Activation of µ-δ opioid receptor heteromers inhibits neuropathic pain behavior in rodents. Issue 4 (April 2020)

• Record Type: Journal Article
• Authors: Tiwari, Vinod; He, Shao-Qiu; Huang, Qian; Liang, Lingli; Yang, Fei; Chen, Zhiyong; Tiwari, Vineeta; Fujita, Wakako; Devi, Lakshmi A.; Dong, Xinzhong; Guan, Yun; Raja, Srinivasa N.
• Is Part Of: Pain. Volume 161:Issue 4(2020)
• Publication Date: 2020-04
• Subjects: Opioid receptor -- Heteromers -- Windup -- Neuropathic pain -- Dorsal root ganglion; Pain -- Periodicals; Douleur -- Périodiques; Anesthésie -- Périodiques; Pain; Electronic journals; Periodicals; Electronic journals; 616.0472
• DOI: 10.1097/j.pain.0000000000001768
• Languages: English
• ISSNs: 0304-3959

Abstract

Abstract : Abstract: Several reports support the idea that µ- and δ-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-δ 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-δ heteromer expression in dorsal root ganglion (DRG) neurons and the effects of a µ-δ heteromer–targeting agonist, CYM51010, on neuropathic pain behavior in rats and mice. An L5 spinal nerve ligation (SNL) in rats significantly decreased µ-δ 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 δ-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-δ heterodimerization in uninjured DRG neurons, and that µ-δ heteromers may be a potential therapeutic target for relieving neuropathic pain, even under conditions of morphine tolerance. Abstract : Supplemental Digital Content is Available in the Text.Spinal nerve injury in rodents increases µ-δ heterodimerization in uninjured dorsal root ganglion neurons, and µ-δ heteromers may be a potential new drug target for relieving neuropathic pain.