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Itch relief from biased agonists
Activating the kappa opioid receptor (KOR) can relieve itching that is not caused by allergic reactions. However, compounds that activate this receptor also cause unwanted side effects, such as dysphoria and sedation. KOR activation can trigger multiple downstream signaling pathways. Brust et al. characterized a biased agonist of this receptor that preferentially activated one downstream pathway over another. This agonist relieved itch in rodents without causing dysphoria or sedation. Thus, biased KOR agonists may provide a long-sought therapeutic option for intractable itch without the unwanted side effects.
Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain. Unlike typical opioid narcotics, KOR agonists do not produce euphoria or lead to respiratory suppression or overdose. However, they do produce dysphoria and sedation, side effects that have precluded their clinical development as therapeutics. KOR signaling can be fine-tuned to preferentially activate certain pathways over others, such that agonists can bias signaling so that the receptor signals through G proteins rather than other effectors such as βarrestin2. We evaluated a newly developed G protein signaling–biased KOR agonist in preclinical models of pain, pruritis, sedation, dopamine regulation, and dysphoria. We found that triazole 1.1 retained the antinociceptive and antipruritic efficacies of a conventional KOR agonist, yet it did not induce sedation or reductions in dopamine release in mice, nor did it produce dysphoria as determined by intracranial self-stimulation in rats. These data demonstrated that biased agonists may be used to segregate physiological responses downstream of the receptor. Moreover, the findings suggest that biased KOR agonists may present a means to treat pain and intractable itch without the side effects of dysphoria and sedation and with reduced abuse potential.