Introduction
Chronic inflammatory and neuropathic pains are complex clinical conditions associated with low quality of life and high economic burden (National Academies of Sciences, 2017). The management of pathological pain remains a clinical issue largely because the available treatments have limited efficacy and cause severe adverse effects. Though opioid analgesics are used to alleviate a myriad of pain conditions, their ability to penetrate the central nervous system (CNS) results in a variety of undesirable side effects, including respiratory depression, cognitive dysfunction, tolerance, and abuse (Dumas & Pollack, 2008). In consideration of the ongoing opioid epidemic, safer analgesics that act outside the CNS are urgently needed.
A potential strategy to avoid CNS-induced drug effects may be to target opioid receptors in the peripheral nervous system. The use of peripherally acting opioid analgesics is supported by their inability to readily cross the blood-brain barrier and activate opioid receptors in the brain (Spahn et al., 2017; Xu et al., 2020). Mu-opioid receptors (MOPs), encoded by the Oprm1 gene, are the target of most opioid agonists, including morphine. They are expressed throughout ascending and descending pain pathways involved in pain transduction, modulation, and perception (Corder, Castro, Bruchas & Scherrer, 2018). In the periphery, MOPs are localized in primary afferent (sensory) neurons of dorsal root ganglia (DRG). Their central and peripheral projections terminate in the spinal dorsal horn and somatic and visceral tissues, respectively. Primary sensory neurons play a critical role in initiating, transmitting, and modulating pain signals from the periphery. However, the contribution of peripheral MOPs to pain signaling and opioid pharmacology is unclear (Corder et al., 2017; Sun, Chen, Chen & Pan, 2019; Weibel et al., 2013).
Experimental and clinical reports have shown that activation of peripheral opioid receptors produces analgesic and anti-inflammatory effects without causing centrally mediated side effects (Iwaszkiewicz, Schneider & Hua, 2013; Machelska & Celik, 2018). Studies of peripherally acting MOP agonists, such as loperamide and dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA), provide pharmacological evidence for the importance of MOPs on primary afferents in the attenuation of tactile and thermal hypersensitivity in rodent models of neuropathic pain (Tiwari et al., 2016). Genetic disruption of MOPs in specific subpopulations of primary sensory neurons has allowed analysis of their contribution to distinct behavioral phenotypes. Strikingly, recent studies that have used the Cre/LoxP recombination system provide evidence that deletion ofOprm1 from primary sensory neurons prevents systemically administered opioids from inducing analgesia in acute and inflammatory pain conditions (Sun, Chen, Chen & Pan, 2019).
In this study, we used transgenic mice in which MOPs had been deleted from >90% of DRG neurons to assess their contribution to acute and chronic pain states. We used behavioral assays, immunohistochemistry, patch-clamp neurophysiology, in vivo pain models, and pharmacological interventions to evaluate the role of peripheral MOPs in opioid-induced analgesia.
Methods