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

Spinal dynorphin A(1-17) (Dyn) has been shown previously to produce an antianalgesic 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 benzodiazepine receptors in the brain and a descending circuit back down to the spinal cord sequentially involving cholecystokinin, leu-enkephalin, and N-methyl-D-aspartate receptors to produce antianalgesia. Interleukin (IL)-1beta is also known to act on peripheral afferent nerves to the brain to activate a descending circuit to release spinal cholecystokinin. The present investigation determined whether IL1beta is a supraspinal mediator for intrathecal Dyn-induced antianalgesia in CD-1 mice. Intracerebroventricular Lys193-D-Pro-Thr195, an IL1beta antagonist, or pretreatment with IL1beta antiserum eliminated intrathecal dynorphin antianalgesia, implicating brain IL1beta; 10 ng of IL(1beta) given intracerebroventricularly produced antianalgesia. Fittingly, Dyn was not antianalgesic in C3H/HeJ mice, which are genetically deficient in release of IL1beta. Activation of central benzodiazepine receptors preceded the IL1beta step because flumazenil inhibited Dyn but not IL1beta 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 tissue, inhibited IL1beta antianalgesia; these latter benzodiazepine receptors formed a separate step after the flumazenil-sensitive benzodiazepine receptor step. IL1beta action in the brain was linked to the linear steps in the spinal cord (cholecystokinin/N-methyl-D-aspartate receptors) as shown by inhibition with appropriate antagonists. Thus, IL1beta is a central physiological mediator in the antianalgesic action evoked by spinal dynorphin.