Involvement of mu-opioid receptor in the salsolinol-associated place preference in rats exposed to conditioned fear stress

Background: Salsolinol, a condensation product of dopamine with acetaldehyd e (the initial oxidation product of ethanol), has long been discussed as an endogenous opioid system-activating factor contributing to the etiology of alcoholism. Moreover, psychological stress has been considered to play an important role in the development of alcoholism. Methods: Male Sprague Dawley rats were subjected to conditioned fear stress (at 24 hr after electric footshock exposure), and then salsolinol or salin e was injected intraperitoneally. For conditioning, rats were immediately c onfined to the nonpreferred compartment after salsolinol injection and to t he preferred compartment after saline injection on alternate days. This con ditioning session was repeated twice daily (for 8 days). Test session was c arried out 1 day after the last conditioning session. Results: Salsolinol [10 mg/kg, but not 1, 3, or 30 mg/kg. intraperitoneally (ip)] without conditioned fear stress induced a slight, but significant, p lace preference. In contrast, salsolinol (1, 3, and 10 mg/kg, ip) with cond itioned fear stress induced a marked and significant place preference. The nonselect ive opioid receptor antagonist naloxone hydrochloride (which can pass into the brain), but not the nonselective peripheral opioid receptor a ntagonist naloxone methiodide (which cannot pass into the brain), significa ntly attenuated the salsolinol (3 mg/kg, ip)-induced place preference under conditioned fear stress. Moreover, the selective mu-opioid receptor antago nist beta-funaltrexamine significantly attenuated the salsolinol-induced pl ace preference. Furthermore, 0.3 mg/kg salsolinol (which produced no signif icant place preference) combined with the mu-opioid receptor agonist morphi ne [0.1 mg/kg, subcutaneously (sc)], at the dose which alone produced no si gnificant place preference, produced a marked and significant place prefere nce. Both naloxone hydrochloride and beta-funaltrexamine significantly atte nuated the salsolinol plus morphine-induced place preference. Conclusions: Salsolinol may have some rewarding effect, and its rewarding e ffect may be potentiated by psychological stress. In addition, the rewardin g effect of salsolinol especially under psychological stress may involve th e endogenous central opioid system, i.e., mu-opioid receptor.