Zhou Rui, Xu Tao, Liu XiaoHong, Chen YuanShou, Kong DeYing, Tian Hong, Yue Mingxia, Huang Dujuan, Zeng Junwei
Department of Physiology, Zunyi Medical College, Zunyi, People's Republic of China.
J Pain Res. 2018 Mar 27;11:615-628. doi: 10.2147/JPR.S154437. eCollection 2018.
The dorsal horn P2Y 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 P2Y receptor in rats with diabetic neuropathic pain (DNP).
A rat model of type 1 DNP was induced by intraperitoneal injection of streptozotocin (STZ). We examined the expression of P2Y receptor, Iba-1, IL-1β, IL-6, JAK2, STAT3, pTyr, and pTyr NR2B in rat spinal dorsal horn.
Compared with normal rats, STZ-diabetic rats displayed obvious mechanical allodynia and the increased expression of P2Y 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 P2Y 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 P2Y 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, pTyr NR2B was significantly decreased, whereas pTyr NR2B was unaffected in the dorsal spinal cord of MRS2211-treated DNP rats.
Intrathecal MRS2211 produces an anti-nociceptive effect in early-stage DNP. A possible mechanism involved in MRS2211-induced analgesia is that blocking the P2Y 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 P2Y receptor can decrease NR2B-containing NMDAR phosphorylation in dorsal spinal cord neurons, thereby attenuating central sensitization in STZ-induced DNP rats.
背角P2Y受体参与外周神经损伤诱导的疼痛行为的发展。糖尿病性神经病理性疼痛（DNP）大鼠中，P2Y受体激活后，脊髓背角促炎细胞因子白细胞介素（IL）-1β和IL-6的表达是否受到影响尚不清楚。
通过腹腔注射链脲佐菌素（STZ）诱导1型DNP大鼠模型。我们检测了大鼠脊髓背角中P2Y受体、Iba-1、IL-1β、IL-6、JAK2、STAT3、pTyr和pTyr NR2B的表达。
与正常大鼠相比，STZ诱导的糖尿病大鼠表现出明显的机械性异常性疼痛，且脊髓背角中P2Y受体、Iba-1、IL-1β和IL-6的表达增加，在DNP大鼠中持续6周。所得数据表明，在DNP大鼠中，给予MRS2211可显著减轻机械性异常性疼痛。与DNP大鼠相比，MRS2211治疗后，STZ注射后4周时P2Y受体、Iba-1、IL-1β和IL-6的表达降低。然而，MRS2211治疗在STZ注射后6周时并未减弱P2Y受体、Iba-1、IL-1β和IL-6的表达。MRS2211在早期抑制JAK2和STAT3的表达，但在后期则无此作用。此外，pTyr NR2B显著降低，而在MRS2211治疗的DNP大鼠脊髓背角中pTyr NR2B未受影响。
鞘内注射MRS2211在DNP早期产生抗伤害感受作用。MRS2211诱导镇痛的一种可能机制是，阻断P2Y受体可下调IL-1β和IL-6水平，进而抑制JAK2/STAT3信号通路的激活。此外，阻断P2Y受体的激活可降低脊髓背角神经元中含NR2B的NMDAR磷酸化，从而减轻STZ诱导的DNP大鼠的中枢敏化。
