The cellular basis of tolerance to many types of drugs, including opiates, remains unknown. Tolerance to opiates cannot be explained simply on the basis of altered metabolism or disposition of the opiate. It has been suggested for many years by various investigators that tolerance to morphine and related substances reflects a change in the sensitivity of cells upon which morphine acts. The changes observed in cells of the myenteric plexus of the ileum from guinea pigs chronically exposed to morphine are strikingly similar to changes observed in association with the phenomenon of postjunctional supersensitivity. Postjunctional supersensitivity represents a cellular homeostatic mechanism by which a variety of types of cells compensate for chronic changes in the net stimulation they receive. Supersensitivity in many instances is nonspecific and has been associated with a partial depolarization scondary to depression of electrogenic Na+, K+ pump activity. The hypothesis which we propose to test is that tolerance to the hyperpolarizing effects of opiates in myenteric ganglion cells is the consequence of a partial depolarizaton of the ganglion cells and a decrease in electrogenic Na+, K+ pumping. The sensitivity of isolated longitudinal muscle-myenteric plexus preparations obtained from control guinea pigs and guinea pigs chronically treated with morphine will be compared using a variety of unrelated excitatory and inhibitory agonists. Concurrently, the electrophysiological characteristics of myenteric ganglion cells will be studied using conventional intracellular recording techniques. By investigating the effects of agonists and pump inhibitors on membrane potential, answers will be sought to the following questions: 1) Is there an electrogenic contribution of the Na+, K+ pump to the membrane potential of type 1 ganglion cells? 2) Are the ganglion cells of animals made tolerant to morphine partially depolarized relative to naive cells? 3) If they are partially depolarized, is the depolarization associated with a reduction in electrogenic pumping?

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA003773-03
Application #
3208394
Study Section
(SRCD)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
West Virginia University
Department
Type
School of Medicine & Dentistry
DUNS #
191510239
City
Morgantown
State
WV
Country
United States
Zip Code
26506
Biser, P S; Thayne, K A; Fleming, W W et al. (2002) Na+, K+ ATPase alpha-subunit isoform distribution and abundance in guinea-pig longitudinal muscle/myenteric plexus after exposure to morphine. Brain Res 931:186-93
Kong, J Q; Meng, J; Biser, P S et al. (2001) Cellular depolarization of neurons in the locus ceruleus region of the guinea pig associated with the development of tolerance to opioids. J Pharmacol Exp Ther 298:909-16
Taylor, D A; Fleming, W W (2001) Unifying perspectives of the mechanisms underlying the development of tolerance and physical dependence to opioids. J Pharmacol Exp Ther 297:11-8
Biser, P S; Thayne, K A; Kong, J Q et al. (2000) Quantification of the alpha(3) subunit of the Na(+)/K(+)-ATPase in developing rat cerebellum. Brain Res Dev Brain Res 123:165-72
Malanga, C J; Meng, J; Fleming, W W et al. (1997) Chronic morphine treatment of guinea pigs induces nonspecific sensitivity changes in the nucleus tractus solitarius in vitro. J Pharmacol Exp Ther 280:16-23
Meng, J; Malanga, C J; Kong, J Q et al. (1997) Hyperpolarizing effects of morphine, clonidine and 2-chloroadenosine in myenteric neurons associated with tolerance to morphine. J Pharmacol Exp Ther 281:41-7
Kong, J Q; Leedham, J A; Taylor, D A et al. (1997) Evidence that tolerance and dependence of guinea pig myenteric neurons to opioids is a function of altered electrogenic sodium-potassium pumping. J Pharmacol Exp Ther 280:593-9
Blume, T W; Green, S; Joanning, H et al. (1994) Social role negotiation skills for substance-abusing adolescents: a group model. J Subst Abuse Treat 11:197-204
Leedham, J A; Kong, J Q; Taylor, D A et al. (1992) Membrane potential in myenteric neurons associated with tolerance and dependence to morphine. J Pharmacol Exp Ther 263:15-9
Taylor, D A; Leedham, J A; Bennett, L E et al. (1991) Effects of GABA in the morphine-tolerant longitudinal muscle, myenteric plexus preparation of the guinea pig. J Pharmacol Exp Ther 259:1094-101

Showing the most recent 10 out of 13 publications