Chronic post-surgical pain, which is long term pain that occurs after surgery (but is not linked to the condition that the surgery was treating), can affect between 20-85% of human patients. These patients experience restrictions on their daily activities, increased use of pain-killers, and reduced quality of life. As chronic post-surgical pain is so common it represents an enormous clinical, societal and economic burden. Therefore, greater understanding of the mechanisms that underlie the development of chronic post-surgical pain and the development of novel therapeutics to treat this condition is warranted. Patients with pre-existing anxiety and depression are at increased risk of developing chronic post-surgical pain. However, how and why depression can lead to the development of chronic post surgical pain is not fully understood. This project will examine the link between depression and post-surgical pain using animal models. Given the increasing knowledge that interactions between the nervous system and immune system play a key role in both depression and chronic pain, the link between these systems will be investigated in the development of post-surgical pain. This will provide valuable information for novel therapeutic targets. The role of the body’s own cannabis-like system (the endocannabinoid system) will also be investigated as a potential therapeutic target. This system controls a host of physiological functions including emotion, pain and inflammation, and therefore may play a role in the link between depression and chronic post-surgical pain. Females are at a higher risk of developing both depression and chronic pain, however most studies have previously focussed on males. This project will examine both males and females to determine if there are sex differences in the development and presentation of chronic post-surgical pain, and if different biological mechanisms are responsible, which will provide information on whether the treatment of this condition would benefit from sex-specific approaches.

All animals will undergo a single multi-step procedure, with a number of independent interventions. Some animals will undergo an intervention to induce depression, where they are confined to a small space for a short period each day. Some animals will undergo a surgery under anaesthesia to create a small wound on the paw, while the remainder of animals will be anaesthetised but will not have a wound created. All animals will undergo a number of tests designed to assess behaviour, including pain-, anxiety-, depression- and cognition-related behaviour. All animals will have therapeutic drugs administered through a number of injections, one of which will require a short period of anaesthesia. Some animals will undergo a second surgery under anaesthesia to allow for drug delivery directly into the the brain. At the end of the procedure, animals may undergo anaesthesia from which they will not awaken, to allow for collection of tissue for further analysis. The maximum duration for this procedure is 63 days.

Depression and pain involve complex processing by the peripheral nervous system, spine and brain, and cannot be fully replicated in vitro (in a laboratory environment, e.g. using cell culture). Therefore the use of living animals is currently required to model depression and pain and to aid in the development of pain-relieving treatments. When attempting to relate brain function and neurochemical/molecular alterations to behaviour, it is essential to investigate the intact nervous system. There are currently no alternative methods that could be used to address the project objectives.