P2Y ₁₂ receptor upregulation in satellite glial cells is involved in neuropathic pain induced by HIV glycoprotein 120 and 2′,3′-dideoxycytidine

Zhihua Yi  ^{1   2   3} , Lihui Xie  ⁴ , Congfa Zhou  ² , Huilong Yuan  ² , Shuai Ouyang  ⁴ , Zhi Fang  ⁴ , Shanhong Zhao  ² , Tianyu Jia  ² , Lifang Zou  ² , Shouyu Wang  ² , Yun Xue  ² , Bing Wu  ² , Yun Gao  ² , Guilin Li  ² , Shuangmei Liu  ² , Hong Xu  ² , Changshui Xu  ² , Chunping Zhang  ² , Shangdong Liang  ^{5   6}

Affiliations

• ¹ School of life Sciences of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China.
• ² Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China.
• ³ Nursing College, Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China.
• ⁴ Undergraduate student of Clinic Medicine School of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China.
• ⁵ School of life Sciences of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China. liangsd@hotmail.com.
• ⁶ Department of Physiology, Basic Medical School of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China. liangsd@hotmail.com.

Abstract

The direct neurotoxicity of HIV and neurotoxicity of combination antiretroviral therapy medications both contribute to the development of neuropathic pain. Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in mechanical and thermal hyperalgesia. The P2Y₁₂ receptor expressed in SGCs of the DRG is involved in pain transmission. In this study, we explored the role of the P2Y₁₂ receptor in neuropathic pain induced by HIV envelope glycoprotein 120 (gp120) combined with ddC (2′,3′-dideoxycytidine). A rat model of gp120+ddC-induced neuropathic pain was used. Peripheral nerve exposure to HIV-gp120+ddC increased mechanical and thermal hyperalgesia in gp120+ddC-treated model rats. The gp120+ddC treatment increased expression of P2Y₁₂ receptor mRNA and protein in DRG SGCs. In primary cultured DRG SGCs treated with gp120+ddC, the levels of [Ca²⁺]_i activated by the P2Y₁₂ receptor agonist 2-(Methylthio) adenosine 5′-diphosphate trisodium salt (2-MeSADP) were significantly increased. P2Y₁₂ receptor shRNA treatment inhibited 2-MeSADP-induced [Ca²⁺]_i in primary cultured DRG SGCs treated with gp120+ddC. Intrathecal treatment with a shRNA against P2Y₁₂ receptor in DRG SGCs reduced the release of pro-inflammatory cytokines, decreased phosphorylation of p38 MAPK in the DRG of gp120+ddC-treated rats. Thus, downregulating the P2Y₁₂ receptor relieved mechanical and thermal hyperalgesia in gp120+ddC-treated rats.

Keywords: Antiretroviral therapy-associated neuropathic pain; Dorsal root ganglia; HIV-gp120-associated neuropathic pain; P2Y12 receptor; Satellite glial cells.