cj-15-208 and Pain

Kappa opioid receptor (KOP) is a G-protein coupled receptor mainly expressed in the cerebral cortex and hypothalamus. It is implicated in nociception, diuresis, emotion, cognition, and immune system functions. KOP agonists possess a strong analgesic effect accompanied by a feeling of dysphoria. On the other hand, antagonists of this receptor were found to block depression, anxiety, and drug-seeking behaviors in animal models. Recently, great interest has been given to the development of selective KOP antagonists as an addiction treatment that does not cause dependence itself or show high relapse rates like the currently used agents. This review provides a comprehensive survey of the KOP antagonists developed for this purpose together with their in vivo studies and clinical trials. In addition, a future perspective and recommendations for the work needed to develop clinically relevant KOP antagonists are presented.

Topics: Animals; Humans; Narcotic Antagonists; Opiate Substitution Treatment; Opioid-Related Disorders; Pain; Receptors, Opioid, kappa

Strong opioid analgesics, including morphine, are the mainstays for treating moderate to severe acute pain and alleviating chronic cancer pain. However, opioid-related adverse effects, including nausea or vomiting, sedation, respiratory depression, constipation, pruritus (itch), analgesic tolerance, and addiction and abuse liability, are problematic. In addition, the use of opioids to relieve chronic noncancer pain is controversial due to the "opioid crisis" characterized by opioid misuse or abuse and escalating unintentional death rates due to respiratory depression. Hence, considerable research internationally has been aimed at the "Holy Grail" of the opioid analgesic field, namely the discovery of novel and safer opioid analgesics with improved opioid-related adverse effects. In this Perspective, medicinal chemistry strategies are addressed, where structurally diverse nonmorphinan-based opioid ligands derived from natural sources were deployed as lead molecules. The current state of play, clinical or experimental status, and novel opioid ligand discovery approaches are elaborated in the context of retaining analgesia with improved safety and reduced adverse effects, especially addiction liability.

Topics: Analgesics, Opioid; Animals; Biological Products; Cell Line, Tumor; Chemistry, Pharmaceutical; Drug Discovery; Humans; Ligands; Pain; Peptides; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu