Anti-hyperalgesic and morphine-sparing actions of propentofylline following peripheral nerve injury in rats: mechanistic implications of spinal glia and proinflammatory cytokines

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Injury to peripheral nerves often produces non-physiological, long-lasting spontaneous pain, hyperalgesia and allodynia that are refractory to standard treatment and often insensitive to opioids, such as morphine. Recent studies demonstrate spinal glial activation and increased proinflammatory cytokines in animal models of neuropathic pain. When these data are considered together, a unifying hypothesis emerges which implicates a role of central neuroimmune processes in the etiology of neuronal and behavioral hypersensitivity. The present investigation assessed the influence of propentofylline, a glial modulating and anti-inflammatory agent, on the development of L5 spinal nerve transection-induced hyperalgesia and associated enhancement of spinal neuroimmune responses using real-time reverse transcription–polymerase chain reaction, RNase protection assay, enzyme-linked immunosorbent assay, and immunocytochemistry in rats. The results show that chronic propentofylline treatment attenuated the development of hyperalgesia and restored the analgesic activity of acute morphine in neuropathic rats. These findings directly correlated with the ability of propentofylline to inhibit glial activation and enhanced spinal proinflammatory cytokines following peripheral nerve injury. These findings along with our earlier observations of an anti-allodynic activity of propentofylline using the identical animal model of mononeuropathy supports the concept that modulation of glial and neuroimmune activation may be potential therapeutic targets to treat or prevent neuropathic pain. Further, restoration of the analgesic activity of morphine by propentofylline treatment suggests that increased glial activity and proinflammatory cytokine responses may account for the decreased analgesic efficacy of morphine observed in the treatment of neuropathic pain.

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