Evaluating the Anti-nociceptive Effects of Novel Kappa Opioid Receptor Agonists in a Model of Chemotherapy-Induced Neuropathic Pain
Authors:   , Scouller Brittany 
Published: November 2024

<p dir="ltr">Chronic pain is a growing global health concern that causes prolonged periods of discomfort and suffering, impacting the individual’s quality of life. Currently, 19.6% of New Zealand adults suffer from chronic pain placing a large socioeconomic burden on society. Drugs that activate the mu opioid receptor (MOPr) such as morphine, oxycodone and fentanyl, are commonly prescribed for the treatment of chronic pain. However, these drugs are associated with tolerance, addiction and respiratory depression, which is responsible for opioid related overdoses. In the United States, prescription opioid-related overdose is the leading cause of accidental death. Therefore, there is an urgent need to develop safer pharmacotherapeutics that are effective in attenuating chronic pain. </p><p dir="ltr">Recently, the kappa opioid receptor (KOPr) has received attention as a possible therapeutic target for chronic pain. KOPr agonists have preclinical anti-nociceptive effects and have low potential for abuse, making them a promising alternative to MOPr agonists. Traditional KOPr agonists such as U50,488 have displayed potent anti-nociceptive effects in multiple models of pain. However, their clinical use has been limited due to associated adverse effects such as dysphoria, aversion and sedation. Structural modifications have been made to U50,488 in order to achieve potent anti-nociceptive effects with reduced side-effects. Therefore, this thesis aimed to evaluate the anti-nociceptive effects of 3 novel U504,88 analogues, LDK93, LDK95 and LDK276. </p><p dir="ltr">The effects of these compounds were measured in acute models of thermal pain including the warm water tail-withdrawal assay and the hot assay. The novel KOPr agonists did not show significant effects in the hot plate assay but U50,488 showed anti-nociceptive effects. LDK93 showed a longer duration of action compared to U50,488 in the warm water tail withdrawal assay. These compounds were also assessed in a chemotherapy-induced neuropathic pain model to allow for greater clinical translation. A dose response analysis showed that LDK93, LDK95 and LDK276 were more potent than U50,488 and all compounds were effective in alleviating mechanical and thermal allodynia and did not develop tolerance following 25 days of administration. Furthermore, respiratory depressive, sedative, locomotor activity and anxiogenic side-effects were also assessed in order to determine the therapeutic window. LDK93, LDK95 and U50,488 showed sedative effects and decreased locomotor activity. However, LDK276 showed limited adverse effects reflecting the response of vehicle treated mice. </p><p dir="ltr">Overall, this study identifies LDK276 as a promising pharmacotherapeutic for the treatment of chronic pain with limited associated adverse effects. This study was the first to assess the anti-nociceptive and side-effect profile of these novel KOPr agonists and this data identifies KOPr agonists as a promising therapeutic approach for the treatment of chronic pain in light of the current opioid epidemic.</p>