SINGLE INTRATHECAL INJECTIONS OF DYNORPHIN-A OR DES-TYR-DYNORPHINS PRODUCE LONG-LASTING ALLODYNIA IN RATS - BLOCKADE BY MK-801 BUT NOT NALOXONE

Neuropathic pain states are accompanied by increased sensitivity to bo th noxious and non-noxious sensory stimuli, characterized as hyperalge sia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuropl astic changes including increased spinal levels of substance P, cholec ystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which con tributes to neuropathic pain. In addition to its opioid activities, dy norphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in anim al models of neuropathic pain, rats received a single intrathecal (i.t .) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17 ) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Fr ey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t, ad ministration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A( 2-13) also produced long-lasting tactile allodynia. Intrathecal pretre atment, but not post-treatment, with MK-801 prevented dynorphin A(1-17 )-induced development of allodynia; i.t. administration of MK-801 alon e had no effect on responses to tactile stimuli. In contrast, i.t. pre treatment with naloxone did not affect the development of tactile allo dynia induced by dynorphin A(1-17) or alter sensory threshold when giv en alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may b e irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the a llodynia is unclear, it seems possible that dynorphin may produce chan ges in the spinal cord, which may contribute to the development of sig ns reminiscent of a 'neuropathic' state. Given that levels of dynorphi n are elevated following nerve injury, it seems reasonable to speculat e that dynorphin may have a pathologically relevant role in neuropathi c pain states.