Endocannabinoids Pitch In for Placebo Effect
Placebos can be powerful pain medicine. In many cases, placebos activate endogenous opioid pathways, and their pain-relieving effects can be blocked by opioid receptor inhibitors. Now there is evidence that placebos can elicit analgesia through endocannabinoids as well. In a paper published online October 2 in Nature Medicine, researchers led by Fabrizio Benedetti at the University of Turin, Italy, report that in some cases, the CB1 cannabinoid receptor antagonist rimonabant can abolish placebo pain relief.
One way to produce a placebo effect is through pharmacological preconditioning, in which subjects are repeatedly given an analgesic drug during painful procedures; when the drug is then secretly replaced by a placebo, subjects continue to experience pain relief. If the conditioning drug is morphine, the subsequent placebo relief can be blocked with the opioid antagonist naloxone. That indicates that the placebo, like the real drug, relieves pain through the opioid system. However, other drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), induce a naloxone-insensitive placebo response (Amanzio and Benedetti, 1999). In that case, the placebo works by another route, whose nature was unknown.
Benedetti and colleagues set out to see whether the missing mechanism might involve endocannabinoids. First, they recorded how long healthy subjects could tolerate a painful tourniquet. In two subsequent sessions, the subjects were given the NSAID ketorolac, which increased their tolerance times. In another session, when the researchers slipped in a placebo in place of the drugs, the subjects bore up just as well as when they were on the painkiller. However, administration of the CB1 antagonist rimonabant wiped out the placebo response. The result indicates that the cannabinoid system plays a crucial role in placebo pain relief.
On the other hand, when subjects were conditioned with morphine, rimonabant did not touch the placebo response. This suggests that the placebos operate by non-overlapping pathways: Placebo analgesia evoked by morphine exposure works through the opioid system, but not the cannabinoid system, and vice versa for NSAIDs.
Just how placebos mobilize the cannabinoid system is not yet known. NSAIDs are thought to relieve pain primarily by inhibiting cyclooxygenase-2 (COX-2) production of inflammatory mediators. However, COX-2 also catalyzes the inactivation of endocannabinoids, and NSAIDs block that pathway, too (see PRF related news story). The latest findings should stimulate a new look at the role of the endocannabinoid system in NSAIDs’ therapeutic activity, and NSAID-induced placebo.
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