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Hypersensitivity resulting from nerve injury or morphine tolerance/hyperalgesia is predicted to involve similar cellular and molecular mechanisms. One expected but incompletely explored mechanism is the activation of central neuroimmune responses associated with these conditions. To begin to address this, we undertook three separate studies: First, we determined the acute antinociceptive action of morphine, the rate of development of opioid tolerance, and withdrawal-induced hyperalgesia/allodynia in nerve-injured and sham-operated rats using noxious (thermal and mechanical) and non-noxious (mechanical allodynia) behavioral paradigms. Second, we investigated the impact of chronic morphine treatment on spinal glial activation and cytokine expression after L5 spinal nerve transection or sham surgery. Third, we examined the consequences of spinal administration of cytokine inhibitors on the development of morphine tolerance and morphine withdrawal-induced hyperalgesia and allodynia. Results demonstrated that after nerve injury, the antinociceptive effect of acute morphine was significantly decreased, and the rate of development of tolerance and opioid withdrawal-induced hyperalgesia/allodynia was significantly enhanced compared with that after sham surgery. Chronic administration of morphine to sham-operated rats activated spinal glia and upregulated proinflammatory cytokines [interleukin (IL)-1β, IL-6, and tumor necrosis factor-α]. This neuroimmune activation was further enhanced in nerve-injured rats after chronic morphine treatment. Spinal inhibition of proinflammatory cytokines restored acute morphine antinociception in nerve-injured rats and also significantly reversed the development of morphine tolerance and withdrawal-induced hyperalgesia and allodynia in nerve-injured or sham-operated rats. Targeting central cytokine production and glial activation may improve the effectiveness of morphine and reduce the incidence of morphine withdrawal-induced hyperalgesia and allodynia in neuropathic pain conditions.

The Role of Spinal Neuroimmune Activation in Morphine Tolerance/Hyperalgesia in Neuropathic and Sham-Operated Rats