Endocannabinoid-mediated modulation of stress responses: physiological importance and pathophysiological significance

David Finn. National University of Ireland, Galway, Galway, Ireland.

The stress response is associated with a broad spectrum of physiological and behavioural effects including hypothalamo-pituitary-adrenal (HPA) axis activation, increased sympathetic and central nervous system activity, neuroimmune alterations, activation of intracellular molecular cascades leading to altered gene transcription, and analgesia. Whilst the acute stress response has essential survival value, chronic stress and dysfunction of the stress response can be maladaptive, contributing to the development and severity of psychiatric (e.g. anxiety, depression) and inflammatory (e.g. rheumatoid arthritis, pain) disorders. It is now clear that the endocannabinoid system plays a key role in mediating and/or modulating behavioural, neurochemical, neuroendocrine, neuroimmune and molecular responses to stress (Viveros et al., 2005). Pharmacological blockade or genetic deletion of cannabinoid1 (CB1) receptors attenuates extinction of conditioned aversive behaviour in rodents (Marsicano et al., 2002; Finn et al., 2004), work which supports the idea that increasing endocannabinoid tone may be a viable pharmacological approach to the treatment of post-traumatic stress disorder or phobias. Meanwhile, studies of the effects of cannabinoid receptor agonists in animal models of anxiety are equivocal with evidence for both anxiolytic and anxiogenic effects depending on the dose, species and model under investigation. The profound analgesia which is expressed following exposure to stressful or fearful stimuli is endocannabinoid-mediated (Finn et al., 2004; Hohmann et al., 2005) although it is still unclear if and how the endocannabinoid system interacts with classical opioidergic and GABAergic systems in this phenomenon. With respect to HPA axis activity, it has recently been shown that CB1 receptor deficiency enhances the peak of circadian activity and leads to central impairment of glucocorticoid feedback (Cota et al., 2006). Moreover, blockade of endocannabinoid signalling potentiates, and enhancement of endocannabinoid signalling attenuates, stress-induced HPA axis activation in rodents (Patel et al., 2004). However, the extent to which such regulation also occurs in humans remains unknown as does its relevance to stress-related disease and dysfunction. Certainly, there has been a lot of interest in the role of stress-induced impairment of neurogenesis in the pathophysiology of depression and evidence indicates that chronic treatment with cannabinoid receptor agonists may enhance neurogenesis in rodents and result in an antidepressant-like phenotype. Indeed, at the molecular level it is clear that the endocannabinoid system may play a critical role in determining cell fate by regulating apoptosis. Finally, the effects of stress on the immune system contribute to neurobiological processes underlying pain and neurodegenerative disorders. Cannabinoids are capable of modulating cytokine release in vitro and in vivo, an effect which supports their potential as novel therapeutic agents for neuroinflammatory disorders.

Patel S et al. (2004) Endocrinology 145(12): 5429-30; Cota D et al. (2006) Endocrinology doi: 10.1210/en.2005-1649

Viveros MP et al. (2005) Pharmacol Biochem Behav 81(2): 331-42

Finn DP et al. (2004) Eur J Neurosci 20(3): 848-852

Marsicano G et al. (2002) Nature 418(6897): 530-4

Hohmann AG et al. (2005) Nature 435(7045): 1108-12