Morphine tolerance in mice changes response of heroin from mu to delta opioid receptors

Heroin produced antinociception in the tail flick test through mu receptors in the brain of ICR and CD-1 mice, a response inhibited by 3-O-methylnaltr exone. Tolerance to morphine was produced by subcutaneous morphine pellet i mplantation. By the third day, the heroin response was produced through del ta opioid receptors, The response was inhibited by simultaneous intracerebr oventricular (i.c.v.) administration of naltrindole, a delta opioid recepto r antagonist. More specifically, delta(1) rather than delta(2) receptors we re involved because 7-benzylidenenaltrexone, a delta(1) receptor antagonist , inhibited but naltriben, a delta(2) antagonist, did not. Also, antinocice ption produced by i.c.v. heroin was inhibited by intrathecal administration of bicuculline and picrotoxin consistent with the concept that delta(1) re ceptors in the brain mediated the antinociceptive response through descendi ng neuronal pathways to the spinal cord to activate GABA(A) and GABA(B) rec eptors rather than spinal alpha(2)-adrenergic and serotonergic receptors ac tivated originally by the mu agonist action in naive mice. The mu response of 6-monoacetylmorphine, a metabolite of heroin, was changed by morphine pe llet implantation to a delta(2) response (inhibited by naltriben but not 7- benzylidenenaltrexone). The agonist action of morphine in these morphine-to lerant mice remained mu. Thus, the opioid receptor selectivity of heroin an d 6-monoacetylmorphine in the brain is changed by production of tolerance t o morphine, such a change explains how morphine tolerant mice are not cross -tolerant to heroin.