G-protein-coupled receptors act as guanine nucleotide exchange factors (GEFs) and facilitate the activation of heterotrimeric G proteins by exchanging GDP for GTP1. This exchange function is not unidirectional2. Here we demonstrate that an agonist can show selective affinity for an active state that prefers the release of GTP. Specifically, for the mu opioid receptor, we show that several agonists have state-selective affinities for promoting GTP release versus GTP binding. We identify two agonists that show a marked preference for promoting release. In mice, marginally efficacious doses of the release-preferring agonist enhance and prolong the antinociceptive effects of morphine and fentanyl without enhancing the respiratory and cardiac effects of fentanyl. Although these observations are limited to simple measures of thermal nociception, they may point to a way to bifurcate physiological responses to such agonists. We propose that the active-state selectivity of an agonist may determine the preferred direction of the receptor GEF function, which may affect the kinetics and selectivity of the engagement of the receptor with downstream effectors; this may ultimately present a means to disentangle multifaceted drug-induced physiological responses.
