Activation of µ-d Opioid receptor heteromers inhibits neuropathic pain behavior in rodents

Vinod Tiwari, Shao Qiu He, Qian Huang, Lingli Liang, Fei Yang, Zhiyong Chen, Vineeta Tiwari, Wakako Fujita, Lakshmi A. Devi, Xinzhong Dong, Yun Guan, Srinivasa N. Raja

Research output: Contribution to journalArticlepeer-review

Abstract

Several reports support the idea that µ- and d-opioid receptors (ORs) may exist as heterodimers in brain regions involved in pain signaling. The unique pharmacology of these heteromers may present a novel analgesic target. However, the role of µ-d heteromers in sensory neurons involved in pain and opioid analgesia remains unclear, particularly during neuropathic pain. We examined the effects of spinal nerve injury on µ-d heteromer expression in dorsal root ganglion (DRG) neurons and the effects of a µ-d heteromer-targeting agonist, CYM51010, on neuropathic pain behavior in rats and mice. An L5 spinal nerve ligation (SNL) in rats significantly decreased µ-d heteromer expression in L5 DRG but increased heteromer levels in uninjured L4 DRG. Importantly, in SNL rats, subcutaneous injection of CYM51010 inhibited mechanical hypersensitivity in a dose-related manner (EC50: 1.09 mg/kg) and also reversed heat hyperalgesia and attenuated ongoing pain (2 mg/kg, subcutaneously). HEK-293T cell surface-labeled with µ- and d-ORs internalized both receptors after exposure to CYM51010. By contrast, in cells transfected with µ-OR alone, CYM51010 was significantly less effective at inducing receptor internalization. Electrophysiologic studies showed that CYM51010 inhibited the C-component and windup phenomenon in spinal wide dynamic range neurons of SNL rats. The pain inhibitory effects of CYM51010 persisted in morphine-tolerant rats but was markedly attenuated in µ-OR knockout mice. Our studies show that spinal nerve injury may increase µ-d heterodimerization in uninjured DRG neurons, and that µ-d heteromers may be a potential therapeutic target for relieving neuropathic pain, even under conditions of morphine tolerance.

Original languageEnglish (US)
Pages (from-to)842-855
Number of pages14
JournalPain
Volume161
Issue number4
DOIs
StatePublished - Apr 1 2020

Keywords

  • Dorsal root ganglion
  • Heteromers
  • Neuropathic pain
  • Opioid receptor
  • Windup

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Anesthesiology and Pain Medicine

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