Altered nociceptive responding in animal models of affective disorders: role of monoamines and immune mediators
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Depression and chronic pain share an intricate, complex relationship, the comorbidity of which is reported to affect up to 80% of patients. This thesis demonstrated enhanced nociceptive responding to mechanical and cold, but not heat, stimuli in a well-validated animal model of depression, the olfactory bulbectomised (OB) rat. In addition, early life stress in the form of maternal deprivation (MD) resulted in enhanced nociceptive responding to mechanical and heat, but not cold, stimuli. OB animals exhibited exacerbated cold, but not mechanical, allodynia following spinal nerve ligation (SNL), a clinically relevant model of neuropathic pain. In addition, MD female, but not male, rats exhibited exacerbated mechanical and cold allodynia following SNL. Thus, neuropathic pain-related behaviour is enhanced in two models of affective disorders in a stimulus- and sex-dependent manner. Despite the high comorbidity of these disorders, the neurobiological mechanisms mediating the relationship between affective disorders and chronic pain remain unknown. Evidence suggests that monoamines and neuroimmune mediators play a role in the relationship between depression and pain. This thesis demonstrated that the enhanced SNL-induced cold allodynia observed in OB rats was accompanied by reduced serotonergic neurotransmission in the hippocampus, reduced inflammatory cytokine gene expression in the amygdala and increased cytokine gene expression and glial activation in the prefrontal cortex (PFC). In addition, early life stress and SNL differentially altered immune gene expression in the PFC and hippocampus in a sex-dependent manner. Pharmacological studies were subsequently employed in order to further probe the role of monoamines and neuroimmune mediators in the OB-related changes in nociceptive responding, prior to and following SNL. Chronic treatment with amitriptyline (a tricyclic antidepressant and first-line treatment for neuropathic pain) and minocycline (an inhibitor of microglial activation) elicited an antidepressant-like effect, but did not alter basal nociceptive responding in the OB rat. However, chronic amitriptyline and minocycline treatment differentially altered neuropathic pain-related behaviour in the presence or absence of a depressive-like phenotype. In brief, amitriptyline attenuated SNL-induced cold allodynia and thermal hyperalgesia, but not mechanical allodynia, in sham (control) rats. In contrast, amitriptyline attenuated SNL-induced mechanical allodynia, but not cold allodynia or thermal hyperalgesia in OB rats. Chronic minocycline treatment attenuated SNL-induced cold and mechanical allodynia in both sham and OB rats. Thus, enhancing monoamines and blocking microglial activation elicits antidepressant-like effects and attenuates SNL-induced mechanical allodynia in the OB model of depression. These studies improve our understanding of supraspinal mechanisms underlying pain, affect and the interaction between these processes, indicating that monoamines and neuroimmune mediators may, in part, underlie this association.