Single intrathecal injections of dynorphin A or des-Tyr-dynorphins produce long-lasting allodynia in rats: blockade by MK-801 but not naloxone.
Neuropathic pain states are accompanied by increased sensitivity to both noxious and non-noxious sensory stimuli, characterized as hyperalgesia and allodynia, respectively. In animal models of neuropathic pain, the presence of hyperalgesia and allodynia are accompanied by neuroplastic changes including increased spinal levels of substance P, cholecystokinin (CCK), and dynorphin. N-Methyl-D-aspartate (NMDA) receptors appear to be involved in maintaining the central sensitivity which contributes to neuropathic pain. In addition to its opioid activities, dynorphin has been suggested to act at the NMDA receptor complex. In an attempt to mimic the increased levels of spinal dynorphin seen in animal models of neuropathic pain, rats received a single intrathecal (i.t.) injection of dynorphin A(1-17), dynorphin A(1-13), dynorphin A(2-17) or dynorphin A(2-13) through indwelling catheters. Tactile allodynia was determined by measuring response threshold to probing with von Frey filaments. Dynorphin A(1-17) administration evoked significant and long-lasting tactile allodynia (i.e. > 60 days). Likewise, the i.t. administration of dynorphin A(1-13) or dynorphin A(2-17) or dynorphin A(2-13) also produced long-lasting tactile allodynia. Intrathecal pretreatment, but not post-treatment, with MK-801 prevented dynorphin A(1-17)-induced development of allodynia; i.t. administration of MK-801 alone had no effect on responses to tactile stimuli. In contrast, i.t. pretreatment with naloxone did not affect the development of tactile allodynia induced by dynorphin A(1-17) or alter sensory threshold when given alone. These results demonstrate that a single dose of dynorphin A, or its des-Tyr fragments, produces long-lasting allodynia which may be irreversible in the rat. Further, this effect appears to be mediated through activation of NMDA, rather than opioid, receptors. While the precise mechanisms underlying the development and maintenance of the allodynia is unclear, it seems possible that dynorphin may produce changes in the spinal cord, which may contribute to the development of signs reminiscent of a "neuropathic' state. Given that levels of dynorphin are elevated following nerve injury, it seems reasonable to speculate that dynorphin may have a pathologically relevant role in neuropathic pain states.
Vanderah
T W
TW
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson 85724, USA.
Laughlin
T
T
Lashbrook
J M
JM
Nichols
M L
ML
Wilcox
G L
GL
Ossipov
M H
MH
Malan
T P
TP
Porreca
F
F
D000818:Animals; D002908:Chronic Disease; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004399:Dynorphins / Q000037:antagonists & inhibitors*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D007278:Injections, Spinal; D008297:Male; D009270:Naloxone / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use*; D010146:Pain / Q000139:chemically induced; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012684:Sensory Thresholds / Q000187:drug effects*
D018691:Excitatory Amino Acid Antagonists; D009292:Narcotic Antagonists; D010446:Peptide Fragments; D009270:Naloxone; D016291:Dizocilpine Maleate; D004399:Dynorphins