Intrathecal injection of dynorphin or des-Tyr-dynorphin fragments, which do not bind to opioid receptors, produce tactile and thermal hypersensitivity in rodents. The maintenance, but not initiation, of experimental neuropathic pain depends upon pronociceptive effects of elevated levels of spinal dynorphin. Recent findings implicated a direct excitatory action of dynorphin A at bradykinin receptors in vitro. Here, the possibility that the pronociceptive actions of pharmacological dynorphin or of pathological levels of endogenous spinal dynorphin are mediated by interaction with bradykinin receptors was explored.; While spinal administration of a wide range of bradykinin did not produce hyperalgesia in rats, intrathecal injection of non-opioid des-tyrosyl-dynorphin A(2-13) produced reversible tactile and thermal hypersensitivities that were reversed by bradykinin receptor antagonists. Dynorphin-induced behavioral hyperesthesias were observed in bradykinin B2 receptor wild-type but not in B2 receptor knockout mice. Spinal administration or infusion of B1, and especially B2, receptor antagonists reversed experimental neuropathic pain behaviors in rats with peripheral nerve injury but only when the antagonists were given at times at which dynorphin was upregulated. After nerve injury, both B1 and B2 receptor mRNA were increased in the dorsal root ganglion, but not in the spinal cord. While a marked increase in mRNA expression for prodynorphin in the lumbar spinal cord was found following nerve injury, expression of mRNA for kininogen was below detection levels. The possible interaction of spinal dynorphin with bradykinin receptors as a basis of the pronociceptive action of this peptide was further tested in the CFA-induced inflammatory pain and DBTC-induced pancreatitis pain. Intrathecal administration of bradykinin receptor antagonists or dynorphin antiserum reversed DBTC-induced abdominal hypersensitivity and CFA-induced hyperalgesia only when spinal dynorphin or prodynorphin is upregulated. The antihyperalgesic effect of the bradykinin receptor antagonists was not due to de novo production of bradykinin.; Taken together, our results unravel a novel, non-opioid molecular target of dynorphin, and indicate that dynorphin acts at bradykinin receptors to produce persistent pain in the pathological pain states. This novel pronociceptive mechanism offers new approaches to the development of therapy for pathological pain states.
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