Neuroimmune interactions after nerve injury and opioid-mediated pain control

Abstract

Here, we investigated pain relief resulting from neuroimmune interactions associated with peripheral nerve damage. Our hypothesis is based on a new concept that activation of opioid receptors on immune cells leads to the release of opioid peptides, which activate neuronal receptors, to improve neuropathic pain. As a model of neuropathy we applied chronic constriction injury of the sciatic nerve in mice. Mechanical sensitivity was evaluated with von Frey filaments. Immune cells infiltrating damaged nerves were isolated 2 days following the injury, and the secretion of opioid peptide Met-enkephalin was examined using radioimmunoassay. In vivo we found that selective agonists of mu-, delta- and kappa-opioid receptors injected at the nerve injury site produced analgesia. This effect was attenuated when immune cells infiltrating damaged nerves were depleted. In vitro, the opioid receptor agonists dose-dependently secreted Met-enkephalin from leukocytes. This release was abrogated by the respective opioid receptor antagonists, by blocking Gαi and Gβγ subunits, phospholipase C, and inositol 1,4,5-trisphosphate receptors, and by removing Ca 2+ from intracellular, but not extracellular, stores. Our results suggest that activation of leukocytic Gαi-coupled opioid receptors induces Ca 2+ -regulated secretion of endogenous opioid peptides, which might contribute to the amelioration of neuropathic pain. These findings provide mechanistic evidence supporting the idea that damaged peripheral nerves infiltrated by opioid-containing immune cells might be a promising target for the control painful inflammatory neuropathies.