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Hohenwarter, Lukas

University of British Columbia

Chronic pain affects approximately 20% of Canadians and is a global healthcare burden with limited treatment options. The high incidence of comorbid chronic pain and depression additionally worsens patient’s quality of life and treatment outcomes. Antidepressants are used for the treatment of persistent pain but show limited efficacy and often induce serious side effects. Opioids are highly potent analgesics but are associated with severe adverse effects frequently limiting their use in chronic pain management. Endogenous opioids act on our nervous system to regulate pain and mood. The endogenous opioid peptide Leucine-enkephalin (Leu-ENK) produces analgesia with fewer adverse effects compared to conventional opioids. However, its poor stability and low membrane permeability make Leu-ENK ineffective when administered peripherally. We developed the N-pivaloyl Leu-ENK analog KK-103, which showed a high relative binding affinity for the delta opioid receptor (DOR) and was stable in plasma for 5 h. In the hotplate model, subcutaneous (s.c.) KK-103 showed 10-fold improved antinociception compared to Leu-ENK and produced a longer-lasting antinociceptive activity than morphine. In the formalin model, KK-103 reduced the licking and biting time of mice by ~60% relative to the vehicle group. We demonstrated a similar dose to maximum antinociceptive-effect relationship of KK-103 in the hotplate and formalin foot models. Contrasting morphine, KK-103 did not induce breathing depression, physical dependence, and tolerance in the models and experimental timelines used in this study. Additionally, KK-103’s minimal gastrointestinal inhibition and absence of sedation demonstrated its potential as a safe and effective analgesic. We also demonstrated KK-103’s increased systemic adsorption and plasma exposure compared to Leu-ENK and observed brain uptake of radiolabeled KK-103 after s.c. administration. The antinociceptive effect of KK-103 was primarily mediated by opioid receptors in the central nervous system and specifically the activation of the DOR. We detected the conversion of KK-103 to Leu-ENK in vitro which may induce the observed effects of KK-103 in mice. Finally, we determined an antidepressant-like activity of KK-103, which was comparable to that of the antidepressant desipramine. This work showed the potential application of KK-103 for pain and depression and provides the theoretical framework for future R&D of ENK therapeutics.

Text

2023-10-18

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/86191

Pharmaceutical Sciences

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/