Drug addiction to prescription mu-opioid agonists used in the setting of pain is a major public health threat, affecting millions of Americans. Kappa opioid agonists (KOAs) may serve as a possible solution. KOAs have demonstrated indistinguishable analgesic activity relative to mu-opioid agonists in models of acute and chronic pain; however, conventional KOAs suffer from central nervous system-mediated psychoactive side-effects. In this review, we discuss our efforts, as well as other's efforts, in developing peripherally-restricted kappa opioid agonists with retained or improved efficacy in rodent models of pain. Results indicate that our lead compound JT09 acts as efficacious as morphine in alleviating peripheral pain, while failing to produce undesired central nervous system-mediated side-effects. In this review, we discuss our former results and future directions.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859935 | PMC |
| http://dx.doi.org/10.4155/fdd-2019-0022 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders or, even, lethal overdose. The systemic administration of opioid agonists makes it both very difficult to decipher their underlying circuit mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse side effects.
View Article and Find Full Text PDFThe endogenous dynorphin/kappa opioid receptor (KOR) system in the brain mediates the dysphoric effects of stress, and KOR antagonists may have therapeutic potential for the treatment of drug addiction, depression, and psychosis. One class of KOR antagonists, the long-acting norBNI-like antagonists, have been suggested to act by causing KOR inactivation through a cJun-kinase mechanism rather than by competitive inhibition. In this study, we screened for other opioid ligands that might produce norBNI-like KOR inactivation and found that nalfurafine (a G-biased KOR agonist) and nalmefene (a KOR partial agonist) also produce long-lasting KOR inactivation.
View Article and Find Full Text PDFPeripheral inflammation enhances opioid-induced gastrointestinal motility inhibition via up-regulating spinal mu opioid receptor.
Toxicol Appl Pharmacol
January 2025
Department of Animal and Biomedical Sciences, School of Life Sciences, Lanzhou University, 222 Tianshui South Road, Lanzhou 730000, China; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, 222 Tianshui South Road, Lanzhou 730000, China. Electronic address:
Opioids are potent analgesics in clinical pain management but exert variable analgesia in different pain types. Opioid-induced constipation is a common side effect of opioid therapy, and whether opioids induce different gastrointestinal motility inhibitions in different pain types is unknown. In this study, we evaluated the antinociceptive effects and inhibition of upper gastrointestinal transit and colonic bead expulsion of morphine, DAMGO, and Deltorphin in mouse CFA chronic inflammatory pain, SNI chronic neuropathic pain, and carrageenan chronic inflammatory pain models.
View Article and Find Full Text PDFDiscovery of the therapeutic potential of naltriben against glutamate-induced neurotoxicity.
Neurochem Int
January 2025
Chemical & Biological Integrative Research Center, Korea Institute of Science and Technology (KIST), Hwarangro 14 gil, Seongbuk-gu, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology (UST), Hwarangro 14 gil, Seongbuk-gu, Seoul 02792, Republic of Korea.
Glutamate-induced neuronal death is associated with neurodegeneration including cerebral ischemia. Several μ-opioid receptor antagonists exhibit a neuroprotective activity and have been considered as a potential therapeutic option for neurodegenerative disorders. For the first time, our current study unveiled the neuroprotective activity of selective δ-opioid receptor antagonists.
View Article and Find Full Text PDFEfficacy and Safety of SHR8554 on Postoperative Pain in Subjects with Moderate to Severe Acute Pain Following Orthopedic Surgery: A Multicenter, Randomized, Double-blind, Dose-explored, Active-controlled, Phase II/III Clinical Trial.
Pharmacol Res
January 2025
Department of Anesthesiology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Key Laboratory of Anesthesiology (Shanghai Jiao Tong University), Ministry of Education, Shanghai, China. Electronic address:
Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled receptor signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, and safety of SHR8554, a biased MOR agonist, for postoperative pain management following orthopedic surgery. In Phase II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses of SHR8554 or morphine.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!