Regulation of G proteins by chronic opiate and clonidine treatment in the guinea pig myenteric plexus.
G proteins have been implicated in the development of opioid dependence of the guinea pig myenteric plexus as chronic fentanyl elevates G0/i alpha and pertussis toxin prevents this phenomenon. Therefore, the present study investigates G proteins more closely in this peripheral nerve plexus after chronic exposure to addictive drugs of the opiate and nonopiate type. After 6 days of treatment with either the mu receptor ligand fentanyl, the kappa- agonist U-50,488H or the alpha-2 adrenergic receptor ligand clonidine, at doses which render the myenteric plexus tolerant and dependent, the G protein subunits Go alpha and G beta were quantified by immunoblot analysis by using polyclonal antisera. Regardless of the drug used, these G proteins were found to be significantly increased in particulate membrane preparations linked to nerve somata and nerve terminals. This increase in G protein subunits is developed maximally after 6 days, is dose-dependent and reversible upon termination of the drug supply. The concentrations found elevated return to control levels within 4 to 5 days after commencing withdrawal. The common increase of Go alpha and G beta subunits observed after chronic opiate or clonidine exposure is associated with the phenomenon of cross-dependence among all drugs studied. The findings may suggest that in the guinea pig myenteric plexus multiple inhibitory receptor types make use of a common pool of G proteins.
Institute of Pharmacology, Toxicology and Pharmacy, University of Munich, Federal Republic of Germany.
H
H
Ammer
L
L
Nice
J
J
Lang
R
R
Schulz
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D003000:Clonidine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006168:Guinea Pigs; D007700:Kinetics; D008297:Male; D008969:Molecular Sequence Data; D009197:Myenteric Plexus / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D009292:Narcotic Antagonists; D011957:Receptors, Opioid / Q000187:drug effects / Q000502:physiology; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019966:Substance-Related Disorders / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
D000316:Adrenergic alpha-Agonists; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D019204:GTP-Binding Proteins; D003000:Clonidine