Abstract:
:Cannabinoid ligands have been shown to be anti-nociceptive in animal models of acute and chronic pain by acting at the two known cannabinoid receptors, cannabinoid-1 receptor (CB-1) and cannabinoid-2 receptor (CB-2). A major concern with the use of cannabinoids for pain relief is that they activate receptors at sites other than those involved in the transmission of nociceptive stimuli. An alternative approach is to target the naturally occurring endocannabinoids, such as anandamide (AEA), 2-arachidonylglycerol (2-AG) and N-arachidonylglycine (N-AG). However in vivo results obtained with these compounds appear to be weak, most probably due to their rapid degradation and subsequent short half-life. The predominant enzyme responsible for the hydrolysis of anandamide (and some other endocannabinoids) in the brain is fatty acid amide hydrolase (FAAH). Recently, the alpha-ketoheterocycle OL135 has been synthesized and shown to be a highly potent and selective inhibitor of FAAH with efficacy in pain models in vivo. In the present study, we have adapted the mild thermal injury (MTI) model of acute pain for the mouse and pharmacologically characterized this model by showing significant reversal of the tactile allodynia by morphine (3, 5 and 10 mg kg(-1) s.c.), gabapentin (100 and 300 mg kg(-1) i.p.), ibuprofen (100 mg kg(-1) i.p.) and OL135 (10, 30 and 100 mg kg(-1) i.p.). Furthermore we have demonstrated, using this model, that a subtherapeutic dose of OL135 can enable the endocannabinoids AEA and 2-AG, but not N-AG to be active at doses where they are otherwise nonanalgesic (20 mg kg(-1) i.p.). The implications of this model in the study of pain in mice, and the therapeutic potential of FAAH inhibition to provide analgesia without the undesirable side effects of direct agonism of cannabinoid receptors are discussed.
journal_name
Neurosciencejournal_title
Neuroscienceauthors
Palmer JA,Higuera ES,Chang L,Chaplan SRdoi
10.1016/j.neuroscience.2008.04.047subject
Has Abstractpub_date
2008-07-17 00:00:00pages
1554-61issue
4eissn
0306-4522issn
1873-7544pii
S0306-4522(08)00650-7journal_volume
154pub_type
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