Endogenous TRPV1 agonist OLDA prevents mu-opioid receptor desensitization and preserves analgesia in sensitized nociceptive circuits

Opioid analgesics acting primarily through the μ-opioid receptor (MOR) are profoundly limited by receptor desensitization, tolerance and opioid-induced hyperalgesia. Recent work has identified functional crosstalk between MOR and the transient receptor potential vanilloid 1 (TRPV1) channel, whereby TRPV1 activation can suppress β-arrestin-dependent MOR desensitization. Whether endogenous TRPV1 ligands contribute to this regulation in intact nociceptive circuits has remained unknown. Here we show that N-oleoyldopamine (OLDA), an endogenous vanilloid, preserves MOR signaling and opioid analgesia by preventing MOR desensitization in the spinal cord. Using electrophysiological recordings from rat spinal cord dorsal horn neurons, we demonstrate that prolonged exposure to the MOR agonist DAMGO induces robust functional desensitization, abolishing opioid-mediated inhibition of synaptic transmission. Co-incubation with OLDA prevents this desensitization in a concentration-dependent manner, maintaining DAMGO efficacy without altering basal synaptic activity. Under neuropathic conditions induced by chronic constriction injury, low concentrations of OLDA that are ineffective in naïve tissue become sufficient to preserve MOR responsiveness, consistent with enhanced TRPV1 sensitization after nerve injury. In vivo, intrathecal OLDA restores opioid-evoked thermal and mechanical hypoalgesia in a chemokine-induced MOR desensitization model. Together, these findings identify OLDA as an endogenous regulator of TRPV1-MOR crosstalk that selectively preserves opioid signaling in sensitized nociceptive circuits. Our results extend recent mechanistic insights into TRPV1-dependent control of β-arrestin pathways and reveal an intrinsic modulatory system that may be harnessed to improve the durability and safety of opioid analgesia in chronic pain.