Confluence of antianalgesic action of diverse agents through brain interleukin(1 beta) in mice

Spinal dynorphin A(1-17) (Dyn) has been shown previously to produce an anti analgesic action against intrathecal morphine in the tail-flick test in CD- 1 mice. This action is known to be mediated indirectly from the spinal cord through an afferent pathway that activates flumazenil-sensitive benzodiaze pine receptors in the brain and a descending circuit back down to the spina l cord sequentially involving cholecystokinin, leu-enkephalin, and N-methyl -D-aspartate receptors to produce antianalgesia. Interleukin (IL)-1 beta is also known to act on peripheral afferent nerves to the brain to activate a descending circuit to release spinal cholecystokinin. The present investig ation determined whether IL1 beta is a supraspinal mediator for intrathecal Dyn-induced antianalgesia in CD-1 mice. Intracerebroventricular Lys(193)-D -Pro-Thr(195), an IL1 beta antagonist, or pretreatment with IL1 beta antise rum eliminated intrathecal dynorphin antianalgesia, implicating brain IL1 b eta; 10 ng of IL1 beta given intracerebroventricularly produced antianalges ia. Fittingly, Dyn was not antianalgesic in C3H/HeJ mice, which are genetic ally deficient in release of IL1 beta. Activation of central benzodiazepine receptors preceded the IL1 beta step because flumazenil inhibited Dyn but not IL1 beta antianalgesia. On the other hand, [1-(2-chlorophenyl)N-methyl- N-(1-methylpropyl)-3-isoquinolinecarboxamide], an antagonist for peripheral benzodiazepine receptors that have also recently been detected in brain ti ssue, inhibited IL1 beta antianalgesia; these latter benzodiazepine recepto rs formed a separate step after the flumazenil-sensitive benzodiazepine rec eptor step. IL1 beta action in the brain was linked to the linear steps in the spinal cord (cholecystokinin/N-methyl-D-aspartate receptors) as shown b y inhibition with appropriate antagonists. Thus, IL1 beta is a central phys iological mediator in the antianalgesic action evoked by spinal dynorphin.