The Kappa Opioid Receptor: A Promising Therapeutic Target for Multiple Pathologies

Abstract

Kappa-opioid receptors (KOR) are widely expressed throughout the central nervous system, where they modulate a range of physiological processes depending on their location, including stress, mood, reward, pain, inflammation, and remyelination. However, clinical use of KOR agonists is limited by adverse effects such as dysphoria, aversion, and sedation. Within the drug-development field KOR agonists have been extensively investigated for the treatment of many centrally mediated nociceptive disorders including pruritis and pain. KOR agonists are potential alternatives to mu-opioid receptor (MOR) agonists for the treatment of pain due to their anti-nociceptive effects, lack of abuse potential, and reduced respiratory depressive effects, however, dysphoric side-effects have limited their widespread clinical use. Other diseases for which KOR agonists hold promising therapeutic potential include pruritis, multiple sclerosis, Alzheimer’s disease, inflammatory diseases, gastrointestinal diseases, cancer, and ischemia. This review highlights recent drug-development efforts targeting KOR, including the development of G-protein–biased ligands, mixed opioid agonists, and peripherally restricted ligands to reduce side-effects. We also highlight the current KOR agonists that are in preclinical development or undergoing clinical trials.

Association Between Opioid Use Disorder and Seizure Incidents Among Alcohol Use Disorder Patients

“…38 The kappa-opioid (KOP) receptor is an opioid receptor that has implications in analgesia, stress, depression, sedation, and diuresis. 39 In a study involving mice, KOP receptor antagonism caused increase seizure-like activity while receptor agonism caused a reduction in seizure-like activity. 40 In addition, inhibition of the serotonin and norepinephrine reuptake pathway has been postulated as a mechanism behind tramadol's adverse effect of lowering the seizure threshold.…”

Peptidomimetics and Their Applications for Opioid Peptide Drug Discovery

“…The address region containing multiple basic amino acid residues was suggested to be responsible for the KOR efficacy. Although the relatively large size of the molecule and the extensive metabolism are more problematic, many studies demonstrated important roles of DYN A and its target receptor, KOR, in pain and other disorders such as depression, anxiety, and drug abuse, and more interest is being focused on the therapeutic potentials of KOR agonists and antagonists [ 182 , 183 , 184 ].…”

Development of a Selective Peptide κ-Opioid Receptor Antagonist by Late-Stage Functionalization with Cysteine Staples

“…The wide expression of the κ-opioid receptor (KOR) throughout the central nervous system (CNS) and the peripheral nervous system (PNS) and its involvement in the control of important physiological processes including antinociception, motivation, emotion, and cognition have stimulated the development of KOR ligands for the treatment of pain, itch, and neuropsychiatric disorders. , KOR agonists provide promising potential to develop safer and more effective analgesics since they lack the undesired effects typical for μ- (MOR) and δ- (DOR) opioid receptor agonists, including respiratory depression, constipation, tolerance, or addiction . Nevertheless, opioid-mediated activation of KOR is often associated with sedation, dysphoria, and hallucinations, which have precluded the clinical development of KOR agonists. , Over recent years, biased opioid ligands selectively activating the G protein over β-arrestin signaling pathways have provided an avenue to develop therapeutics with reduced KOR side effects .…”