Actions of intrathecal diphtheria toxin substance P fusion protein on models of persistent pain

Substance P (SP) plays a central role in the transduction of second messeng er signals from primary afferent nociceptive terminals to second-order neur ons in the spinal cord. We have tested a recombinant engineered diphtheria toxin/SP fusion protein (DAB389SP) in acute and chronic pain models in the rat. DAB389SP binds to the SP receptor (SPR) and is internalized and kills SPR-expressing cells by blocking cellular protein synthesis. DAB389SP deliv ery was by intrathecal infusion, of varying duration, at the lumbar level. In the chronic constriction injury model of neuropathic pain a significant reduction in mechanically induced hyperalgesia was obtained. This effect wa s less marked in an acute carageenan inflammation model. Although other pai n characteristics (mechano-allodynia, cold-allodynia, and heat-hyperalgesia ) showed some improvement, these were less pronounced. Immunocytochemistry revealed a toxin-induced reduction in lamina I, of SPR and of NMDA NR1 subu nit receptor expressing neurons, and of c-Fos, an inducible molecular marke r of persistent nociceptive activity. The use of cytotoxic fusion proteins to target specific cell types may be of considerable benefit in the study o f nociception and the treatment of chronic pain. (C) 1999 International Ass ociation for the Study of Pain. Published by Elsevier Science B.V.