Divergence in μ and δ opioid receptor pharmacology in neurons and antinociceptive efficacy in neuropathic pain: Insights from MP135 and CYM51010

BACKGROUND AND PURPOSE: Opioids targeting the μ opioid receptor remain largely ineffective in neuropathic pain conditions, emphasizing the need for novel therapeutic strategies. MP135 was reported to reduce thermal nociception in naive animals by activating μ-δ opioid receptor heteromers. In this study, we compared its pharmacological profile and antinociceptive properties in naive and neuropathic conditions to those of the μ-δ biased agonist CYM51010 and the μ opioid agonist morphine. EXPERIMENTAL APPROACH: Ligand affinity and activation of the G protein and β-arrestin pathways were determined using opioid receptors in their native environment. The impact of acute administration on thermal and mechanical nociceptive thresholds was evaluated in naive male and female mice. The impact on mechanical threshold and respiratory depression was also evaluated in mice with sciatic nerve injury. Pharmacological selectivity was established using μ or δ opioid receptor knock-out mice. KEY RESULTS: The three drugs showed similar binding profile and activation of G protein-dependent pathways. However, only MP135 and CYM51010 activated the β-arrestin pathway. In naive female mice, the drugs induced shorter thermal antinociception together with reduced maximal efficacy for morphine and MP135. In neuropathic conditions, morphine and MP135 were respectively poorly effective or ineffective whereas CYM51010 increased the mechanical threshold. The three drugs induced respiratory depression. CONCLUSION AND IMPLICATIONS: The antinociceptive effect was receptor selective and affected by sex and neuropathic condition. This was unexpected based on the drug ex vivo pharmacological profiles and emphasizes the shortcomings of cell-based approaches to reliably predict behavioural responses.