Up-regulation and trafficking of δ opioid receptor in a model of chronic inflammation: implications for pain control

Pharmacological and physiological evidence supports a role for delta (δ) opioid receptors in the nociceptive mechanisms of inflammation. However, few data exist regarding δ opioid receptor expression and localization in such conditions. In this study, we have assessed the distribution and function of δ opioid receptors in the rat spinal cord following induction of chronic inflammation by intraplantar injection of complete Freund's adjuvant (CFA). Intrathecal administration of the selective δ opioid receptor agonist, d-[Ala2, Glu4] deltorphin, dose-dependently reversed thermal hyperalgesia induced by CFA. In situ hybridization and Western blotting experiments revealed an increase in δ opioid receptor mRNA and protein levels, respectively, in the dorsal lumbar spinal cord ipsilateral to the CFA injection site compared to the contralateral side and sham-injected controls. By electron microscopy, immunopositive δ opioid receptors were evident in neuronal perikarya, dendrites, unmyelinated axons and axon terminals. Quantification of immunopositive signal in dendrites revealed a twofold increase in the number of immunogold particles in the ipsilateral dorsal spinal cord of CFA-injected rats compared to the contralateral side and to sham-injected rats. Moreover, the relative frequency of immunogold particles associated with or in close proximity to the plasma membrane was increased in the ipsilateral dorsal spinal cord, indicating a more efficient targeting of δ opioid receptors to neuronal plasma membranes. These data demonstrate that CFA induces an up-regulation and increased membrane targeting of δ opioid receptors in the dorsal spinal cord which may account for the enhanced antinociceptive effects of δ opioid receptor agonists in chronic inflammatory pain models.