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Surprise role for endocannabinoids

The molecules play an unexpected part in stress-induced analgesia, new study shows

By | June 23, 2005

Endogenous cannabinoids play a crucial and unsuspected role in the phenomenon of stress-induced analgesia, researchers report in Nature this week.

Researchers have known that stress-induced analgesia involves two mechanisms: a well-characterized opioid pathway, and a mysterious nonopioid pathway, lead author Andrea Hohmann of the University of Georgia told The Scientist. In their latest work, Hohmann and colleagues established that the second pathway is mediated via the lipids 2-arachidonoylglycerol (2-AG) and anandamide, which bind cannabinoid CB1 receptors in the periaqueductal gray region in the midbrain.

"It all started with an interest in examining the natural conditions that would activate the release of the body's own marijuana-like compounds," said Hohmann. The researchers examined whether the phenomenon could be mediated by cannabinoids, because those molecules are known to suppress pain by inhibiting pain-sensitive neurons.

To quantify stress-induced analgesia and to measure basal nociceptive thresholds, they delivered brief electric foot shocks to rats and examined their sensitivity to pain after stress by using the "tail-flick test," which measures how quickly rats move their tails away from heat sources.

The team first focused on the mechanism underlying stress-induced analgesia. "When we used cannabinoid antagonists to block their receptors, the nonopioid stress-induced analgesia virtually disappeared," said Hohmann. When they injected an inhibitor of monoacylglycerol lipase–an enzyme responsible for deactivating 2-AG–in the periaqueductal gray matter, the cannabinoid concentrations increased, and stress-induced analgesia was enhanced in a CB1-dependent manner.

Similarly, an inhibitor of fatty-acid amide hydrolase–an enzyme that deactivates anandamide–elevated anandamide concentrations and exerted comparable effects. The results clearly pointed to the two well-known endocannabinoids and the CB1 receptors.

"The authors found the way to tap into an endogenous cannabinoid system, which is interesting," said Allan Basbaum of the University of California, San Francisco. "The real question is how significant is it? I think that this is really not addressed."

Basbaum criticized the fact that the authors only used the tail-flick test—which is commonly used to predict the efficacy of morphine as an analgesic. "It's not at all clear how these results translate to the real problem of clinical, persistent pain, such as inflammatory pain," he added. "There are other tests that could be used to test whether these manipulations influence pain and whether cannabinoids affect it."

"This is one of those rare papers where a long-standing problem of substantial importance has been solved in a simple, straightforward, and convincing way," said Miles Herkenham of the National Institute of Mental Health, who did not participate in the research. "It's a big finding for basic science because the mechanism was not even suspected. But I don't know if this is going to have direct applications. Its first application might be in the treatment of obesity. It's hard to imagine a scenario where there is a natural stress-induced analgesia that we'd like to augment."

Hohmann, however, was optimistic about the potential applications. "We've identified monoacylglycerol lipase as a previously unrecognized target for the treatment of stress- and pain-related disorders, and fatty-acid amide hydrolase is also likely to be of interest," she said.

"We might be able to manipulate the levels of the brain's own cannabinoids, which produce the same pain suppression effect as cannabinoid agonists like THC, the active component in marijuana," she said. "You can have a therapeutic target that isn't going to have the same kind of political baggage as marijuana."

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