Spinal and supraspinal mechanisms of neuropathic pain.
Neuropathic pain is associated with abnormal tactile and thermal responses that may be extraterritorial to the injured nerve. Importantly, tactile allodynia and thermal hyperalgesia may involve separate pathways, since complete and partial spinal cord lesions have blocked allodynia, but not hyperalgesia, after spinal nerve ligation (SNL). Furthermore, lesions of the dorsal column, and lidocaine microinjected into dorsal column nuclei block only tactile allodynia. Conversely, thermal hyperalgesia, but not tactile allodynia was blocked by desensitization of C-fibers with resiniferotoxin. Therefore, it seems that tactile allodynia is likely to be mediated by large diameter A beta fibers, and not susceptible to modulation by spinal opioids, whereas hyperalgesia is mediated 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 entry 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 antinociception. Finally, afferent drive may induce descending facilitation from the rostroventromedial medulla (RVM). Blocking afferent drive with bupivicaine 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 neuropathic pain to opioids.
Department of Pharmacology, College of Medicine, University of Arizona, Tucson 85724, USA.
M H
MH
Ossipov
J
J
Lai
T P
TP
Malan
F
F
Porreca
D000818:Animals; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004399:Dynorphins / Q000502:physiology; D006801:Humans; D006930:Hyperalgesia / Q000209:etiology; D008012:Lidocaine / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D010146:Pain / Q000209:etiology*; D013116:Spinal Cord / Q000502:physiology*
D016291:Dizocilpine Maleate; D004399:Dynorphins; D009020:Morphine; D008012:Lidocaine