DynorphinA-(1-17) is an endogenous opioid peptide, but some of its physiological, pharmacological and behavioral effects appear to be mediated through non-opioid mechanisms. Several of these effects are of particular interest, because they may be subject to dual regulation by dynorphin, involving both opioid and nonopioid mechanisms. These include antagonism of cocaine sensitization, release of ACTH from the fetal pituitary, and attenuation of morphine tolerance. The nonopioid contribution of dynorphin in each of these cases is demonstrated by the activity of dynorphinA-(2-17), which does not bind to opioid receptors. Yet experiments with classical opioid agonists and antagonists also indicate a role for opioid receptors in each of these phenomena. The purpose of this component is to elucidate the nonopioid receptor mechanisms underlying dynorphin attenuation of morphine tolerance. Dynorphin potentiates morphine antinociception in the morphine tolerant animal, and suppresses withdrawal symptoms. These actions suggest that dynorphin could be useful for patients requiring long term pain relief as well as for treatment of opioid addicts. In addition, identification of the receptor mechanisms involved in dynorphin modulation of opioid tolerance is likely to be relevant to understanding dynorphin's other nonopioid actions. The mechanism by which dynorphin modulates opioid tolerance/dependence is not known, but an important clue is provided by studies of opioid synergism, or multiplicative effects. Several groups have demonstrated that opioid agonists administered simultaneously to both spinal and supraspinal sites are much more potent than would be expected from a simple addition of their effects at each site alone. Moreover, some evidence indicates that a decrease of synergism accompanies tolerance development, so that the degree of this synergism is inversely correlated with the degree of tolerance. Based on these observations, we have hypothesized that dynorphin's enhancement of morphine's potency in tolerant animals is exerted through a regulation of spinal--supraspinal synergism. In support of this hypothesis, we have found that administration of dynorphinA-(2-17) partially restores the spinal-supraspinal synergism that is lost during morphine tolerance. To explore this phenomenon further, we propose to determine whether spinal/supraspinal synergism is also exhibited by selective m, d and k opioid agonists, and if so, the effect of dynorphinA-(2-17) on restoring it in the tolerant animals. In addition, we will evaluate the role of spinal NMDA receptors in this phenomenon, using selective agonists and antagonists, as some evidence indicates that they may also modulate the chronic effects of opioids. Overall, this proposal is designed to test a novel hypothesis of opioid tolerance, as well as obtain further insight into the nonopioid actions of dynorphin.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Program Projects (P01)
Project #
5P01DA011470-02
Application #
6346081
Study Section
Special Emphasis Panel (ZDA1)
Project Start
2000-09-01
Project End
2001-07-31
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
$124,146
Indirect Cost
Name
California Pacific Medical Center Research Institute
Department
Type
DUNS #
071882724
City
San Francisco
State
CA
Country
United States
Zip Code
94107