Suppression of active phase voluntary wheel running in male rats by unilateral chronic constriction injury: Enduring therapeutic effects of a brief treatment of morphine combined with TLR4 or P2X7 antagonists.
Suppression of active phase voluntary wheel running in male rats by unilateral chronic constriction injury: Enduring therapeutic effects of a brief treatment of morphine combined with TLR4 or P2X7 antagonists.
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DOI：
10.1002/jnr.24645
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发表时间：
2022-01
影响因子：
4.2
通讯作者：
Grace PM
中科院分区：
文献类型：
--
作者：
Green-Fulgham SM;Ball JB;Maier SF;Rice KC;Watkins LR;Grace PM
目前的一系列研究探讨了在停止给药后数周内，全身给药治疗对周围神经损伤（男性；单侧坐骨慢性压迫性损伤[CCI]）引起的随意轮跑抑制的影响。 CCI 之后，活跃阶段的跑步距离和速度在整个 7 周的观察期内受到抑制。然而，短暂的吗啡疗程却增加了同一时期活跃期跑步的距离和速度，这种效果仅在假大鼠中明显。对于 CCI 大鼠，全身同时给予吗啡和 P2X7 (A438079) 或 TLR4 ((+)-纳洛酮)（对 NLRP3 炎性体激活和随后的炎症级联反应至关重要的受体）拮抗剂，使 CCI 大鼠的跑步行为在停止给药后 5 周以上恢复到假手术的状态。与我们之前使用全身吗啡加上鞘内递送这些相同拮抗剂的CCI异常性疼痛结果相比，这是一个显着的效果差异，其中观察到对神经性疼痛的持续但部分抑制。这可能表明全身药物在沿神经轴的多个部位发挥作用，调节受伤坐骨神经和/或背根神经节、脊髓以及潜在更高水平的损伤诱导的炎性体介导的作用。鉴于我们迄今为止的数据表明吗啡会放大因神经损伤而引发的神经炎症过程，因此推测联合使用 TLR4 和/或 P2X7 拮抗剂可以以有益的方式干预这些炎症过程，这是很有趣的。也就是说，全身施用此类化合物可以抑制多个部位的炎症损伤，快速而持久地使神经病动物恢复到假反应水平。
The present series of studies examine the impact of systemically administered therapeutics on peripheral nerve injury (males; unilateral sciatic chronic constriction injury [CCI])-induced suppression of voluntary wheel running, across weeks after dosing cessation. Following CCI, active phase running distance and speed are suppressed throughout the 7-week observation period. A brief course of morphine, however, increased active phase running distance and speed throughout this same period, an effect apparent only in sham rats. For CCI rats, systemic co-administration of morphine with antagonists of either P2X7 (A438079) or TLR4 ((+)-naloxone) (receptors critical to the activation of NLRP3 inflammasomes and consequent inflammatory cascades) returned running behavior of CCI rats to that of shams through 5+ weeks after dosing ceased. This is a striking difference in effect compared to our prior CCI allodynia results using systemic morphine plus intrathecal delivery of these same antagonists, wherein a sustained albeit partial suppression of neuropathic pain was observed. This may point to actions of the systemic drugs at multiple sites along the neuraxis, modulating injury-induced, inflammasome-mediated effects at the injured sciatic nerve and/or dorsal root ganglia, spinal cord, and potentially higher levels. Given that our data to date point to morphine amplifying neuroinflammatory processes put into motion by nerve injury, it is intriguing to speculate that co-administration of TLR4 and/or P2X7 antagonists can intervene in these inflammatory processes in a beneficial way. That is, that systemic administration of such compounds may suppress inflammatory damage at multiple sites, rapidly and persistently returning neuropathic animals to sham levels of response.
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影响因子：
16.6
作者：
Koyama S;Akbay EA;Li YY;Herter-Sprie GS;Buczkowski KA;Richards WG;Gandhi L;Redig AJ;Rodig SJ;Asahina H;Jones RE;Kulkarni MM;Kuraguchi M;Palakurthi S;Fecci PE;Johnson BE;Janne PA;Engelman JA;Gangadharan SP;Costa DB;Freeman GJ;Bueno R;Hodi FS;Dranoff G;Wong KK;Hammerman PS
通讯作者：
Hammerman PS
影响因子：
4.8
作者：
Deuis JR;Dvorakova LS;Vetter I
通讯作者：
Vetter I
DOI：
10.1016/j.bbi.2017.08.018
发表时间：
2018-08
期刊：
Brain, behavior, and immunity
影响因子：
--
作者：
Grace PM;Strand KA;Galer EL;Rice KC;Maier SF;Watkins LR
通讯作者：
Watkins LR
影响因子：
2.7
作者：
Hook, Michelle A.;Liu, Grace T.;Grau, James W.
通讯作者：
Grau, James W.
影响因子：
25
作者：
Ferrini F;Trang T;Mattioli TA;Laffray S;Del'Guidice T;Lorenzo LE;Castonguay A;Doyon N;Zhang W;Godin AG;Mohr D;Beggs S;Vandal K;Beaulieu JM;Cahill CM;Salter MW;De Koninck Y
通讯作者：
De Koninck Y