Mu Opioid Receptors on Primary Afferent Nav1.8 Neurons Contribute to Opiate-Induced Analgesia: Insight from Conditional Knockout Mice

Abstract

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.

Mu Opioid Receptors in Gamma-Aminobutyric Acidergic Forebrain Neurons Moderate Motivation for Heroin and Palatable Food

“…Dlx-MOR mice were created by breeding our floxed Oprm1 ( Oprm1 f l /fl ) mice (18) with Dlx5/6-Cre mice (19), obtained from Beat Lutz (Institute of Physiological Chemistry, Johannes Gutenberg University, Germany) in our vivarium. Details in Supplemental Information.…”

Functional Selectivity of Kappa Opioid Receptor Agonists in Peripheral Sensory Neurons

“…Both clinical and animal studies have shown that peripheral opioid receptors, when activated, can inhibit the transmission of nociceptive signals from the periphery to the CNS (Gupta et al, 2001;Kalso et al, 2002;Stein et al, 2003;Zollner et al, 2008). Moreover, recent evidence suggests that activation of these peripheral opioid receptors can contribute to analgesia produced by systemic opioid administration (Labuz et al, 2007;Weibel et al, 2013;Jagla et al, 2014). However, unlike their CNS counterparts, much less is known about the function and regulation of peripheral opioid receptor systems expressed by nociceptors.…”

(206) Modulation of multiple modalities of somatosensory information by peripheral kappa opioid receptors

“…To do so, the floxed KOR allele could be used, in which the KOR gene is surrounded by loxP sites, and this mouse could be crossed to a mouse line that expresses cre either in primary afferents or in immune cells. A recent study using a conditional knockout (cKO) of the MOR in Nav1.8-expressing sensory neurons (primarily Cfibers) reported that cKO mice showed reduced opiate-induced analgesia compared to wild-type controls (Weibel et al, 2013). These data suggest that MORs on primary afferents play a critical part in exogenous opioid agonist-induced analgesia.…”