Administration of myr(+)-G(i2)alpha subunits prevents acute tolerance (tachyphylaxis) to mu-opioid effects in mice.
The administration of efficacious doses of morphine or beta-endorphin causes acute tolerance (tachyphylaxis) to the effects of additional administrations of these opioids. Mice intracerebroventricularly (icv)-injected with biologically active myristoylated (myr(+))-G(i2)alpha subunits developed no tachyphylaxis to morphine antinociception in the tail-flick test. This treatment increased the potency of opioid-induced analgesia during the declining phase. Moreover, animals showing tachyphylaxis to opioid effects exhibited normal responses to the agonists after icv-administration of myr(+)-G(i2)alpha subunits. In morphine tolerant/dependent mice, an icv dose of 12 pmol/mouse myr(+)-G(i2)alpha subunits facilitated complete restoration of morphine antinociception in only 4 or 5 days instead of the 10 to 11 days required for post-dependent mice. This was observed when myr(+)-G alpha subunits were injected within the first 24 h of chronic morphine administration -- but not later when long-term tolerance takes place. These results suggest that during the course of an opioid effect a progressive reduction of receptor-regulated G-proteins occurs, and hence tachyphylaxis develops. Exogenous administration of myr(+)-G alpha subunits may be of therapeutic potential in improving agonist activity and accelerating the recovery of post-dependent receptors.
Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, Consejo Superior de Investigaciones Científicas, Avenida Doctor Arce 37, E-28002 Madrid, Spain. jgarzon@cajal.csic.es
J
J
Garzón
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P
Sánchez-Blázquez
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism / Q000494:pharmacology*; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009020:Morphine / Q000097:blood / Q000378:metabolism / Q000494:pharmacology; D009021:Morphine Dependence / Q000503:physiopathology; D009226:Myristates / Q000378:metabolism; D009270:Naloxone / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology; D013618:Tachyphylaxis / Q000502:physiology*; D013997:Time Factors; D001615:beta-Endorphin / Q000494:pharmacology
D000701:Analgesics, Opioid; D009226:Myristates; D017450:Receptors, Opioid, mu; D009270:Naloxone; D001615:beta-Endorphin; D009020:Morphine; D019206:GTP-Binding Protein alpha Subunits, Gi-Go