant injection there were increases in electrical activity in sensory nerves innervating a joint. Blockade of this activity prevented the rapid induction in b-PPT-A and CGRP mRNA expression in DRG neurones. Increased expression of heteronuclear (intron E) b-PPT-A RNA suggests that increases in b-PPT-A mRNA levels were, at least in part, due to transcription. Pre-treatment with the protein synthesis inhibitor cycloheximide had no effect upon the early rise in neuropeptide mRNAs. This and the rapid time course of these changes suggest that increased sensory neural discharge and activation of a latent modulator of transcription are involved.