No abstract

Vagal, spinal and intestino-fugal fibres all potentially transmit mechanosensory afferent information from the gastrointestinal tract. We aimed to characterize the relative mechanosensitivity of these three different afferent populations supplying the rat jejunum. Afferent nerve discharge was recorded from pentobarbitone-anaesthetized rats during different distension protocols. Saline ramp distension (1 mL min(-1)) and barostat ramp distension (2 mmHg 4 s(-1)) each evoked biphasic responses but with the latter significantly attenuated especially at low distending pressures. Barostat controlled phasic distensions (10-50 mmHg, 25 s) evoked an afferent response with a peak at the onset of distension adapting to a plateau level that was maintained and comparable to the barostat ramp responses at the corresponding pressures. Chronic subdiaphragmatic vagotomy significantly attenuated the low pressure component of the response to balloon ramp distension and both peak and plateau responses to phasic distension. Single unit analysis showed an absence of low threshold afferent activity after vagotomy while the response to fibres with wide-dynamic range and high threshold sensitivity were preserved hexamethonium had no effect on the responses to either ramp or phasic distension. These findings suggest that the nature of the distension stimulus is critical in determining the pattern of response observed from the various subpopulations of afferents supplying the bowel wall.

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,

The aim of the present study was to examine the sensitivity of mesenteric afferents supplying the rat small intestine to mu-opioid receptor ligands. Mesenteric afferent discharge was recorded electrophysiologically in response to [D-ALA2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO; 100 mug kg(-1) i.v.), before and after treatment with the mu-receptor antagonist alvimopan (1 mg kg(-1) i.v.). DAMGO markedly stimulated whole nerve mesenteric afferent discharge (P < 0.05), an effect completely blocked by alvimopan. The response of mesenteric afferents to 2-methyl-5-hydroxytryptamine (30 microg kg(-1) i.v.), bradykinin (0.1-1 microg kg(-1) i.a.) and both low- and high-threshold distension (0-60 mmHg) was unaffected by alvimopan. In chronically vagotomized animals, the low-threshold response to distension was attenuated while the remaining high-threshold response was unaffected by alvimopan. In conclusion, mesenteric afferent fibres are markedly stimulated by mu-opioid receptor agonists, an effect blocked by alvimopan, which may contribute to the gastrointestinal reflex and behavioural responses to opiate treatment or abuse. However, alvimopan did not influence the normal sensitivity of intestinal afferents to chemical and mechanical stimuli that activate different subpopulations of vagal and spinal afferents. Thus, alvimopan may be useful for the treatment of gastrointestinal sequelae following opiate treatment for postoperative or chronic pain.

Ghrelin has been shown to decrease firing of gastric vagal afferents at doses comparable with circulating levels in the fasted state. This raises the possibility that ghrelin may have a hormonal action on other vagal afferent populations. The aim of this study was to determine the effects of ghrelin on jejunal afferent activity; including responses to distension, 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) and cholecystokinin (CCK) in both naïve and vagotomized rats. Ghrelin significantly augmented the afferent response to distension. No effect was observed on baseline afferent discharge, or the response to 2-methyl-5-HT and CCK. The effect of ghrelin was more pronounced at lower ramp distending pressures (0-30 mmHg). Similarly, ghrelin augmented the jejunal afferent responses to phasic distension at 10-30 mmHg, but had no effect at higher pressures. Chronic subdiaphragmatic vagotomy and administration of the growth hormone secretagogue receptor (GHS-R) antagonist [D-Lys3]-GHRP-6 prevented the augmentation of the afferent responses to distension indicating ghrelin is acting through the GHS-R on vagal afferent fibres. Ghrelin augments the mechanosensation of jejunal vagal afferents and hence may lead to increased perception of hunger contractions.