Abstract
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, andN-methyl-d-aspartate receptors to produce antianalgesia. Interleukin (IL)-1β 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 IL1β is a supraspinal mediator for intrathecal Dyn-induced antianalgesia in CD-1 mice. Intracerebroventricular Lys193-d-Pro-Thr195, an IL1β antagonist, or pretreatment with IL1βantiserum eliminated intrathecal dynorphin antianalgesia, implicating brain IL1β; 10 ng of IL1β given intracerebroventricularly produced antianalgesia. Fittingly, Dyn was not antianalgesic in C3H/HeJ mice, which are genetically deficient in release of IL1β. Activation of central benzodiazepine receptors preceded the IL1β step because flumazenil inhibited Dyn but not IL1β 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 IL1βantianalgesia; these latter benzodiazepine receptors formed a separate step after the flumazenil-sensitive benzodiazepine receptor step. IL1β 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, IL1β is a central physiological mediator in the antianalgesic action evoked by spinal dynorphin.
Footnotes
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This study was supported by VA Medical Funds (VA Merit Review, Research Career Scientist Award, to J.M.F.).
- Abbreviations:
- Dyn
- dynorphin A(1–17)
- i.t.
- intrathecal(ly)
- CCK
- cholecystokinin
- LE
- leu-enkephalin
- NMDA
- N-methyl-d-aspartate
- IL
- interleukin
- LPS
- lipopolysaccharide
- Lys-d-Pro-Thr
- Lys193-d-Pro-Thr195
- PK11195
- [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide]
- % MPE
- percentage of maximum possible effect
- CCK8s
- sulfated cholecystokinin 8
- MK801
- dizocilpine
- BNTX
- 7-benzylidenenaltrexone
- Received May 1, 2001.
- Accepted July 24, 2001.
- U.S. Government
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