Endogenous opioid-mediated antinociception in cholestatic mice is peripherally, not centrally, mediated Lisa Nelson 1 , Nathalie Vergnolle 2 , Charlotte D’Mello 1 , Kevin Chapman 2 , Tai Le 1 , Mark G. Swain 1, * 1 Liver Unit, Gastrointestinal Research Group, Health Sciences Center, University of Calgary, 3330 Hospital Dr., NW, Calgary, AB, Canada T2N 4N1 2 Mucosal Inflammation Research Group, University of Calgary, Calgary, AB, Canada T2N 4N1 Background/Aims: Cholestasis is associated with naloxone reversible antinociception and opiate receptor antagonists are used clinically to treat pruritus. Pain and pruritus are closely interrelated and opioids modulate both sensations. Therefore, we undertook a series of experiments to characterize opioid-mediated antinociception in cholestasis and determine if it occurs inside or outside the CNS. Methods: Antinociception scores to both thermal and mechanical stimuli were determined in mice with cholestasis due to bile duct resection vs sham controls. Results: Cholestatic mice demonstrated significant antinociception to both stimuli compared to controls, which was reversible by the opiate receptor antagonist naloxone. The experiments were repeated with a naloxone derivative, which does not cross the blood–brain-barrier (i.e. naloxone methiodide) with similar results, indicating an opioid antinociceptive effect mediated outside of the CNS. Experiments with intraplantar injections of low dose naloxone methiodide confirmed that cholestasis-associated antinociception occurs at the level of cutaneous nerve endings. These findings were supported by findings of increased dermal met-enkephalin expression in cholestatic mice. Conclusions: Cholestasis in mice is associated with antinociception due to local effects of endogenous opioids (i.e. met- enkephalin) at the level of sensory nerve endings. These findings may have direct implications in the management of cholestasis associated pruritus. q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Keywords: Opioids; Met-enkephalin; Analgesia; Opioid receptor; Naloxone; C-fibers 1. Introduction Pruritus is commonly encountered in patients with cholestatic liver diseases and can be a profoundly bother- some and disabling symptom [1,2]. However, the patho- genesis of pruritus in cholestasis remains poorly understood. Traditionally, cholestasis associated itch has been postu- lated as resulting from the interaction of free unmyelinated cutaneous nerve endings with a substance(s) retained in the circulation as part of the cholestatic syndrome. The likely unmyelinated neuron involved in this process is the recently defined C-fiber, which carries itch related nerve impulses from the skin to the spinal dorsal horn [3,4]. Afferent spinal projections then carry the itch signals in the contralateral spinothalamic tract to the thalamus and ultimately to the somatosensory cortex [5]. These central neural connections involved in itch allow for the modulation of pruritus and potentially for the de novo induction of pruritus within the CNS [5,6]. Opioids have well documented roles in both antinocicep- tion and pruritus [7]. In addition, although pruritus and pain are distinct sensations, there exist complex interactions between them. Specifically, itch can be inhibited by pain and inhibition of the central processing of pain can induce itch [8]. Therefore, increasing severity of pruritus appears to Journal of Hepatology 44 (2006) 1141–1149 www.elsevier.com/locate/jhep 0168-8278/$32.00 q 2005 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.jhep.2005.11.043 Received 22 June 2005; received in revised form 17 October 2005; accepted 7 November 2005; available online 27 December 2005 * Corresponding author. Tel.: C1 403 220 8457; fax: C1 403 270 0995. E-mail address: swain@ucalgary.ca (M.G. Swain).