Our current tools for treating chronic severe pain are inadequate at best. Opioids such as morphine or methadone reduce chronic pain on average about 30%, with a range of perhaps 0-50%. And of course they come with multiple liabilities, such as constipation, sweating, nausea and physiological tolerance which means that symptoms occur if the drug is suddenly stopped. Although unproven there is concern that chronic use of these medications could actually increase pain sensitivity. Other methods such as cognitive behavioral therapy, moderate exercise, physical therapy, injections, surgery, neurostimulators, biofeedback, etc., have a modest impact if any. We desperately need new tools. This article describes new research on a compound that may reduce pain without the disadvantages of opioids. Cannabinoid receptors, by the way, are those that responde to drugs like marijuana and hashish. There are more of these receptors in peripheral tissues than the brain. It is possible that the effect of cannabis on pain are due to their effects on these peripheral receptors.
Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism
Jason R Clapper, Guillermo Moreno-Sanz, Roberto Russo, Ana Guijarro, Federica Vacondio, Andrea Duranti, Andrea Tontini, Silvano Sanchini, Natale R Sciolino, Jessica M Spradley, Andrea G Hohmann, Antonio Calignano, Marco Mor, Giorgio Tarzia & Daniele Piomelli
Nature Neuroscience 13, 1265–1270 (2010) doi:10.1038/nn.2632
Peripheral cannabinoid receptors exert a powerful inhibitory control over pain initiation, but the endocannabinoid signal that normally engages this intrinsic analgesic mechanism is unknown. To address this question, we developed a peripherally restricted inhibitor (URB937) of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide. URB937 suppressed FAAH activity and increased anandamide levels outside the rodent CNS. Despite its inability to access brain and spinal cord, URB937 attenuated behavioral responses indicative of persistent pain in rodent models of peripheral nerve injury and inflammation and prevented noxious stimulus–evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CB1 cannabinoid receptor blockade prevented these effects. These results suggest that anandamide-mediated signaling at peripheral CB1 receptors controls the access of pain-related inputs to the CNS. Brain-impenetrant FAAH inhibitors, which strengthen this gating mechanism, might offer a new approach to pain therapy.