Acute Cross-Tolerance to Opioids in Heroin Delta-Opioid-Responding Swiss Webster Mice

It is generally thought that the μ receptor actions of metabolites, 6-monoacetylmorphine (6MAM) and morphine, account for the pharmacological actions of heroin. However, upon intracerebroventricular (i.c.v.) administration in Swiss Webster mice, heroin and 6MAM act on δ receptors while morphine acts on μ receptors. Swiss Webster mice made tolerant to subcutaneous (s.c.) morphine by morphine pellet were not cross-tolerant to s.c. heroin (at 20 min in the tail flick test). Now, opioids were given in combination, s.c. (6.5 h) and i.c.v. (3 h) preceding testing the challenging agonist i.c.v. (at 10 min in the tail flick test). The combination (s.c. + i.c.v.) morphine pretreatment induced tolerance to the μ action of morphine but no cross-tolerance to the δ action of heroin, 6MAM and DPDPE and explained why morphine pelleting did not produce cross-tolerance to s.c. heroin above. Heroin plus heroin produced tolerance to δ agonists but not to μ agonists. Surprisingly, all combinations of morphine with the δ agonists produced tolerance to morphine which now acted through δ receptors (inhibited by i.c.v. naltrindole), an unusual change in receptor selectivity for morphine.