Although an understanding of the neural systems involved in opioid dependence has progressed significantly in recent years, little is yet known about the basic changes in brain function produced by opioids and, consequently, how opioid dependence-producing effects might be prevented therapeutically. Our broad objective is to utilize the hibernating brain, which we have shown to display a unique natural suppression of morphine dependence, to study the neural basis of opioid physical dependence (and, ultimately, its prevention). Thus, this proposal will: 1) determine if the hibernation state is one in which the rate and/or magnitude of development of morphine dependence is attenuated or if it is virtually absent; 2) determine if tolerance to morphine actions in the bran is retarded during the hibernation state; and 3) examine if the hibernation-related change in brain dopamine metabolism is a primary mechanism responsible for the reduction of morphine dependence during the hibernation state; and 3) examine if the hibernation-related change in brain dopamine metabolism is a primary mechanism responsible for the reduction of morphine dependence during hibernation.
The specific aims are measure and compare the hibernation state versus the nonhibernation state characteristics in ground squirrels of: 1) dependence produced by a wide range of morphine doses and durations of intracerebral (ic) administration; 2) dependence produced by mu receptor opioid agonists possessing greater lipid solubility than morphine; 3) tolerance to morphine analgesic and nonanalgesic actions; 4) morphine effects on caudate nucleus dopamine (DA) metabolism. The methods will include: chronic ic cannulation, for opioid microinjection and microinfusion in freely moving animals; measurement of naloxone-precipitated abstinence; recording of body temperature and skin twitch responses to assess tolerance to morphine actions; high performance liquid chromatography/electrochemical detection and in vivo push-pull perfusion to determine morphine effects on caudate DA metabolism.
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