12 Spinal and Supraspinal Mechanisms of Neuropathic Pain MICHAEL H. OSSIPOV, JOSEPHINE LAI, T. PHILIP MALAN, JR., AND FRANK PORRECA a Department of Pharmacology, College of Medicine, University of Arizona, Tucson, Arizona 85724, USA ABSTRACT: Neuropathic pain is associated with abnormal tactile and thermal responses that may be extraterritorial to the injured nerve. Importantly, tac- tile allodynia and thermal hyperalgesia may involve separate pathways, since complete and partial spinal cord lesions have blocked allodynia, but not hype- ralgesia, after spinal nerve ligation (SNL). Furthermore, lesions of the dorsal column, and lidocaine microinjected into dorsal column nuclei block only tac- tile allodynia. Conversely, thermal hyperalgesia, but not tactile allodynia was blocked by desensitizatin of C-fibers with resiniferotoxin. Therefore, it seems that tactile allodynia is likely to be mediated by large diameter A fibers, and not susceptible to modulation by spinal opioids, whereas hyperalgesia is medi- ated by unmyelinated C-fibers, and is sensitive to blockade by spinal opioids. Additionally, abnormal, spontaneous afferent drive in neuropathic pain may contribute to NMDA-mediated central sensitization by glutamate and by non- opioid actions of spinal dynorphin. Correspondingly, SNL elicited elevation in spinal dynorphin content in spinal segments at and adjacent to the zone of en- try of the injured nerve along with signs of neuropathic pain. Antiserum to dynorphin A (1–17) or MK-801 given spinally blocked thermal hyperalgesia, but not tactile allodynia, after SNL, and also restored diminished morphine anti- nociception. Finally, afferent drive may induce descending facilitation from the rostroventromedial medulla (RVM). Blocking afferent drive with bupivic- aine also restored lost potency of PAG morphine, as did CCK antagonists in the RVM. This observation is consistent with afferent drive activating descending facilitation from the RVM, and thus diminishing opioid activity, and may underlie the clinical observation of limited responsiveness of neuro- pathic pain to opioids INTRODUCTION One of the most significant health problems in our country is the inadequate treat- ment of chronic pain states. As many as one-third of all Americans suffer from some form of chronic pain, and one-third of these have pain which is resistant to the treat- ment efforts of the medical community. 1 Nerve damage arising from either trauma or disease affecting peripheral nerves can lead to abnormal pain states. Such pain may be long-lasting and continue for long periods after the initial injury has healed or in the persist in the absence of observable tissue damage. Individuals afflicted a Address for correspondence: Frank Porreca, Ph.D. Department of Pharmacology, University of Arizona HSC, Tucson, AZ 85724. Voice: 520-626-7421; fax: 520-626-4182. e-mail: frankp@u.arizona.edu