The Endocannabinoid System as a Novel Therapeutic Target for Pain and CNS Disorders: Can the Promise be Realised?

David P. Finn

Pharmacology and Therapeutics, Galway Neuroscience Centre and Centre for Pain Research, NCBES, National University of Ireland Galway, University Road, Galway, Ireland.

Pain and affective state interact reciprocally, whereby the latter can both influence, and be influenced by, the pain experience.  We have used animal models to elucidate supraspinal neurochemical and receptor mechanisms involved in (1) hyperalgesia associated with negative affect (anxiety/depression) and (2) fear-induced analgesia.  Wistar-Kyoto rats exhibit an anxiety- and depressive-like phenotype and also display hyperresponsivity to noxious stimuli.  These effects are 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 Wistar-Kyoto 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 Wistar-Kyoto model of hyperalgesia associated with negative affective state. Our most recent results also suggest an important role for TRPV1 and PPARg in the periaqueductal grey 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.  Interestingly, we have also shown that induction of neuropathic pain in the Wistar-Kyoto rat (L5 spinal nerve ligation) is associated with significantly increased anxiety- and depressive-like behaviour compared with Sprague-Dawley counterparts, results which may be due, at least in part, to deficits in endocannabinoid signalling.  This result maps onto clinical data that we and others have generated indicating increased anxiety and depression in neuropathic pain patients.  Our work also points to a role for non-CB1 receptor targets of endocannabinoids and N-acylethanolamines in the affective dimension of pain, particularly in higher brain centres including the medial prefrontal cortex.  These targets include peroxisome proliferator activated receptors (PPARs) and GPR55.  Finally, using the place escape avoidance paradigm we have generated evidence for an affective component associated with our recently developed novel rat model of post-operative pain associated with inguinal hernia repair and we are elucidating the role of the endocannabinoid system in the affective dimension of post-operative pain in both rodents and humans.  Increased understanding of the neurochemical and receptor mechanisms underpinning endocannabinoid-mediated regulation of pain-affect interactions may facilitate identification of novel therapeutic targets for the treatment of pain, affective disorders, and their co-morbidity.