However, KOR modulation of central limbic circuits may play a substantial role in pain processing, particularly regarding the affective component of pain and the comorbidity of chronic pain and depression ( 20). To bypass such adverse side effects, one approach has been to develop KOR agonists that do not penetrate the blood-brain barrier in an attempt to isolate their actions to peripheral sites for the treatment of pain ( 5). It is believed that this drop in dopamine is responsible for the dysphoric effects produced by KOR agonists ( 12, 15– 19). However, activation of KOR on dopaminergic nerve terminals leads to decreases in extracellular dopamine concentrations in mice and rats ( 13, 14). In addition to providing pain relief without the threat of overdose, KOR agonists are unlikely to be addictive because they do not induce euphoria, nor do they promote increases in dopamine release, as abused drugs do ( 10– 12). Currently, nalfurafine is the only clinically available KOR agonist, and it is used in the treatment of pruritis ( 9). KOR agonists have also been proven to be efficacious in the treatment of intractable, non–histamine-related itch, or pruritis ( 5– 8). Like other opioid receptors, its activation promotes antinociception, and therefore, it has been a target for development of pain therapeutics ( 4). The kappa opioid receptor (KOR) is a G protein–coupled receptor (GPCR) that is distributed throughout the nervous system and is activated by opioid peptides, such as dynorphins ( 1– 3). 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. These data demonstrated that biased agonists may be used to segregate physiological responses downstream of the receptor. 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. We evaluated a newly developed G protein signaling–biased KOR agonist in preclinical models of pain, pruritis, sedation, dopamine regulation, and dysphoria. 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. However, they do produce dysphoria and sedation, side effects that have precluded their clinical development as therapeutics. Unlike typical opioid narcotics, KOR agonists do not produce euphoria or lead to respiratory suppression or overdose. Agonists targeting the kappa opioid receptor (KOR) have been promising therapeutic candidates because of their efficacy for treating intractable itch and relieving pain.
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