Differential effects of gestational buprenorphine, naloxone, and methadone on mesolimbic μ opioid and ORL1 receptor G protein coupling

In addition to its use for heroin addiction pharmacotherapy in general, buprenorphine has advantages in treating maternal heroin abuse. To examine the gestational effects of buprenorphine on opioid receptor signaling, the [ ³⁵S]-GTPγS in situ binding induced by the μ agonist [D-Ala²,MePhe⁴,Gly⁵-ol] enkephalin (DAMGO) or the nociceptin/orphanin FQ (N/OFQ) agonist was measured in mesolimbic structures of pup brains from pregnant rats administered with buprenorphine± naloxone, naloxone, or methadone by osmotic minipump. Drug- and gender-based changes in DAMGO- and N/OFQ-induced GTPγS binding were discovered in mesolimbic regions of dam, P2, and P7 brains. Buprenorphine and/or methadone gestational treatment attenuated DAMGO-induced GTPγS binding in some dam and male P2 mesolimbic regions. Methadone diminished DAMGO-induced GTPγS binding in almost all monitored brain regions of the dam but had few effects on their N/OFQ-induced GTPγS binding. Naloxone used in combination with buprenorphine blocked the inhibition by buprenorphine alone on DAMGO-induced GTPγS binding. In contrast to its inhibitory effects on DAMGO-induced GTPγS binding, buprenorphine stimulated N/OFQ-induced GTPγS binding in male P2 nucleus accumbens and lateral septum. Brain region-dependent gender differences in DAMGO-induced GTPγS binding were seen in P2 pups, and males showed greater sensitivity to buprenorphine and methadone than females. Our findings on μ opioid receptor (MOR) GTP-binding regulatory protein (G protein) coupling and its gender dependency are consistent with our earlier studies on μ receptor binding adaptation induced by buprenorphine in dams and neonatal rats after in utero treatment regimens, and they extend the gestational effects of this opiate to μ and N/OFQ receptor functionality.