The Effect Of Interleukin-10on Gabapentin Attenuating Morphine Tolerance In Na(?)ve And Neuropathic Pain Rats

Aim: To study the effects of anti-inflammatory cytokine IL-10at spinal cord level ingabapentin attenuating morphine tolerance and the possible underlying signal pathway inna ve and neuropathic pain rats.Methods: First, we detected the role of IL-10in gabapentin attenuating morphinetolerance in na ve rats. Then, we studied gabapentin enhancing the anti-nociceptive effect onmorphine in neuropathic pain via the IL-10-HO-1signaling pathway in rats. Using IL-10antibody or HO-1antagonist ZnPP intrathecal daily injection to observe the effect ofgabapentin on attenuating morphine tolerance. With behavior test (Tail-Flick, Von-Frey), wedetected the role of IL-10on gabapentin enhancing the anti-nociceptive effects on morphine.By using ELISA we checked the expression of gliocyte (microglial, astrocyte), pro-inflammatory cytokines IL-1β, IL-6, TNF-α，anti-inflammatory cytokines IL-10; usingWestern-blot we checked the expression of HO-1in spinal cords in rats. Withco-immunoflurence, we checked the interaction between IL-10and HO-1or Iba1in spinalcord in rats.Results: In na ve rats, the anti-nociceptive effect of single dose morphine wasaccelerated and prolonged by a signal dose of gabapentin. Meantime, the chronic morphinetolerance was attenuated by co-administration of gabapentin with morphine twice a day for7days. IL-10antibody reversed the effects of gabapentin on morphine. The protein expressionof pro-inflammatory cytokines IL-1β, IL-6, and TNF-α was significantly reduced after dailygabapentin and morphine administration compared with morphine administration alone. When morphine was continuously administered for7days, the ED50value significantlyincreased compared with the saline group（morphine group31.65μg，saline group8.53μg）,which indicates morphine tolerance. When gabapentin was co-administrated with morphine,it enhanced the anti-nociceptive effect on morphine, attenuated morphine tolerance. Theeffects of gabapentin on morphine were through IL-10.In SNL rats, over7days, chronic morphine infusion produced anti-nociceptive tolerance.Gabapentin enhanced the anti-nociceptive effect of morphine. This effect could be explained,at least in part, by gabapentin-induced down-regulation of gliocyte (microglial, astrocyte),pro-inflammatory cytokine TNF-α, IL-1β, and IL-6expression, and up-regulation ofanti-inflammatory cytokine IL-10expression in the rats spinal cord. Improvement of theanalgesic effects of morphine by gabapentin was partially blocked by co-administration ofanti-IL-10antibody or the HO-1antagonist ZnPP. Neutralisation of the IL-10antibodyreversed the gabapentin-induced increase in HO-1expression and inhibition of gliocyte(microglial, astrocyte), pro-inflammatory cytokines expression, suggesting that the HO-1pathway is involved in gabapentin–mediated induction of IL-10expression. These resultssuggested that the suppressive effect of gabapentin co-infusion on pro-inflammatory cytokineproduction in morphine–infused rats maybe act via increasing IL-10and HO-1proteinexpression.Conclusion: Gabapentin attenuated morphine tolerance in na ve and neuropathic painrats via IL-10. IL-10co-administrated with morphine not only improved the anti-nociceptiveeffect on morphine, also IL-10antibody and HO-1antagonist ZnPP reversed the effect ofgabapentin on morphine and increased the expression of microglial, astrocyte, pro-inflammatory cytokines TNF-α, IL-1β, IL-6in SNL rats spinal cords, which acceleratedmorphine tolerance. Taken together, these findings suggested that gabapentin maybe used asan adjuvant in combination with morphine for treatment of chronic neuropathic paincondition and for treatment of patients who required long-term morphine administration for pain management in clinical practice. Our research provides a new target for novel drugs tobenefit pain patients in clinical practice.