G protein-gated inwardly rectifying
potassium (GIRK) channels are
potassium-selective
ion channels. As their name suggests, GIRK channels are effectors of Gi/o
G protein-couple receptors whereby activation of these GPCRs leads to increased GIRK channel activity resulting in decreased cellular excitability. In this way, GIRK channels play diverse roles in physiology as effectors of Gi/o-coupled GPCRs: peacemaking in the heart rate, modulation of
hormone secretion in endocrine tissues, as well as numerous CNS functions including learning, memory, and addiction/reward. Notably, GIRK channels are widely expressed along the spinothalamic tract and are positioned to play roles in both ascending and descending
pain pathways. More notably, GIRK channel knockout and knock-down studies have found that GIRK channels play a major role in the action of
opioid analgesics which act predominantly through Gi/o-coupled,
opioid-activated GPCRs (e.g., μ-
opioid receptors). Recent advances in GIRK channel pharmacology have led to the development of small molecules that directly and selectively activate GIRK channels. Based on research implicating the involvement of GIRK channels in
pain pathways and as effectors of
opioid analgesics, we conducted a study to determine whether direct pharmacological activation of GIRK channels could produce
analgesic efficacy and/or augment the
analgesic efficacy
morphine, an
opioid receptor agonist capable of activating μ-
opioid receptors as well as other
opioid receptor subtypes. In the present study, we demonstrate that the small-molecule GIRK activator,
VU0466551, has
analgesic effects when dosed alone or in combination with submaximally effective doses of
morphine.