Agonists at the mu opioid receptor (MOR) are widely recognized for their effects on reward and pain. Although prior studies have attributed some of these effects to MORs on GABA neurons in the ventral tegmental area (VTA), recent studies have identified a region of particularly strong MOR immunostaining residing caudal to the VTA, in a region denoted the rostromedial tegmental nucleus (RMTg).

Hence, we examined whether rats would self-administer small doses (50–250 pmol) of the selective MOR agonist endomorphin-1 (EM1) into the RMTg and adjacent sites. EM1 was chosen due to its short half-life, thus limiting drug spread, and due to its presence endogenously in brain neurons, including some afferents to the RMTg.

The highest rates of EM1 self-administration occurred within 0.5 mm of the RMTg center, in a region roughly 0.8–1.6 mm caudal to the majority of VTA DA neurons. In contrast, self-administration rates were much lower in the adjacent VTA, interpeduncular nucleus, central linear nucleus, or median raphe nucleus. Furthermore, EM1 infusions into the RMTg, but not surrounding regions, produced conditioned place preference, while EM1 infusions into the RMTg but not anterior VTA markedly reduced formalin-induced pain behaviors. EM1 effects were mimicked by infusions of the GABA agonist muscimol into the same region, consistent with EM1 having inhibitory actions on its target neurons.

These results implicate a novel brain region in modulating MOR influences on both appetitive and aversive behavior.