Date Published: September 12, 2013
Publisher: Public Library of Science
Author(s): Raphaël Weibel, David Reiss, Laurie Karchewski, Olivier Gardon, Audrey Matifas, Dominique Filliol, Jérôme A. J. Becker, John N. Wood, Brigitte L. Kieffer, Claire Gaveriaux-Ruff, Thiago Mattar Cunha.
Opiates are powerful drugs to treat severe pain, and act via mu opioid receptors distributed throughout the nervous system. Their clinical use is hampered by centrally-mediated adverse effects, including nausea or respiratory depression. Here we used a genetic approach to investigate the potential of peripheral mu opioid receptors as targets for pain treatment. We generated conditional knockout (cKO) mice in which mu opioid receptors are deleted specifically in primary afferent Nav1.8-positive neurons. Mutant animals were compared to controls for acute nociception, inflammatory pain, opiate-induced analgesia and constipation. There was a 76% decrease of mu receptor-positive neurons and a 60% reduction of mu-receptor mRNA in dorsal root ganglia of cKO mice. Mutant mice showed normal responses to heat, mechanical, visceral and chemical stimuli, as well as unchanged morphine antinociception and tolerance to antinociception in models of acute pain. Inflammatory pain developed similarly in cKO and controls mice after Complete Freund’s Adjuvant. In the inflammation model, however, opiate-induced (morphine, fentanyl and loperamide) analgesia was reduced in mutant mice as compared to controls, and abolished at low doses. Morphine-induced constipation remained intact in cKO mice. We therefore genetically demonstrate for the first time that mu opioid receptors partly mediate opiate analgesia at the level of Nav1.8-positive sensory neurons. In our study, this mechanism operates under conditions of inflammatory pain, but not nociception. Previous pharmacology suggests that peripheral opiates may be clinically useful, and our data further demonstrate that Nav1.8 neuron-associated mu opioid receptors are feasible targets to alleviate some forms of persistent pain.
Opiates such as morphine, acting at mu opioid receptors, represent the most widely used drugs for the management of severe pain. The three mu delta and kappa opioid receptors are major receptors for analgesia and are expressed at central and peripheral sites within the pain control circuits. Opioid receptors are also largely distributed in other neural pathways where they regulate reward and affective states [1-3]. Opioid receptors have been shown to inhibit pain transmission in ascending pain pathways including primary afferent fibers  synapsing second order neurons in the spinal cord as well as in the ‘pain matrix’ in the brain where pain messages are integrated . Opioids also regulate descending inhibitory pain pathways by recruiting receptors in periacqueductal grey and rostral ventral medulla [5,6].
Both clinical and preclinical  studies have shown the potential for developing peripheral mu opioid analgesics to avoid central side effects. The implication of peripheral receptors has been investigated mainly based on pharmacological approaches and the use of peripheral antagonists [36-38]. In the present study, we reproduced these pharmacological data, and more importantly, our data provide the first genetic demonstration for the implication of mu receptors on primary afferent neurons in opiate-induced analgesia.