Dynorphin A-(1-17) induces alterations in free fatty acids, excitatory amino acids, and motor function through an opiate-receptor-mediated mechanism

Abstract

The endogenous opioid dynorphin A-(1-17) (Dyn A) has been implicated as a mediator of tissue damage after traumatic spinal cord injury (TSCI) and causes hindlimb paralysis when administered intrathecally. Motor impairment following intrathecal Dyn A is attenuated by antagonists of excitatory amino acids (EAAs); whether opioid receptors mediate such injury has been questioned. TSCI causes various biochemical changes associated with secondary tissue damage, including alterations in tissue amio acids, phospholipids, and fatty acids. Such changes reflect injury severity and correlate with motor dysfunction. The present studies examined whether dynorphin administration causes similar biochemical alterations and whether effects of Dyn A can be modified by treatment with opioid-receptor antagonists. At 24 hr after intrathecal Dyn A, there were significant declines in tissue levels of glutamate, aspartate, and glycine. Increases in total free fatty acids were found at 2 and 24 hr, reflecting changes in both saturated and unsaturated components, which were associated with significant decreases in tissue cholesterol and phospholipid phosphorus at the earlier time point. Each of these neurochemical changes, as well as corresponding motor deficits, were limited by pretreatment with the opioid antagonist nalmefene. In separate experiments, both nalmefene and the selective kappa-opioid antagonist nor-binaltorphimine (nor-BNI) limited dynorphin-induced motor dysfunction; effects of nor-BNI were dose related, and those of nalmefene were stereospecific. Therefore, behavioral and neurochemical consequences of Dyn A administration are mediated in part through opiate receptors, most likely kappa-receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Dynorphin increases extracellular levels of excitatory amino acids in the brain through a non-opioid mechanism

“…2). Consistent with this observation, administration of a relatively high dose of the opioid receptor antagonist nalmefene (Bakshi et al, 1990) failed to modify the effects of Dyn 1-17 on EAA release (Fig. 3).…”

“…in the tissue levels of glutamate and aspartate (Bakshi et al, 1990). A variety of structurally different NMDA antagonists, with differing mechanisms of action, reduce neurological and histological abnormalities produced by dynorphin (Long et al, 1989;Bakshi and Faden, 1990a,b).…”

“…In contrast to the results of the present study and some of the reports mentioned above, in other model systems the effects of endogenous opioids on EAA release appear to be mediated, at least in part, by opioid receptors. Thus, opioid receptor antagonists stereospecifically reduce the release of EAA following global cerebral ischemia and reperfusion (Graham et al, 1990b) and attenuate alterations of EAA after intrathecal dynorphin (Bakshi et al, 1990).…”

“…Administration of antiserum to dynorphin, but not antiserum to leucin-nkephalin, reduces posttraumatic neurological dysfunction after SC1 (Faden, 1990); in contrast, central administration of dynorphin exacerbates the consequences of TBI or SC1 Faden, 1990). Consistent with its proposed pathophysiological role, intrathecal dynorphin administration causes biochemical changes within the spinal cord, diminished blood flow (Long et al, 1987), motor deficits Received July 11, 1991;revised Sept. 11, 1991;accepted Sept. 18, 1991 (Faden and Jacobs, 1984;Herman and Goldstein, 1985;Long et al, 1988) and histological damage that simulate the consequences of spinal cord trauma (for review, see Bakshi et al, 1990). Excitatory amino acids (EAA) have also been implicated as pathophysiological factors in SC1 and TBI through actions mediated by NMDA receptors.…”

“…This concept was supported and extended by others. Intrathecal dynorphin administration was shown to cause depletion of tissue levels of glutamate and aspartate (Bakshi et al, 1990). Moreover, NMDA antagonists (including competitive, noncompetitive, or glycine site antagonists) were found to limit dynorphin-induced behavioral changes and mortality (Long et al, 1989;Bakshi and Faden, 1990a,b).…”