Involvement of spinal tyrosine kinase in inflammatory and N-methyl-D-aspartate-induced hyperalgesia in rats

Phosphorylation of a subunit of N-methyl-D-aspartate (NMDA) receptor by protein tyrosine kinase (PTK) Src or Trk is known to enhance its channel activity. We examined whether a spinally administered selective PTK inhibitor, lavendustin A, which has high affinity for Src and Trk tyrosine kinases, could influence the development and maintenance of inflammatory hyperalgesia or NMDA-induced hyperalgesia. Inflammation was induced by injection of a mixture of carrageenan and kaolin into the tail base of rats. In another group of rats, hyperalgesia, was induced by intrathecal administration of NMDA. Intrathecal administration of lavendustin A (1.0 mug) or NMDA receptor antagonist, (+)5-methyl- 10, 11-dihydro-5H-dibenzo[a,d]cycloheptane-5,10-iminemaleate, MK-801 (3.0 mug) before injection of a mixture of carrageenan and kaolin or after the development of inflammation inhibited carrageenan-kaolin-induced mechanical hyperalgesia. Intrathecal injection of 1.0 mug NMDA produced thermal and mechanical hyperalgesia. Co-administration of 1.0 mug lavendustin A with NMDA significantly reduced the duration of spontaneous pain behaviour and inhibited NMDA-induced hyperalgesia. Lavendustin A itself did not cause any sedation, motor impairment or analgesia. Our results suggest that inhibition of PTK could be therapeutically effective as an analgesic in some NMDA receptor-mediated hyperalgesic states. (C) 2003 Elsevier Science B.V. All rights reserved.