Background and objective The role of peripheral mu-opioid receptors (MOPs) in chronic pain conditions is not well understood. Here, we used a combination of mouse genetics, behavioral assays, and pharmacologic interventions to investigate the contribution of primary afferent MOPs to nociceptive, inflammatory, and neuropathic pain, as well as to opioid analgesia.
Methods We generated conditional knockout mice in which MOPs were selectively deleted in primary sensory neurons. Inflammatory and neuropathic pain states were induced in mutant and control wild-type mice and their behavioral responses to noxious stimuli were compared. Gross motor function was also evaluated. Immunohistochemistry was used to assess MOP expression in the dorsal root ganglia, periaqueductal gray, and small intestine. The effects of MOP agonists DALDA (dermorphin [D-Arg2, Lys4] (1–4) amide) and morphine were evaluated in pain behavior assays, and their effects on neuronal physiology in the dorsal root ganglia were evaluated in whole-cell patch-clamp recordings.
Results Conditional MOP knockouts and control mice exhibited similar behavioral responses to acute nociceptive stimuli and developed similar inflammation-induced hypersensitivity. Unilateral nerve injury in animals lacking peripheral MOPs induced enhanced, bilateral mechanical allodynia. Subcutaneously administered DALDA was unable to decrease the hypersensitivity induced by inflammation and nerve injury in MOP knockout animals, and morphine’s antinociceptive effects were significantly attenuated in the absence of peripheral MOPs.
Conclusion MOPs in primary sensory neurons contribute to the modulation of neuropathic pain behavior and opioid analgesia. Our observations highlight the clinical potential of peripherally acting opioid agonists in the management of inflammatory and neuropathic pain.
- chronic pain
- pain management
- drug-related side effects and adverse reactions
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Contributors AB, NF, QH, and S-QH conducted the experiments and performed the data analysis. SR, YG, AB, CG-R, and XD conceived the project and wrote the manuscript with input from the other authors. CG-R and XD provided the transgenic mice and expertise in the generation of the conditional knockout mice. All authors approved the final version of the manuscript submitted for publication and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.
Funding This work was facilitated by the Pain Research Core, which is funded by the Blaustein Fund and the Neurosurgery Pain Research. This work was supported by the National Institutes of Health NS026363 (SR), NS070814 (YG), and NS110598 (YG); the European Union Seventh Framework Programme (FP7-Health-2013-Innovation) under grant agreement 1602919; and by the Université de Strasbourg (CG-R).
Competing interests YG serves as the executive editor for basic science for the Regional Anesthesia & Pain Medicine journal. SR is a consultant for Allergan, Averitas Pharma, Bayer, and Lexicon Pharmaceuticals, and has consulted for Aptinyx, Heron Therapeutics, and Insys Therapeutics. YG and SR are principal and co-investigators in a research grant from Medtronic.
Patient consent for publication Not required.
Ethics approval Experimental protocols were approved by the Animal Care and Use Committee of Johns Hopkins University and complied with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request from SR (Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA; email: firstname.lastname@example.org).