The role of the endocannabinoid system in the affective modulation of pain
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Pain represents a major unmet clinical need and affects a large number of individuals worldwide. Numerous studies indicate a very high prevalence of chronic pain comorbid with psychiatric disorders such as anxiety and depression. Mounting evidence suggests that pain and negative affect share a reciprocal relationship that can influence severity and treatment outcomes in both conditions. Some evidence suggests that the presence of affective disorder can increase the risk of developing a chronic pain condition. The Wistar–Kyoto (WKY) inbred rat strain exhibits a stress-hyperresponsive and depressive- and anxiety-like phenotype. Additionally, WKY rats display increased sensitivity to visceral and somatic noxious stimuli, compared with other rat strains. Therefore the WKY rat represents a useful model with which to study the impact of genetic background and negative affect on pain processing. There exists a plethora of evidence demonstrating an important role for endocannabinoids in stress–pain interactions, regulating both stress-induced analgesia and stress-induced hyperalgesia. However, there is a paucity of studies examining the contribution of the endocannabinoid system to altered nociceptive responding in genetic backgrounds predisposed to negative affect and no studies investigating the involvement of the endocannabinoid system within periaqueductal grey (PAG); an important brain region involved in pain and stress responding. The aims of the work presented in this thesis were to characterise forced swim stress-induced hyperalgesia in a model of inflammatory pain after intra-plantar formalin injection and investigate the role of the endocannabinoid system; to examine the role of CB1 receptor in the PAG subcolumns on formalin-induced nociceptive behaviour in WKY and SD rats and to investigate if negative affective state in WKY rats is associated with altered pain- ,anxiety- and depressive-like behaviour in a model of neuropathic pain, and if behavioural alterations are associated with alterations in the endocannabinoid system in the PAG. SD rats exposed to 10 days of forced swim stress displayed enhanced formalin-evoked nociceptive behaviour that was associated with increased ipsilateral spinal expression of the endocannabinoid-catabolising enzyme monoacylglycerol lipase (MAGL) and a reduction in levels of anandamide in the contralateral amygdala. Conversely, exposure of WKY rats to the same forced swim stress paradigm reduced formalin-evoked nociceptive behaviour, with no associated effects on the spinal or amygdalar endocannabinoid system. Stress-induced and side-related (ipsilateral versus contralateral) alterations in the endocannabinoid system at the level of the spinal cord and amygdala may contribute to the differential effects of forced swim stress on nociceptive behaviour in WKY versus SD rats. To examine the role of CB1 receptors in the subcolumns of the PAG of WKY rats in response to inflammatory pain; formalin-evoked nociceptive behaviour was measured after microinjection of the CB1 receptor agonist, ACEA, into each PAG subcolumn of WKY and SD rats. Intra-dorsolateral (dl) PAG and intra-lateral (l) II PAG administration of ACEA resulted in reduced formalin-evoked nociceptive behaviour in SD rats only, that was attenuated by co-administration with the CB1 receptor antagonist/inverse agonist, AM251. The ACEA-induced reduction of formalin-evoked nociceptive behaviour in SD rats after intra-lPAG administration was associated with an increase in neuronal activity in the RVM and reduced neuronal activity in the dorsal horn of the spinal cord. In sharp contrast to these results observed in SD rats, direct injection of ACEA into each PAG subcolumn failed to alter formalin-evoked nociceptive behaviour or neuronal activity in the RVM and spinal cord of WKY. Thus, alterations in the endocannabinoid system within the descending inhibitory pain pathway may contribute to the hyperalgesic phenotype of WKY rats. The induction of neuropathic pain following L5 spinal nerve ligation (SNL) in SD rats resulted in mechanical and cold allodynia with increased anxiety-like behaviour whereas SNL in WKY rats resulted in the development of mechanical and cold allodynia, heat hyperalgesia and an enhancement of both anxiety- and depressive-like behaviour. SNL-induced increases in CB1 receptor expression in the dlPAG and lPAG were seen in both strains; however SNL resulted in an increase and decrease of CB1 receptor expression in the vlPAG of SD and WKY rats, respectively. Thus, hyperalgesia to SNL is exacerbated in the WKY model of negative affective state, and pain-related depressive and anxiety-like behaviour following SNL is associated with changes in CB1 receptor expression in the PAG. In conclusion, the work presented herein suggests that alterations in the endocannabinoid within the PAG of the WKY rat model of negative affect may contribute to their hyperalgesic phenotype. These results enhance our understanding of the fundamental physiology of pain and its modulation in negative affective states and may facilitate the development of new therapeutic approaches to the treatment of pain, mood disorders and their co-morbidity.