Investigation of behaviour, the endocannabinoid system, and phytocannabinoids in rat models of wound-related pain

Pain, anxiety, and depression are prevalent in individuals with chronic wounds and have a profound impact on their quality of life. Pain has been reported to be one of the most debilitating aspects of having a chronic wound. Despite their negative impact on individuals, there is a lack of management of pain and these comorbidities in current wound care strategies. Furthermore, there is a paucity of studies examining the molecular mechanisms underlying comorbid anxiety and depression associated with chronic wounds. The endocannabinoid system is involved in many physiological processes, including mood, anxiety, and pain modulation, and has a role in skin homeostasis and wound healing. Therefore, the endocannabinoid system is a potential therapeutic target for the treatment of anxiety, depression, and pain associated with chronic wounds. Anxiety- and depression-related behaviour has not been extensively investigated in models of wound-related pain, and as far is known, has not been characterised in the dorsum incision or hind limb ischemia-reperfusion models of wound-related pain. There is evidence that phytocannabinoids may attenuate pain in several models of pain, but their effects on nociceptive behaviour following dorsum incision have not been examined previously. The work presented in this thesis tested the hypothesis that anxiety- and depression-related behaviour would be present in the dorsum incision and hind limb ischemia reperfusion models of wound-related pain and that the endocannabinoid system would be altered in brain regions associated with anxiety and depression. It was also hypothesised that the phytocannabinoids, cannabidiol and cannabigerol, would attenuate nociceptive behaviour in the dorsum incision model of wound-related pain. The overarching aims of the work presented herein were to 1) characterise anxiety- and depression-related behaviour and the endocannabinoid system in a rat incisional wound model and a rat model of ischemia-reperfusion injury, 2) investigate the effects of cannabidiol and cannabigerol on nociceptive behaviour following incision wound, and 3) investigate the effects of cannabidiol and cannabigerol on the endocannabinoid system. There was no effect of dorsum incision or hind limb ischemia reperfusion injury on anxiety- or depression-related behaviour in male or female rats, but sex differences in locomotor activity and anxiety-related behaviour were present. Investigation into the endocannabinoid system following ischemia-reperfusion injury revealed that there were lower levels of 2-arachidonoyl glycerol in the contralateral amygdala of female HLIR rats compared to female shams 30 days post-injury. Investigation into the endocannabinoid system following dorsum incision revealed that male incision rats had lower levels of PEA and OEA in the contralateral hippocampus compared to male sham rats on post-incision day 35. Female incision rats had higher levels of mRNA encoding Faah in the contralateral amygdala compared to female shams on post-incision day 35. Next, the effect of the phytocannabinoids, cannabidiol and cannabigerol, on nociceptive behaviour following dorsum incision was investigated. The impact of these phytocannabinoids on endocannabinoid and N-acylethanolamine levels, and the expression of their targets in brain regions involved in pain modulation were also assessed. Following dorsum incision, cannabidiol partially attenuated primary mechanical hypersensitivity in the dorsum, while cannabigerol attenuated primary and secondary hypersensitivity in the dorsum and hind paws. Cannabigerol increased circulating levels of PEA and OEA, and increased levels of PEA in the rostral ventromedial medulla. Cannabigerol also increased levels of mRNA encoding Pparg in the thoracic spinal cord and Faah in the periaqueductal grey, in a dose-specific manner. In conclusion, these findings provide evidence of sex differences in anxiety-related behaviour and alterations in the endocannabinoid system in two models of wound-related pain. The data presented in this thesis also provides preclinical evidence to support the contention that cannabidiol and cannabigerol may have therapeutic potential for the alleviation of incisional wound-related pain.

Funder

Taighde Éireann -Research Ireland
European Union

Publisher

University of Galway

Rights

CC BY-NC-ND

cbn

Collections

University of Galway Theses (PhD Theses)