Excitatory effect of P2X receptor activation on mesenteric afferent nerves in the anaesthetised rat

Autor: Charlotte E. Booth, Patrick P.A. Humphrey, Anthony J. Kirkup, I P Chessell, David Grundy
Jazyk: angličtina
Rok vydání: 1999
Předmět:
Popis: We examined the effects of P2X purinoceptor agonists and P2 purinoceptor antagonists on mesenteric afferent nerves supplying the jejunum in the pentobarbitone sodium-anaesthetised rat. ATP (0.01–10 mg kg−1, i.a.) and α,β-methylene-ATP (1–30 μg kg−1, i.a.) each induced dose-dependent increases in afferent nerve discharge and intrajejunal pressure. The effect on afferent nerves comprised an early ( 2 s after administration), less pronounced in comparison, which coincided with elevated intrajejunal pressure. Pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (20 mg kg−1, i.v.) and suramin (80 mg kg−1, i.v.) each antagonised both the early and later increases in afferent nerve discharge elicited by α,β-methylene-ATP (30 μg kg−1, i.a.). Co-administration of ω-conotoxin MVIIA and ω-conotoxin SVIB (each at 25 μg kg−1, i.v.), or treatment with the selective 5-HT3 receptor antagonist alosetron (30 μg kg−1, i.v.), did not affect the rapid burst of afferent nerve activity elicited by α,β-methylene-ATP (30 μg kg−1, i.a.). However, toxin treatment did attenuate the elevations in intrajejunal pressure and the corresponding later phases of evoked afferent discharge, while alosetron inhibited basal afferent nerve activity. In summary, ATP and α,β-methylene-ATP each evoke excitation of mesenteric afferent nerves in the anaesthetised rat. We propose that the early increase in mesenteric afferent nerve activity represents a direct effect on the nerve ending, mediated by P2X receptors, whereas the later increase reflects activation of mechanosensitive fibres secondary to elevated intrajejunal pressure. A multiplicity of ionotropic P2X and metabotropic P2Y purinoceptors mediate the now well-established extracellular role of ATP as a neurotransmitter (for reviews see Humphrey et al. 1998; Harden et al. 1998). Amongst its many important physiological actions, ATP may subserve as an extracellular transducer of sensory stimuli (see Burnstock & Wood, 1996, for review; Nakamura & Strittmatter, 1996; Cook et al. 1997). For example, ATP and analogues activate inward currents in cells dispersed from amphibian and mammalian sensory ganglia (Krishtal et al. 1988; Bean, 1990; Evans et al. 1992; Khakh et al. 1995; Robertson et al. 1996). The biophysical characteristics of these currents suggested that they were mediated by ionotropic P2X receptors and, indeed, mRNA for several P2X receptors is present in these neural tissues (Chen et al. 1995; Lewis et al. 1995; Kidd et al. 1995; Collo et al. 1996). Moreover, ATP stimulates mammalian dorsal horn neurones (Jahr & Jessell, 1983), depolarises isolated vagus nerve trunks (Trezise et al. 1994) and evokes excitation of cutaneous (Bleehen, 1978), visceral (Pelleg & Hurt, 1996) and knee joint afferent nerves (Dowd et al. 1998a) and carotid chemoreceptors (McQueen et al. 1998). These latter four effects would also appear to be mediated through the activation of ionotropic P2X receptors (Trezise et al. 1994; Pelleg & Hurt, 1996; Dowd et al. 1998a; McQueen et al. 1998). Furthermore, both the ability of exogenous ATP and analogues to stimulate pain (Bleehen & Keele, 1977; Bland-Ward & Humphrey, 1997; Hamilton et al. 1999) and the analgesic effect of P2 receptor antagonists in human and animal pain models (Ho et al. 1992; Driessen et al. 1994) are consistent with a role for ATP as a physiological mediator of a form of nociception. Within the gastrointestinal tract, there is abundant evidence that ATP acts as a neurotransmitter, being released from either extrinsic sympathetic efferent nerves (Burnstock, 1990; Vanner & Surprenant, 1996) or from intrinsic or enteric neurones (Galligan & Bertrand, 1994). Patch-clamp experiments performed on cells obtained from nodose and dorsal root ganglion cells (the locations of the cell bodies of afferent nerves which project to the intestines along vagal and spinal pathways, respectively) suggest that ATP, via the stimulation of P2X receptors, may be involved in the perception of intraluminal and, perhaps, even nociceptive stimuli arising from the gut (Lewis et al. 1995; Khakh et al. 1995; Robertson et al. 1996). However, there is no direct evidence for the presence of functional P2X receptors on the terminals of either intrinsic or extrinsic intestinal afferent nerves. Since ATP is released from cells at sites of tissue injury (see Kennedy & Leff, 1995; Burnstock & Wood, 1996), an effect of this substance at P2X receptors present on intestinal afferent nerve endings may contribute to the abdominal discomfort and pain associated with functional and organic disorders of the bowel. Thus it was pertinent to determine whether ATP affected intestinal afferent nerve discharge and to establish the mechanism(s) involved. Therefore, in the present study we examined the effects of ATP and the selective P2X receptor agonist α,β-methylene-ATP and the P2 receptor antagonists pyridoxalphosphate-6-azophenyl-2′,4′-disulphonic acid (PPADS) and suramin on the activity of extrinsic intestinal afferent nerves supplying the jejunum in the anaesthetised rat.
Databáze: OpenAIRE
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