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New disease paradigm: CECD

Posted by Larry Hoover on August 15, 2004, at 10:35:10

A little background....

We all know that marijuana is psychoactive, and that the principle active ingredient is THC. In our typically arrogant manner, we identified two types of "cannabis" receptors, and only later did we begin to identify what they really do. It seems there is a whole new realm of neuromodulation opening up to researcher's probing minds, and the first endogenous (coming from our own body's chemistry) ligand (the thing that is meant to bind to the receptor) identified is called anandamide (ananda is Sanskrit for "bliss"...thanks, jimi). There are likely to be many other natural ligands, and other forms of the receptor (two known already). There are huge numbers of recent research reports in Pubmed, but I've pulled a couple of them that are probably not too "big-worded" that you can't get the idea.


Neuro Endocrinol Lett. 2004 Feb-Apr;25(1-2):31-9.

Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions?

Russo EB.

GW Pharmaceuticals, 2235 Wylie Avenue, Missoula, MT 59802, USA.

OBJECTIVES: This study examines the concept of clinical endocannabinoid deficiency (CECD), and the prospect that it could underlie the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome, and other functional conditions alleviated by clinical cannabis. METHODS: Available literature was reviewed, and literature searches pursued via the National Library of Medicine database and other resources. RESULTS: Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging. CONCLUSION: Migraine, fibromyalgia, IBS and related conditions display common clinical, biochemical and pathophysiological patterns that suggest an underlying clinical endocannabinoid deficiency that may be suitably treated with cannabinoid medicines.

J Pharmacol Exp Ther. 2004 Jun 30 [Epub ahead of print]

Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: evidence for an unprecedented combination of potency and selectivity.

Lichtman AH, Leung D, Shelton C, Saghatelian A, Hardouin C, Boger D, Cravatt BF.

Virginia Commonwealth University.

Fatty acid amide hydrolase (FAAH) is the primary catabolic regulator of several bioactive lipid amides in vivo, including the endogenous cannabinoid anandamide and the sleep-inducing substance oleamide. Accordingly, inhibitors of FAAH are considered a potential therapeutic approach for the treatment of several nervous system disorders, including pain, anxiety, and insomnia. However, for FAAH inhibitors to achieve clinical utility, they must not only display efficacy in vivo, but also selectivity for this enzyme relative to the numerous other serine hydrolases present in mammalian proteomes. Here, we report a general strategy for evaluating the pharmacological activity and target specificity of FAAH inhibitors and its implementation to develop the first class of selective reversible inhibitors of this enzyme that are highly efficacious in vivo. Using a series of functional proteomics, analytical chemistry, and behavioral pharmacology assays, we have identified a class of alpha-keto-heterocycles that show unprecedented selectivity for FAAH relative to other mammalian hydrolases, and, when administered to rodents, raise central nervous system levels of anandamide and promote cannabinoid receptor 1-dependent analgesia in several assays of pain sensation. These studies provide further evidence that FAAH may represent an attractive therapeutic target and describe a general route by which inhibitors of this enzyme can be optimized to achieve exceptional potency, selectivity, and efficacy in vivo.




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