In view of the many undesirable actions of morphine and other opium derivatives, considerable research has been devoted to developing new drugs that retain morphine's analgesic efficacy but are less likely to result in abuse and physical dependence. A class of drugs that has been developed specifically for these reasons are the partial mu agonists. Although these drugs have recently gained popularity for the management of pain and in the treatment of opioid abuse and dependence, they have not proven to be devoid of abuse potential or physical dependence liability. It is essential, therefore, to critically evaluate the behavioral and pharmacological properties of these opioids and develop reliable methods and strategies that can be used to further advance our understanding of this widely used and abused class of drugs. Moreover, given the exceptionally large number of partial mu agonists available, of which most are presumed to have varying degrees of activity at different opioid receptor types, this heterogeneous class of opioids can serve as a tool for delineating the fundamental properties of drugs with limited efficacy at a given receptor site, as well as drugs with simultaneous actions at multiple receptor types. Although these drugs have been examined extensively in physiological and antinociceptive assays, information concerning the nature of their stimulus properties, development of tolerance to their behavioral effects and the receptor mechanisms that underlie their diverse actions, have not been well documented. A goal of the proposed studies is to address these and other fundamental issues regarding the actions of partial mu agonists using different operant methodologies and pharmacological techniques. Specifically, we propose to (1) evaluate the relative contribution of activity at mu, kappa and delta opioid receptors to the stimulus effects of different partial mu agonists, and establish a discrimination between a full mu agonist and saline in order to determine if this procedure can be used to distinguish between partial mu agonists that share similar stimulus effects with morphine, yet can be differentiated from morphine in other assays, (2) evaluate the contribution of activity at the delta receptor in mediating the stimulus effects of partial mu agonists, (3) evaluate the extent to which the irreversible antagonists alter the behavioral effects of partial mu agonists with the goal of providing a quantitative estimate of rank ordering of their relative efficacy at the mu receptor, and (4) evaluate the behavioral consequences of long-term exposure to opioids and determine the extent to which tolerance development relates to the drug used to induce tolerance, the dose of the drug used to induce tolerance, and the test opioid's efficacy at and selectivity for the mu receptor. Although the work proposed here will evaluate the actions of partial mu agonists within the conceptual framework of receptor pharmacology, it also acknowledges the unique contribution of environmental determinants of drug action as well as the limitations of receptor theory as it applies under conditions in which multiple receptor types contribute to a drug's behavioral actions.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA010277-03
Application #
2733570
Study Section
Special Emphasis Panel (SRCD (26))
Program Officer
Wetherington, Cora Lee
Project Start
1996-07-01
Project End
1999-11-30
Budget Start
1998-07-01
Budget End
1999-11-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
078861598
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Lomas, Lisa M; Terner, Jolan M; Picker, Mitchell J (2008) Sex differences in NMDA antagonist enhancement of morphine antihyperalgesia in a capsaicin model of persistent pain: comparisons to two models of acute pain. Pharmacol Biochem Behav 89:127-36
Lomas, Lisa M; Barrett, Andrew C; Terner, Jolan M et al. (2007) Sex differences in the potency of kappa opioids and mixed-action opioids administered systemically and at the site of inflammation against capsaicin-induced hyperalgesia in rats. Psychopharmacology (Berl) 191:273-85
Fee, J R; Knapp, D J; Sparta, D R et al. (2006) Involvement of protein kinase A in ethanol-induced locomotor activity and sensitization. Neuroscience 140:21-31
Terner, Jolan M; Barrett, Andrew C; Lomas, Lisa M et al. (2006) Influence of low doses of naltrexone on morphine antinociception and morphine tolerance in male and female rats of four strains. Pain 122:90-101
Terner, Jolan M; Lomas, Lisa M; Picker, Mitchell J (2005) Influence of estrous cycle and gonadal hormone depletion on nociception and opioid antinociception in female rats of four strains. J Pain 6:372-83
Lomas, Lisa M; Picker, Mitchell J (2005) Behavioral assessment of temporal summation in the rat: sensitivity to sex, opioids and modulation by NMDA receptor antagonists. Psychopharmacology (Berl) 180:84-94
Walker, Ellen A; Picker, Mitchell J; Granger, Arthur et al. (2004) Effects of opioids in morphine-treated pigeons trained to discriminate among morphine, the low-efficacy agonist nalbuphine, and saline. J Pharmacol Exp Ther 310:150-8
Fee, Jon R; Sparta, Dennis R; Knapp, Darin J et al. (2004) Predictors of high ethanol consumption in RIIbeta knock-out mice: assessment of anxiety and ethanol-induced sedation. Alcohol Clin Exp Res 28:1459-68
Terner, Jolan M; Lomas, Lisa M; Smith, Eric S et al. (2003) Pharmacogenetic analysis of sex differences in opioid antinociception in rats. Pain 106:381-91
Barrett, Andrew C; Smith, Eric S; Picker, Mitchell J (2003) Capsaicin-induced hyperalgesia and mu-opioid-induced antihyperalgesia in male and female Fischer 344 rats. J Pharmacol Exp Ther 307:237-45

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