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 lacking the prodynorphin gene were studied for sensitivity to non-noxious and noxious stimuli, before and after induction of experimental neuropathic pain. Prodynorphin knock-out (KO) mice had normal responses to acute non-noxious 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 pain. However, whereas neuropathic pain was sustained in WT mice, KO mice showed 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. Intrathecal 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) receptor density and G-protein activation were not different between WT and KO mice and were unchanged by SNL injury. The observations suggest (1) an early, dynorphin-independent phase of neuropathic pain and a later dynorphin-dependent stage, (2) that upregulated spinal dynorphin is pronociceptive and required for the maintenance of persistent neuropathic pain, and (3) that processes required for the initiation and the maintenance of the neuropathic pain state are distinct. Identification of mechanisms that maintain neuropathic pain appears important for strategies to treat neuropathic pain.
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA.
Z
Z
Wang
L R
LR
Gardell
M H
MH
Ossipov
T W
TW
Vanderah
M B
MB
Brennan
U
U
Hochgeschwender
V J
VJ
Hruby
T P
TP
Malan
J
J
Lai
F
F
Porreca
D000818:Animals; D002908:Chronic Disease; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000008:administration & dosage; D004399:Dynorphins / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D006941:Hyperesthesia / Q000378:metabolism / Q000503:physiopathology; D007106:Immune Sera / Q000008:administration & dosage; D007278:Injections, Spinal; D008026:Ligation; D008161:Lumbosacral Region; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009437:Neuralgia / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology*; D010147:Pain Measurement / Q000187:drug effects; D017288:Pain Threshold / Q000187:drug effects; D010812:Physical Stimulation; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000032:analysis / Q000378:metabolism; D013116:Spinal Cord / Q000737:chemistry / Q000378:metabolism / Q000503:physiopathology; D013127:Spinal Nerves / Q000503:physiopathology* / Q000601:surgery
D018691:Excitatory Amino Acid Antagonists; D007106:Immune Sera; D011957:Receptors, Opioid; D016291:Dizocilpine Maleate; D004399:Dynorphins