Department of Physical Medicine & Rehabilitation, Qilu Hospital, Medical School of Shandong University, Jinan 250012, China.
Behav Brain Res. 2010 Mar 17;208(1):194-201. doi: 10.1016/j.bbr.2009.11.034. Epub 2009 Dec 3.
The aim of the present study was to test the hypothesis that the TRPV4-NO-cGMP-PKG cascade is involved in the maintenance of thermal hyperalgesia following chronic compression of the dorsal root ganglion (DRG) (the procedure hereafter termed CCD) in rats. CCD rats showed thermal hyperalgesia and increased nitrite production. Intrathecal administration of ruthenium red (TRPV4 antagonist, 0.1-1 nmol), TRPV4 antisense ODN (TRPV4 AS, 40 microg, daily for 7 days), N(G)-L-nitro-arginine methyl ester (l-NAME, inhibitor of NO synthase, 30-300 nmol), 1H-[1,2,4]-oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, a soluble guanylate cyclase inhibitor, 50-100 nmol) or 8-(4-Chlorophenylthio) guanosine 3',5'-cyclic Monophosphothioate, Rp-Isomer sodium salt (Rp-8-pCPT-cGMPS, a PKG inhibitor, 25-50 nmol) induced a significant (P<0.001) and dose-dependent increase in the paw withdrawal latency (PWL) compared with control rats, respectively. Ruthenium red (1 nmol), TRPV4 AS (40 microg, daily for 7 days) or L-NAME (300 nmol) decreased nitrite (an index of nitric oxide formation) in the DRG of CCD rats. In addition, the phorbol ester 4alpha-phorbol 12,13-didecanoate (4alpha-PDD, TRPV4 synthetic activator, 1 nmol), co-administered with L-NAME (300 nmol), attenuated the suppressive effect of L-NAME on CCD-induced thermal hyperalgesia and nitrite production. Our data suggested that the TRPV4-NO-cGMP-PKG pathway could be involved in CCD-induced thermal hyperalgesia.
本研究旨在验证下述假设，即瞬时受体电位香草酸亚型 4（TRPV4）-一氧化氮（NO）-环鸟苷酸（cGMP）-蛋白激酶 G（PKG）级联反应参与了大鼠背根神经节（DRG）慢性压迫（此后称为 CCD）后热痛觉过敏的维持。CCD 大鼠表现出热痛觉过敏和亚硝酸盐生成增加。鞘内给予钌红（TRPV4 拮抗剂，0.1-1 nmol）、TRPV4 反义寡核苷酸（TRPV4 AS，40 μg，每天 7 天）、N（G）-L-硝基精氨酸甲酯（NO 合酶抑制剂，30-300 nmol）、1H-[1,2,4]-恶二唑并[4,3-a]喹喔啉-1-酮（可溶性鸟苷酸环化酶抑制剂，50-100 nmol）或 8-（4-氯苯硫基）鸟苷 3'，5'-环单磷酸硫代酯，Rp-异构体钠盐（PKG 抑制剂，25-50 nmol），与对照组大鼠相比，均显著（P<0.001）且呈剂量依赖性地增加了 paw withdrawal latency（PWL）。钌红（1 nmol）、TRPV4 AS（40 μg，每天 7 天）或 L-NAME（300 nmol）降低了 CCD 大鼠 DRG 中的亚硝酸盐（一氧化氮形成的指标）。此外，佛波酯 4α-佛波醇 12,13-二癸酸酯（4α-PDD，TRPV4 合成激活剂，1 nmol）与 L-NAME（300 nmol）联合给药可减弱 L-NAME 对 CCD 诱导的热痛觉过敏和亚硝酸盐生成的抑制作用。我们的数据表明，TRPV4-NO-cGMP-PKG 途径可能参与了 CCD 诱导的热痛觉过敏。
