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

摘要

Objective: The dorsal horn P2Y₁₃ 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)-1β and IL-6 at the spinal dorsal horn are influenced after the activation of P2Y₁₃ 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 P2Y₁₃ receptor, Iba-1, IL-1β, IL-6, JAK2, STAT3, pTyr₁₃₃₆, and pTyr₁₄₇₂ NR2B in rat spinal dorsal horn. Results: Compared with normal rats, STZ-diabetic rats displayed obvious mechanical allodynia and the increased expression of P2Y₁₃ receptor, Iba-1, IL-1β, 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 P2Y₁₃ receptor, Iba-1, IL-1β, and IL-6 were reduced 4 weeks after the STZ injection. However, MRS2211 treatment did not attenuate the expression of the P2Y₁₃ receptor, Iba-1, IL-1β, 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, pTyr₁₃₃₆ NR2B was significantly decreased, whereas pTyr₁₄₇₂ 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 P2Y₁₃ receptor downregulates levels of IL-1β and IL-6, which subsequently inhibit the activation of the JAK2/STAT3 signaling pathway. Furthermore, blocking the activation of the P2Y₁₃ receptor can decrease NR2B-containing NMDAR phosphorylation in dorsal spinal cord neurons, thereby attenuating central sensitization in STZ-induced DNP rats.