Latent Pain Sensitization unmasks µ-δ opioid heteromer in neuropathic and inflammatory pain

Rodent models of latent pain sensitization can be used to study the episodic nature that chronic pain can exhibit. At pain remission, central sensitization is countered by the activity of endogenous opioid receptors. In animal models, latent pain sensitization can be unmasked by antagonizing opioid receptors resulting in pain relapse. Due to previous studies have focused predominantly on inflammatory pain, the presence of latent pain sensitization in animal model of chemotherapy-induced peripheral neuropathic pain and in female mice is unknown. This study investigates whether μ- and δ-OR suppress latent pain sensitization in model of chemotherapy-induced neuropathic pain in both sexes. We first targeted μ- and δ-OR separately in a model of chemotherapy induced neuropathy after remission to investigate whether antagonizing the receptors reinstated pain hypersensitivity. We then were able to specifically target the μ-δ OR heteromer using a novel peptide to prevent its heteromerization. We used this peptide to investigate whether disruption of the μ-δOR heteromer, after remission, reinstates pain hypersensitivity. At remission from cisplatin-induced neuropathic pain, antagonism of µOR and δOR reinstates pain hypersensitivity in both sexes. Disruption of the μ-δOR heteromer reinstates pain hypersensitivity in both sexes after remission from cisplatin-induced neuropathic and postsurgical pain. 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. American Pain Society and the Rita Allen Foundation.