The µ-δ opioid heteromer masks latent pain sensitization in neuropathic and inflammatory pain in male and female mice.

The episodic nature of chronic pain can be studied in the rodent model of latent pain sensitization. After remission, central sensitization is opposed by activation of opioid receptors. At the behavioral level, latent pain sensitization is unmasked when pain hypersensitivity is reinstated by opioid receptor (OR) antagonism. Previous studies have focused on inflammatory pain and male rodents. Whether latent pain sensitization occurs in models of chemotherapy-induced neuropathic pain in female and male mice is unknown. The first aim of this study was to investigate whether μ- and δ-OR suppress latent pain sensitization in our model of chemotherapy-induced neuropathic pain in both sexes. Mounting evidence suggests that μ-and δ-ORs form a heteromer and that the heteromer modulates pain sensitivity. Potential implications of the μ-δ OR heteromer in latent pain sensitization have not been fully explored due to a lack of tools to effectively modulate the heteromer. To specifically target the μ-δ OR heteromer, we used a specific interfering peptide blocking the heteromerization. The second aim of this study was to investigate whether disruption of the μ-δOR heteromer, after remission, reinstates pain hypersensitivity. After remission from cisplatin-induced neuropathic pain, antagonism of µ-OR and δOR reinstates pain hypersensitivity in both sexes. After remission from cisplatin-induced neuropathic pain and postoperative pain, disruption of the μ-δOR heteromer reinstates pain hypersensitivity in both sexes. Taken together our findings suggest that the μ-δOR heteromer plays a crucial role in remission in various pain models and may represent a novel therapeutic target to prevent the relapse to pain and the transition to chronic pain.