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Endocannabinoids Rein in Pain Outside the Brain

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Endocannabinoids Rein in Pain Outside the Brain NEWS AND VIEWS Endocannabinoids rein in pain outside the brain David M Lovinger Enhancers of endocannabinoid signaling are potential analgesics, but they cause unacceptable psychiatric side effects. A new study reports an inhibitor of endocannabinoid breakdown that has analgesic activity and cannot enter the CNS. Medical marijuana is a popular topic among scientists, clinicians, activists and politicians. Indeed, preparations of the Cannabis sativa BCRP plant are now being used in medicinal settings to stimulate appetite and for symptomatic relief in multiple sclerosis. The major psychoactive URB937 ingredient of these preparations activates can- Sensory neuron nabinoid type 1 (CB1) receptors in the brain, the same receptors that recognize endogenous lipid-like mediators known as endocannabi- noids. Although potential medicinal uses of can- nabis preparations have garnered the lion’s share CB1 of public attention, steady progress has been URB937 made in determining the potential therapeutic uses of a variety of drugs that target the com- ponents of the endocannabinoid system, which FAAH AEA consists of the endocannabinoids, their recep- tors and the enzymes involved in their biosyn- AA + EtH N thesis and degradation. Pain relief is a potential 2 indication for drugs targeting the endocannabi- noid system. CB1 receptors mediate analgesic Figure 1 Mechanism of analgesic action of the peripherally targeted FAAH inhibitor URB937. The drug actions and endocannabinoids modulate neural is excluded from the brain by a transporter with a pharmacology resembling BCRP, but is free to act on nociceptive mechanisms1,2. Receptors present in peripheral FAAH. The site of analgesic action is most likely peripheral pain-sensing nerve endings (red both the peripheral nervous system (PNS) and circle). Expanded red circle shows the suspected molecular mechanism of drug action, inhibition of FAAH- CNS participate in these pain-relieving effects3. catalyzed conversion of anandamide (arachidonoyl ethanolamide or AEA) to arachidonic acid (AA) and ethanolamide (EtH2N). This allows for persistent AEA activation of peripheral cannabinoid type 1 (CB1) However, separating the roles of PNS and CNS receptors on peripheral nerve endings. Activation of CB1 receptors ultimately reduces transmission of endocannabinoid actions has been difficult pain signals to the spinal cord, preventing pain sensation. given that most drugs targeting cannabinoi- dergic transmission readily penetrate the blood- © 2010 Nature America, Inc. All rights reserved. All rights Inc. America, Nature © 2010 brain barrier, acting on receptors in all nervous interfere with the function of other endocan- sciatic nerve ligation, and injection of periph- system areas. Endocannabinoid-targeted drugs nabinoid targets did not prevent analgesia. eral nerve inflammatory agents and irritants. that act only in the periphery have the poten- These findings indicate that peripheral canna- However, URB937 did not have generalized tial to provide anti- nociceptive benefit without binoidergic transmission is indeed important anti-nociceptive effects (for example, it did producing intoxication or other CNS impairing in pain control. Clapper et al.4 also highlight not alter responses on the hot plate test) and effects. Such drugs would not only be safer for the newly developed peripheral FAAH antago- the peripheral effects were restricted to limbs users, but would also avoid the legal problems nist as a representative of a potential new class affected by the nerve injury and inflammation that have bedeviled some cannabinoidergic of anti-nociceptive drugs. models. Furthermore, the drug did not affect drugs proposed for medicinal use. The new FAAH inhibitor was found to be feeding or locomotor activity, unlike CNS- Clapper et al.4 applied a new, peripherally excluded from the CNS largely via a trans- penetrant FAAH inhibitors. The peripheral acting inhibitor of the endocannabinoid- porter present in cells of the blood/brain bar- actions of URB937 led to alterations in spinal degrading enzyme fatty acid amide hydrolase rier, with pharmacological properties similar processing of nociceptive information, as indi- (FAAH) to mouse models of visceral, neuro- to the breast cancer resistance protein (BCRP). cated by the observation that the drug reduced pathic and inflammatory pain. The effects of Compounds recognized by BCRP, such as pain-induced activation of spinal neurons, as the drug, URB937, were lost in mice lacking URB937, are extruded from the brain by indicated by c-Fos staining. FAAH or the CB1 receptor. Compounds that active transport from the cerebrospinal fluid The anandamide-elevating effects of URB937 block CB1 