Vol. 299, Issue 2, 659-665, November 2001

Confluence of Antianalgesic Action of Diverse Agents through Brain Interleukin₁ in Mice

Jodie J. Rady and James M. Fujimoto

Research Service, Veterans Administration Medical Center, Milwaukee, Wisconsin

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)-1 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 IL₁ is a supraspinal mediator for intrathecal Dyn-induced antianalgesia in CD-1 mice. Intracerebroventricular Lys¹⁹³-D-Pro-Thr¹⁹⁵, an IL₁ antagonist, or pretreatment with IL₁ antiserum eliminated intrathecal dynorphin antianalgesia, implicating brain IL₁; 10 ng of IL₁ given intracerebroventricularly produced antianalgesia. Fittingly, Dyn was not antianalgesic in C3H/HeJ mice, which are genetically deficient in release of IL₁. Activation of central benzodiazepine receptors preceded the IL₁ step because flumazenil inhibited Dyn but not IL₁ 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 IL₁ antianalgesia; these latter benzodiazepine receptors formed a separate step after the flumazenil-sensitive benzodiazepine receptor step. IL₁ 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, IL₁ is a central physiological mediator in the antianalgesic action evoked by spinal dynorphin.