Pronociceptive actions of dynorphin maintain chronic neuropathic pain

Whereas tissue injury increases spinal dynorphin expression, the functional relevance of this upregulation to persistent pain is unknown. Here, mice l acking the prodynorphin gene were studied for sensitivity to non-noxious an d noxious stimuli, before and after induction of experimental neuropathic p ain. Prodynorphin knock-out (KO) mice had normal responses to acute nonnoxi ous stimuli and a mild increased sensitivity to some noxious stimuli. After spinal nerve ligation (SNL), both wild-type (WT) and KO mice demonstrated decreased thresholds to innocuous mechanical and to noxious thermal stimuli , indicating that dynorphin is not required for initiation of neuropathic p ain. However, whereas neuropathic pain was sustained in WT mice, KO mice sh owed a return to baselines by post-SNL day 10. In WT mice, SNL upregulated lumbar dynorphin content on day 10, but not day 2, after injury. Intratheca l dynorphin antiserum reversed neuropathic pain in WT mice at post-SNL day 10 (when dynorphin was upregulated) but not on post-SNL day 2; intrathecal MK-801 reversed SNL-pain at both times. Opioid (mu, delta, and kappa) recep tor density and G-protein activation were not different between WT and KO m ice and were unchanged by SNL injury. The observations suggest (1) an early , dynorphin-independent phase of neuropathic pain and a later dynorphin-dep endent stage, (2) that upregulated spinal dynorphin is pronociceptive and r equired for the maintenance of persistent neuropathic pain, and (3) that pr ocesses required for the initiation and the maintenance of the neuropathic pain state are distinct. Identification of mechanisms that maintain neuropa thic pain appears important for strategies to treat neuropathic pain.