Medicine in Drug Discovery (Dec 2020)
Counterbalanced microcircuits for Orx1 and Orx2 regulation of stress reactivity
Abstract
Orexins are hypothalamic neuropeptides regulating a range of behaviors broadly associated with sleep, motivation, and feeding. These responses highlight the importance of orexins in maintaining foundational biological processes, but also indicate a connection to stress-related dysfunction, which results in aberrations to normal states of sleep, motivation, and feeding. As such, we predict, based on clinical and preclinical evidence, that irregularities in orexin signaling contribute to changes in affect and the formation of psychological disorders. In support of this, orexin-producing neurons innervate several brain areas important for mediating stress responses, including the prefrontal cortex and amygdala, where intracellular signaling results from activation of orexin receptors (Orx1 and Orx2). While stimulation of Orx1 and Orx2 initiate similar intracellular pathways, signaling dynamics may be modified through receptor location, dimerization, or genetic regulation. We further note, based on evidence from our lab, that Orx1 and Orx2 elicit opposing stress responses after activation, suggesting the existence of a counterbalanced mechanism for inducing physiological and behavioral stress states. Our research and others’ demonstrate that antagonistic neurocircuits promoting either pro- or anti-stress responses, may be bidirectionally shifted with activation of Orx1 or Orx2. Although clinically approved drugs that target the orexin system, like dual orexin receptor antagonists (DORAs), are moderately effective for the treatment of sleep- and, perhaps, addiction-related disorders, they may inadvertently disrupt mood or exaggerate existing affective dysfunction. We propose a novel idea for pharmacological intervention that accounts for the counterbalanced influence of orexin receptor activity on stress-induced behaviors: selective orexin receptor crossover drugs (SORCOs).
