ULTRA-LOW DOSES OF NALTREXONE OR ETORPHINE INCREASE MORPHINES ANTINOCICEPTIVE POTENCY AND ATTENUATE TOLERANCE DEPENDENCE IN MICE/

In previous studies we showed that low (pM) concentrations of naloxone (NTX), naltrexone (NTX) or etorphine selectively antagonize excitator y, but not inhibitory, opioid receptor-mediated functions in nocicepti ve types of sensory neurons in culture. Cotreatment of these neurons w ith pM NTX or etorphine not only results in marked enhancement of the inhibitory potency of acutely applied nM morphine [or other bimodally- acting (inhibitory/excitatory) opioid agonists], but also prevents dev elopment of cellular manifestations of tolerance and dependence during chronic exposure to mu M morphine. These in vitro studies were confir med in vivo by demonstrating that acute cotreatment of mice with morph ine plus a remarkably low dose of NTX (ca. 10 ng/kg) does, in fact, en hance the antinociceptive potency of morphine, as measured by hot-wate r tail-flick assays. Furthermore, chronic cotreatment of mice with mor phine plus low doses of NTX markedly attenuates development of naloxon e-precipitated withdrawal-jumping in physical dependence assays. The p resent study provides systematic dose-response analyses indicating tha t NTX elicited optimal enhancement of morphine's antinociceptive poten cy in mice when co-administered (i.p.) at about 100 ng/kg together wit h morphine (3 mg/kg). Doses of NTX as low as 1 ng/kg or as high as 1 m u g/kg were still effective, but toe lesser degree. Oral administratio n of NTX in the drinking water of mice was equally effective as i.p. i njections in enhancing the antinociteptive potency of acute morphine i njections and even more effective in attenuating development of tolera nce and NLX-precipitated withdrawal-jumping during chronic cotreatment . Cotreatment with a subanalgesic dose of etorphine (10 ng/kg) was equ ally effective as NTX in enhancing morphine's antinociceptive potency and attenuating withdrawal-jumping after chronic exposure. These studi es provide a rationale for the clinical use of ultra-low-dose NTX or e torphine so as to increase the antinociteptive potency while attenuati ng the tolerance/dependence liability of morphine or other conventiona l bimodally-acting opioid analgesics.