How is it that a soldier in the heat of battle, or a sportsman caught up in a crucial match, can keep going despite injuries that would normally be cripplingly painful? New insights into how stressful situations can make us less sensitive to pain come from a study by Hohmann and colleagues. They find that the release of endogenous cannabinoid compounds is crucial for this effect, termed stress-induced analgesia.

Cannabinoids, such as 2-arachidonoylglycerol (2AG) and anandamide, are endogenous substances that act through cannabinoid 1 receptors (CB1) in the brain. Agonists of these receptors have an anti-nociceptive effect, and antagonists enhance nociception, which indicates that endogenous cannabinoids might also be anti-nociceptive. Hohmann and colleagues therefore investigated whether endocannabinoids are involved in opioid-independent stress-induced analgesia.

In the rat model of stress-induced analgesia, the stressful event is an electric shock to the foot, after which the rats' sensitivity to pain is measured using a tail-flick test. Normally, the electric shock reduces pain sensitivity, and this effect does not require opioid peptides. However, when the authors treated the rats with a CB1 antagonist, the anti-nociceptive effect was greatly reduced, which supports the idea that endocannabinoids are at least partly responsible for stress-induced analgesia. To test the idea further, the authors gave a cannabinoid agonist to rats every day for two weeks, so that they became tolerant to its effects. After this regime, not only were the analgesic effects of cannabinoid agonists reduced, but stress-induced analgesia was also decreased.

Which parts of the brain are involved in this effect? The existing evidence points towards the activation of pathways from the amygdala to the midbrain periaqueductal grey, brainstem and spinal cord. When Hohmann et al. injected a CB1 antagonist into the dorsolateral periaqueductal grey, stress-induced analgesia was greatly reduced. More evidence for the importance of the midbrain came from measurements of endocannabinoid levels: after the footshock, both anandamide and 2AG were upregulated in the midbrain, but not in other parts of the brain, such as the occipital cortex. Interestingly, though, these two endocannabinoids showed different timescales of upregulation: 2AG concentrations increased rapidly, within 2 min of the footshock, whereas anandamide concentrations peaked 7–15 min after the shock.

To investigate whether the rapid release of 2AG mediates stress-induced analgesia, the authors developed an inhibitor of monoacylglycerol lipase (MGL). MGL hydrolyses 2AG and thereby deactivates it. Injection of the MGL inhibitor into the periaqueductal grey (which would be expected to increase the concentrations of 2AG) enhanced the anti-nociceptive effect of stress. Inhibitors of the enzyme that deactivates anandamide, fatty acid amide hydrolase (FAAH), also enhanced stress-induced analgesia. These results are consistent with the idea that, in the periaqueductal grey, both 2AG and anandamide mediate the analgesic effect of stress.

As well as increasing our understanding of intrinsic anti-nociceptive mechanisms in mammals, these results might point towards the use of MGL or FAAH inhibitors as possible therapeutic agents for the treatment of pain.