| Prolonged activation of mu opioid receptors (MOR) induces the migration of delta opioid receptors (DOR) from intracellular compartments to neuronal plasma membranes. This is correlated with an increase in effectiveness of DOR agonists to elicit antinociception. Our recent findings have suggested that the trafficking of DORs is preceded by opioid-induced glial activation, a phenomenon that was previously shown to contribute to the loss in MOR-induced analgesic potency. The goal of this study was to investigate whether spinal glial activation has a role in the trafficking of DORs in a model of opioid tolerance.; Male Sprague Dawley rats were administered either of saline, morphine (5mg/kg, s.c.), morphine with concomitant propentofylline (10mug/30muL, i.t.), a glial activation inhibitor, or propentofylline alone for 6 days. Thermal nociceptive thresholds were assessed on days 1 and 6 using the 52°C hot water tail flick test to assess the degree of analgesic tolerance. On day 7, animals were injected with the DOR agonist, deltorphin II (10mug/30muL, i.t.), via a lumbar puncture and thermal nociceptive thresholds were assessed for 40 minutes following the drug injections. Animals were then transcardially perfused with 4% paraformaldehyde and the lumbar region of the spinal cords were removed for immunohistochemical analysis of astrocytic and microglial surface proteins, glial fibrillary acidic protein (GFAP) and complement receptor 3 (CR3), respectively.; Animals treated chronically with morphine developed tolerance to its analgesic effect by day 6. On day 7, these animals showed a significant increase in the spinal analgesic action of deltorphin II compared with chronic saline treated animals. The occurrence of analgesic tolerance was accompanied by a significant increase in astrocytic activation as indicated by glial hypertrophy. No microglial activation was observed in response to chronic morphine. Co-administration of propentofylline with morphine attenuated the development of tolerance, and blocked both the increased sensitivity to the spinal analgesic action of deltorphin II and the astrocyte hypertrophy induced by chronic morphine.; These results suggest that chronic morphine-induced astrocyte activation contributes to the increased sensitivity to a DOR agonist such as deltorphin II. Astrocyte activation could contribute to the translocation of delta opioid receptors from intracellular compartments to the plasma membrane in opioid tolerant states. |
