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Investigating the Anti-Pain and Anti-Inflammatory Effects of Peripherally Restricted Kappa Opioid Receptor Agonists

Reports of research work funded by grants prior to 2013

Victoria University of Wellington

Investigating  the Anti-Pain and Anti-Inflammatory Effects of Peripherally Restricted Kappa Opioid Receptor Agonists

BM Kivell, N Kumar, K Paton, J Harper and TE Prisinzano
School of Biological Sciences, Centre for Biodiscovery

Pain is a normal physiological response mediated by the nervous system and is the most common reason for doctor visits costing an estimated $100 billion annually in the US alone.  Post-operative pain, chronic pain and pain resulting from cancer and arthritis, particularly in the context of New Zealand’s aging population are a major economic burden to New Zealand, and negatively impact on the quality of life for pain sufferers.  Current gold-standard anti-pain drugs such as the predominately Mu opiate, morphine, while effective at controlling severe pain is also addictive, exhibits tolerance after repeated use, causes respiratory depression and constipation.  Therefore more effective anti-pain pharmacotherapies with reduced side effects and lower abuse potential would be of enormous benefit to millions of people.  Opioid agonists that do not cross the blood-brain barrier have been shown in humans to have the same analgesic efficacy as traditional opioids.  Therefore, there is growing support for the development of peripherally restricted opioids to treat pain.  During this preliminary study we have established behavioural techniques to measure pain and are building a collaborative team to develop new pharmacotherapies to treat pain.  To date, we have screened kappa opioid receptor agonists (KOPr) for anti-pain and anti-inflammatory effects in mice utilising the formalin intradermal injection pre-clinical model of pain.  We have shown that the KOPr agonist ICI (3 mg/kg) inhibits peripheral pain (Fig. 1A). Briefly behaviour was recorded for 90 min and scored by observer blinded to the treatment.  A behaviour score of 0 represents full weight bearing, 1, partial weight bearing, 2, raised paw and 3 licking flicking of paw.  Results show a decrease in pain scoring with ICI. Additional KOPr agonist will be screened in future utilising this model.  We have also shown that Sal A, but not ICI significantly reduces local footpad oedema compared to vehicle/formalin treated controls (Fig. 1B).  Haematoxylin and eosin (H&E) stained footpad tissue from vehicle/vehicle treated controls (no pain), vehicle/formalin controls (positive pain) and Sal A/formalin treated mice show that there was also a reduction in the number of neutrophils present following Sal A (3 mg/kg) treatment suggesting anti-inflammatory effects (Fig. 2).  Additional footpad tissue will be processed for the presence of CD4+ cells utilising flow cytometry techniques to extend our knowledge of KOPr agonist effects on inflammation.

Lumbar spinal cord tissue is also currently being processed for the presence of pain markers, including Substance P receptor staining utilising immunofluorescence.  Ongoing experiments measuring centrally mediated side effects including sedation (rotorod test) and centrally mediated pain effects (tail flick tests) will also be utilised in future to determine the degree of peripheral restriction of these compounds and centrally mediated side effects.  We plan to complete this preliminary study in December and aim for initial findings to be prepared for publication in early 2014.  I currently have an Honours student and a Part 2 MSc student working on this project.  The long term goal is to develop more effective, non-addictive pharmacotherapies to treat pain and inflammation.

Investigating the Anti-Pain and Anti-Inflammatory Effects of Peripherally Restricted Kappa Opioid Receptor Agonists

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