Gogas K R, Levine J D, Basbaum A I
Department of Molecular and Developmental Neuroscience, Massachusetts General Hospital, Charlestown, USA.
J Pharmacol Exp Ther. 1996 Feb;276(2):801-9.
In this study, the effect of intracerebroventricular (icv) administration of (5R)-(5 alpha, 7 alpha, 8 beta)-N-methyl-N-[7-(1-pyrrolindinyl)-1- oxaspiro[4,5]dec-8-yl]-4-benzofurnacetamide monohydrochloride (Cl-977) on pain behaviors and on spinal cord fos-like immunoreactivity (FLI) evoked by unilateral formalin injection into the hindpaw of rats was examined. Intracerebroventricular administration of Cl-977 (0.13-13.00 nmol) produced a dose-dependent inhibition of formalin-evoked pain behaviors, with significant inhibition after 1.30, 4.40 and 13.00 nmol. The estimated ED50 for icv Cl-977 inhibition of formalin-evoked behaviors was 0.95 nmol and the Emax was 53%. The inhibitory effect of 4.40 nmol of icv Cl-977 on formalin-evoked behaviors was prevented by either pretreatment with the kappa selective antagonist nor-binaltorphimine (10 or 100 nmol) or coadministration of the opiate receptor antagonist, naloxone (30 nmol). The lowest dose of icv Cl-977 tested (0.13 nmol) produced a 50% reduction in FLI in the superficial laminae but did not inhibit the expression of FLI in any other regions of the spinal cord. The fos-inhibitory effect of low-dose icv Cl-977 in the superficial cord was reversed by coadministration of naloxone (30 nmol). Higher doses of icv Cl-977 that suppressed formalin-evoked behaviors did not inhibit the expression of FLI in any region of the spinal cord. Finally, neither the inhibitory effect of 4.40 nmol Cl-977 on formalin-evoked behaviors nor the formalin-evoked pattern of FLI expression in the spinal cord of rats treated with this dose of Cl-977 was affected by lesions of the dorsolateral funiculus. These results provide the first evidence that supraspinal kappa receptor-mediated antinociception is not dependent on the integrity of the dorsolateral funiculus and may be mediated exclusively at the supraspinal level, suggesting that there are multiple mechanisms through which opioids can evoke antinociceptive effects.
在本研究中，检测了脑室内（icv）注射（5R）-（5α，7α，8β）-N-甲基-N-[7-（1-吡咯烷基）-1-氧杂螺[4,5]癸-8-基]-4-苯并呋喃乙酰胺盐酸盐（Cl-977）对大鼠后爪单侧注射福尔马林所诱发的疼痛行为以及脊髓中类Fos免疫反应性（FLI）的影响。脑室内注射Cl-977（0.13 - 13.00 nmol）可产生剂量依赖性地抑制福尔马林诱发的疼痛行为，在注射1.30、4.40和13.00 nmol后有显著抑制作用。脑室内注射Cl-977抑制福尔马林诱发行为的估计半数有效剂量（ED50）为0.95 nmol，最大效应（Emax）为53%。用κ选择性拮抗剂去甲二氢吗啡酮（10或100 nmol）预处理或与阿片受体拮抗剂纳洛酮（30 nmol）共同给药，均可阻止4.40 nmol脑室内注射Cl-977对福尔马林诱发行为的抑制作用。所测试的最低剂量脑室内注射Cl-977（0.13 nmol）可使脊髓浅层的FLI降低50%，但不抑制脊髓其他区域的FLI表达。纳洛酮（30 nmol）共同给药可逆转低剂量脑室内注射Cl-977对脊髓浅层的Fos抑制作用。更高剂量的脑室内注射Cl-977抑制福尔马林诱发行为，但不抑制脊髓任何区域的FLI表达。最后，4.40 nmol Cl-977对福尔马林诱发行为的抑制作用以及用该剂量Cl-977处理的大鼠脊髓中福尔马林诱发的FLI表达模式均不受背外侧索损伤的影响。这些结果首次证明，脊髓上κ受体介导的镇痛作用不依赖于背外侧索的完整性，可能仅在脊髓上水平介导，并提示阿片类药物可通过多种机制诱发镇痛作用。
