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Activation of µ-δ Opioid Receptor Heteromers Inhibits Neuropathic Pain Behavior in Rodents

Activation of µ-δ 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

Pain. 2020 Apr;161(4):842-855.

PMID: 31815916

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1069498969	CYM51010		1069498-96-9	Price

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