Commentary Cellscience Reviews Vol 2 No.1 ISSN 1742-8130

Using the brain’s own cannabinoids

T. Philip Malan, Jr., Ph.D., M.D.

A stressor is an event, either internal or external, that poses a real or perceived threat to the maintenance of an organism’s homeostasis. Exposure to a stressor produces a set of physiological and behavioral responses, one of which is an increase in nociceptive (pain) threshold. This phenomenon is known as stress-induced analgesia. Considerable evidence suggests that opioid systems mediate the analgesia which follows exposure to a variety of stressors. However, it appears that there is also non-opioid-mediated stress-induced analgesia, since in some experimental paradigms stress-induced analgesia is not sensitive to the opioid receptor antagonist naloxone[1]. It is not clear what dictates when stress-induced analgesia is mediated by opioid or non-opioid mechanisms. Terman et al. [2] proposed that opioid-mediated systems are activated when the stressor is weak or brief, and non-opioid mechanisms become predominant when the stressor is more intense or of longer duration. A number of neurotransmitter and neuromodulator systems have been suggested to participate in non-opioid mediated stress-induced analgesia.

Recently, Hohmann et al. tested the hypothesis that endocannabinoids, endogenous agonists of cannabinoid receptors, mediate non-opioid mediated stress-induced analgesia [3]. This hypothesis was based on findings that stress-induced analgesia depends on neural pathways that descend from the amygdala to the midbrain periaqueductal grey matter to the rostral ventromedial medulla to the dorsal horn of the spinal cord. These pathways respond to opioids, potentially explaining opioid-mediated stress induced analgesia. It has also been demonstrated that microinjection of cannabinoid receptor agonists into the rostral ventromedial medulla inhibits nociceptive responses in the tail [4] and that nociception-enhancing neurons in the rostral-ventromedial medulla are activated by CB1 cannabinoid receptor agonists [5], suggesting that endogenous cannabinoid tone in the brainstem may regulate cannabinoid–responsive descending pathways, similar to the way endogenous opioid receptor agonists regulate opioid-responsive descending pathways.

Hohmann et al. showed that application of brief, continuous electric foot shock produces non-opioid stress-induced analgesia which is sensitive to injection of the CB1 cannabinoid receptor-selective agonist rimonabant into the dorsolateral portion of the midbrain periaqueductal grey matter, suggesting that this form of non-opioid stress-induced analgesia is may be mediated by endocannaboids in the brainstem. Critically, quantitative analysis showed that this stressor elicited the formation of two endocannabinoids, 2-arachidonyl glycerol (2-AG) and anandamide in the dorsal midbrain. Further, inhibitors of the enzymes responsible for the hydrolysis of 2-AG or anandamide enhanced stress-induced analgesia when injected in the periaqueductal grey area. Systemic administration of an inhibitor of anadamide transport did so as well. Interestingly, these drugs had no effect on nociception in the absence of prior exposure to a stressor, suggesting that any increase they produced in basal endocannabinoid levels was not sufficient to produce antinociception. However, when they magnified the increases in endocannabinoids produced by stress, endocannabinoid concentrations may have reached antinoiceptive levels.

These results have two potential clinical implications. First, they raise the question of whether rimonabant, which is in clinical trials for the treatment of obesity, would enhance pain sensitivity in settings where stress-induced endogenous analgesic mechanisms might be activated (for example, following injury or surgery). More intriguing is the possibility that inhibitors of endocannabinoid transport or metabolism might be useful in the treatment of clinical pain. In preclinical studies, inhibitors of endocannabinoid hydrolysis or transport have not been consistently effective in inhibiting responses to acute nociceptive stimuli. However, the results of Hohmann et al. suggest that these classes of drugs might be effective pain treatments in patients in whom stress responses have been activated. While we do not know the role of stress-induced analgesia in patients with pain, it is likely that stress responses are activated in a variety of clinical settings where pain is present. If pain can be treated by enhancing endocannabinoid levels, this approach might produce fewer side effects than administration of exogenous cannabinoid agonists, since these drugs should only enhance cannabinoid effects produced in regions of the nervous system where endogenous cannabinoids are present.

References

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2. Terman GW, Shavit Y, Lewis JW, Cannon JT, Liebeskind JC. Intrinsic mechanisms of pain inhibition: activation by stress. Science. 1984; 226:1270-7.

3. Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, Krey JF, Walker JM, Holmes PV, Crystal JD, Duranti A, Tontini A, Mor M, Tarzia G, Piomelli D. An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005; 435(7045):1108-12.

4. Martin WJ, Tsou K, Walker JM. Cannabinoid receptor-mediated inhibition of the rat tail-flick reflex after microinjection into the rostral ventromedial medulla. Neurosci Lett. 1998; 242(1):33-6.

5. Meng ID, Manning BH, Martin WJ, Fields HL. An analgesia circuit activated by cannabinoids. Nature. 1998; 395(6700):381-3.