Objective

Pain and negative affective state interact reciprocally, whereby the latter can both influence, and be influenced by, the pain experience. Wistar-Kyoto (WKY) rats exhibit an anxiodepressive phenotype and also display hyperresponsivity to noxious stimuli. They therefore represent a useful model to elucidate supraspinal neurochemical and receptor mechanisms involved in hyperalgesia associated with negative affect (anxiety/depression). We have shown that this behavioural phenotype in WKY rats is associated with alterations in levels of endogenous cannabinoids (endocannabinoids) and related N-acylethanolamines and altered expression of their receptor targets or metabolizing enzymes in key brain regions regulating pain and affect. Pharmacological blockade of the CB1 receptor exacerbates hyperalgesia to persistent inflammatory pain in WKY rats, while pharmacological blockade of endocannabinoid degradation attenuates hyperalgesia. Additional data suggest an important role for the endocannabinoid system in the periaqueductal grey and rostral ventromedial medulla in regulating hyperalgesia in the WKY model of hyperalgesia associated with negative affective state. Our most recent results also suggest an important role for the endogenous opioid system in the Wistar-Kyoto model. Further evidence that deficits in the functionality of the descending inhibitory pain pathway likely underlie the hyperalgesic phenotype of Wistar-Kyoto rats comes from our recent data suggesting that these rats exhibit impaired expression of fear-induced analgesia. Increased understanding of the neurochemical and receptor mechanisms underpinning pain-affect interactions may facilitate identification of novel therapeutic targets for the treatment of pain, affective disorders, and their co-morbidity.