Opioid modulation of ferret vagal afferent mechanosensitivity

Abstract

Page AJ, O'Donnell TA, Blackshaw LA. Opioid modulation of ferret vagal afferent mechanosensitivity. Am J Physiol Gastrointest Liver Physiol 294: G963-G970, 2008. First published February 7, 2008 doi:10.1152/ajpgi.00562.2007.-Despite universal use of opioids in the clinic to inhibit pain, there is relatively little known of their peripheral actions on sensory nerve endings, where in fact they may be better targeted with more widespread applications. Here we show differential effects of -, -, and ␦-opioids on mechanosensitive ferret esophageal vagal afferent endings investigated in vitro. The effects of selec- -80), respectively, on mechanosensory stimulus-response functions were quantified. DAMGO (10 Ϫ7 to 10 Ϫ5 M) reduced the responses of tension receptors to circumferential tension (1-5 g) by up to 50%, and the responses of mucosal receptors to mucosal stroking (10 -1,000 mg von Frey hair) by Ͼ50%. DAMGO effects were reversed by naloxone (10 Ϫ5 M). Tension/mucosal (TM) receptor responses to tension and stroking were unaffected by DAMGO. ICI 199441 (10 Ϫ6 to 10 Ϫ5 M) potently inhibited all responses except TM receptor responses to tension, and SNC-80 (10 Ϫ5 to 10 Ϫ3 M) had no effect other than a minor inhibition of mucosal receptor responses to intense stimuli at 10 Ϫ3 M. We conclude that -and -opioids have potent and selective peripheral effects on esophageal vagal afferents that may have applications in treatment of disorders of visceral sensation. vagal afferents; neuromodulation; esophagus OPIOID RECEPTORS WERE IDENTIFIED more than 30 years ago as the primary targets with which morphine and its derivatives interact to exert their analgesic and other effects. The receptors, along with their endogenous ligands, enkephalins, endorphins, and other opioid peptides, are widely distributed in the central and peripheral nervous system and play an important role in modulating endocrine, immune, cardiovascular, and gastrointestinal functions. Three major types of opioid receptors, , ␦, and , have been defined pharmacologically. Both spinal and vagal sensory neurons express different numbers of -, ␦-, and -opioid receptors that are transported into the peripheral axons (1,13,15,17,31). The -opioid receptor (KOR) agonist fedotozine decreases sensitivity of rat visceral afferents to gastric and colonic distension (7). Despite robust effects of KOR ligands, -and ␦-opioid receptor agonists have not been found to affect mechanosensitivity in these models (20, 34), indicating selectivity of expression within rodent distensionsensitive afferents. The effect of opioid agonists in other species and on different classes of visceral afferents is unknown: for instance mucosal mechanoreceptors, which only respond to mucosal stroking (22, 23). Such effects may have an important bearing on interpretation of clinical findings, such as the inhibitory effect of the -opioid receptor (MOR) agonist morphine on triggering of transient lower esophageal sphincter (LES) relaxation by gastric distension in humans (27) and the effect of opioids...

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