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 language | English (US) |
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Pages (from-to) | 842-855 |
Number of pages | 14 |
Journal | Pain |
Volume | 161 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2020 |
Keywords
- Dorsal root ganglion
- Heteromers
- Neuropathic pain
- Opioid receptor
- Windup
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
- Anesthesiology and Pain Medicine