receptor function also blocked the to the peripheral circulation. Thus, peripheral were lost in gene-targeted mice lacking FAAH. URB937 analgesic actions, whereas drugs that administration of URB937 elevated anan- CB1 endocannabinoid receptors were neces- damide in peripheral organs, but not in the sary for the analgesic effects of the com- The author is at the Laboratory for Integrative CNS (Fig. 1). Drug administration reduced pound. Notably, URB937 did not alter tissue Neuroscience, National Institute on Alcohol Abuse nociception in rat and mouse tests involving levels of the other major endocannabinoid, and Alcoholism, Bethesda, Maryland, USA. peripheral nerve injury and inflammation, 2- arachidonoyl glycerol (2-AG). Other FAAH e-mail: [email protected] including peripheral weak acid injection, metabolites such as palmitoyl ethanolamide NATURE NEUROSCIENCE VOLUME 13 | NUMBER 10 | OCTOBER 2010 1155 NEWS AND VIEWS did not appear to mediate the analgesic effects excitability and neurotransmitter release. It will side effects. However, targeting the anand- of this drug. Thus, the mechanism of drug be interesting to see whether the CB1 receptors amide degrading enzyme may provide more action is via anandamide actions on peripheral responsible for anandamide control of pain act specificity and fewer side effects in com- CB1 receptors. This raises questions regarding at peripheral nerve endings and, if so, what parison to cannabinoid receptor agonists. the relative roles of anandamide and 2-AG in molecular targets and other neurotransmitters Previously, it was noted that endocannabi- peripheral analgesic actions that will no doubt are implicated in these analgesic actions. noids were elevated locally by inflammatory/ be addressed in future experiments, possibly Other recent reports have also highlighted painful stimuli3. Thus, inhibiting FAAH may through the use of peripherally restricted the potential therapeutic usefulness of drugs predominantly affect endocannabinoid/CB1 inhibitors of the 2-AG degrading enzymes targeting the peripheral endocannabinoid sys- signaling in affected regions, avoiding wide- MAGL or ABDH6 (refs. 5,6). It is interest- tem7. For example, CB1 antagonists are known spread effects produced by activation of all ing that elimination of the FAAH enzyme in to reduce weight via effects on eating behavior peripheral cannabinoid receptors. gene-targeted mice did not produce an analge- and peripheral metabolism8,9. Indeed, the CB1 Ultimately, clinical studies of safety and effi- sic effect similar to FAAH inhibitors, whereas antagonist rimonabant that acts both peripher- cacy will be needed to assess the usefulness the antinociceptive actions of URB937 did not ally and centrally was developed for treatment of the peripherally targeted FAAH inhibitor. diminish after 7 d of drug treatment. These of obesity and metabolic syndrome, but its use For now, Clapper et al.4 have found that anan- findings indicate that compensation for loss was quickly discontinued as a result of side damide participates in important antinocicep- of FAAH activity can occur, but perhaps only effects likely arising from CNS drug actions10, tive actions in the PNS. when the enzyme is out of commission for highlighting the need for peripherally re stricted COMPETING FINANCIAL INTERESTS prolonged periods or early in development. endocannabinoid-targeted drugs. A recent The author declares no competing financial interests. This bodes well for use of peripheral FAAH study11 found that a peripherally restricted inhibitors in pain management, at least with CB1 antagonist reduced untoward metabolic 1. Calignano, A., La Rana, G., Giuffrida, A. & Piomelli, D. Nature 394, 277–281 (1998). relatively short-term treatment. However, effects of obesity, suggesting another use for 2. Walker, J.M. & Hohmann, A.G. Handb. Exp. Pharmacol. more extensive testing will be necessary to peripherally restricted drugs targeting the 168, 509–554 (2005). determine whether the inhibitor is effective endocannabinoid system. Particularly rel- 3. Agarwal, N. et al. Nat. Neurosci. 10, 870–879 4 (2007). with prolonged exposure. evant to Clapper et al. is a recent preliminary 4. Clapper, J.R. et al. Nat. Neurosci. 13, 1265–1270 Additional studies will also be needed to report that peripherally active cannabinoid (2010). identify the site and mechanisms of the periph- receptor agonists do not reduce acute pain in 5. Marrs, W.R. et al. Nat. Neurosci. 13, 951–957 (2010). eral URB937 analgesic actions. Although the humans with chronic lower back pain, while 6. Kinsey, S.G. et al. J. Pharmacol. Exp. Ther. 330, authors suggest that spinal mechanisms con- some weight gain and metabolic side effects 902–910 (2009). tribute to the antinociceptive effects, the initial were observed12. These findings suggest that 7. Kunos, G., Osei-Hyiaman, D.,
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