Activation of spinal dorsal horn P2Y13 receptors can promote the expression of IL-1β and IL-6 in rats with diabetic neuropathic

Objective: The dorsal horn P2Y(13) receptor is involved in the development of pain behavior induced by peripheral nerve injury. It is unclear whether the expression of proinflammatory cytokines interleukin (IL)-1 beta and IL-6 at the spinal dorsal horn are influenced after the activation of P2Y(13) receptor in rats with diabetic neuropathic pain (DNP). Methods: A rat model of type 1 DNP was induced by intraperitoneal injection of streptozotocin (STZ). We examined the expression of P2Y(13) receptor, Iba-1, IL-1 beta, IL-6, JAK2, STAT3, pTyr(1336), and pTyr(1472) NR2B in rat spinal dorsal horn. Results: Compared with normal rats, STZ-diabetic rats displayed obvious mechanical allodynia and the increased expression of P2Y(13) receptor, Iba-1, IL-1 beta, and IL-6 in the dorsal spinal cord that was continued for 6 weeks in DNP rats. The data obtained indicated that, in DNP rats, administration of MRS2211 significantly attenuated mechanical allodynia. Compared with DNP rats, after MRS2211 treatment, expression of the P2Y(13) receptor, Iba-1, IL-1 beta, and IL-6 were reduced 4 weeks after the STZ injection. However, MRS2211 treatment did not attenuate the expression of the P2Y(13) receptor, Iba-1, IL-1 beta, and IL-6 at 6 weeks after the STZ injection. MRS2211 suppressed JAK2 and STAT3 expression in the early stage, but not in the later stage. Moreover, pTyr(1336) NR2B was significantly decreased, whereas pTyr(1472) NR2B was unaffected in the dorsal spinal cord of MRS2211-treated DNP rats. Conclusion: Intrathecal MRS2211 produces an anti-nociceptive effect in early-stage DNP. A possible mechanism involved in MRS2211-induced analgesia is that blocking the P2Y(13) receptor downregulates levels of IL-1 beta and IL-6, which subsequently inhibit the activation of the JAK2/STAT3 signaling pathway. Furthermore, blocking the activation of the P2Y(13) receptor can decrease NR2B-containing NMDAR phosphorylation in dorsal spinal cord neurons, thereby attenuating central sensitization in STZ-induced DNP rats.