Novel approaches to the understanding and treatment of postoperative pain

Postoperative pain constitutes a significant medical need. Greater understanding of the mechanisms will allow for more effective treatments. The endogenous cannabinoid (endocannabinoid) and opioid systems play a key role in regulation of pain. The studies described in this thesis aimed to examine the endocannabinoid and opioid systems in a rat model of postoperative pain following inguinal hernia repair. This project also aimed to develop a novel device which elutes levobupivacaine to treat postoperative pain at the site of injury and investigate its effects on inflammatory and endocannabinoid signalling. First, the results demonstrate that latent sensitisation is a feature of this model, with subcutaneous administration of the μ-opioid receptor inverse agonist naloxone at 6- and 12-days post-surgery re-instating allodynia. Subcutaneous administration of the CB1 receptor inverse agonist rimonabant had no effect suggesting divergent roles for endocannabinoid and opioid signalling in postoperative recovery. Second, the data indicate reduced levels of AEA, OEA and PEA, increased levels of 2-arachidonoylglycerol and increased mRNA encoding for fatty acid amide hydrolase in inguinal tissue of surgery versus sham rats. In the ipsilateral spinal cord, there was a surgery-induced increase in POMC mRNA levels. In the amygdala there was a surgery-induced increase in CB1 receptor mRNA on the ipsilateral side and increased POMC mRNA on the contralateral side. Reduced expression of KOP mRNA was observed in the periaqueductal grey of surgery versus sham rats. Third, a novel collagen-based device was developed which elutes up to 100mg of levobupivacaine over ~48hrs. This device represents a novel approach due to the multilayer design, and the use of the less cardiotoxic enantiomer levobupivacaine. Finally, the device was tested in vivo to examine feasibility, safety and efficacy. The device was well-tolerated and partially attenuated surgery-induced increases in responses to von Frey stimulation of the inguinal area. The device reduced locomotor activity compared to surgery animals with no device. There was a surgery-induced reduction in mRNA of cytokines IL-1β and IL-6 in inguinal tissue at 48 hours post-surgery. The device also further reduced IL-6 mRNA levels and increased PEA levels. In conclusion this project has generated new data on the role of the endocannabinoid and opioid systems in postoperative pain as well as the development of a device capable attenuating mechanical hypersensitivity associated with postoperative pain. This thesis has further contributed to the understanding of endocannabinoid and opioid signalling in a clinically relevant animal model of postoperative pain as well as exploring novel approaches to the treatment of postoperative pain.2023-12-0