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