| First Author | Tiwari V | Year | 2020 |
| Journal | Pain | Volume | 161 |
| Issue | 4 | Pages | 842-855 |
| PubMed ID | 31815916 | Mgi Jnum | J:329576 |
| Mgi Id | MGI:6728571 | Doi | 10.1097/j.pain.0000000000001768 |
| Citation | Tiwari V, et al. (2020) Activation of micro-delta opioid receptor heteromers inhibits neuropathic pain behavior in rodents. Pain 161(4):842-855 |
| abstractText | Several reports support the idea that micro- and delta-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 micro-delta 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 micro-delta heteromer expression in dorsal root ganglion (DRG) neurons and the effects of a micro-delta heteromer-targeting agonist, CYM51010, on neuropathic pain behavior in rats and mice. An L5 spinal nerve ligation (SNL) in rats significantly decreased micro-delta 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 micro- and delta-ORs internalized both receptors after exposure to CYM51010. By contrast, in cells transfected with micro-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 micro-OR knockout mice. Our studies show that spinal nerve injury may increase micro-delta heterodimerization in uninjured DRG neurons, and that micro-delta heteromers may be a potential therapeutic target for relieving neuropathic pain, even under conditions of morphine tolerance. |
