Pain modulation by release of the endogenous cannabinoid anandamide

Abstract

Synthetic cannabinoids produce behavioral analgesia and suppress pain neurotransmission, raising the possibility that endogenous cannabinoids serve naturally to modulate pain. Here, the development of a sensitive method for measuring cannabinoids by atmospheric pressure-chemical ionization mass spectrometry permitted measurement of the release of the endogenous cannabinoid anandamide in the periaqueductal gray (PAG) by in vivo microdialysis in the rat. Electrical stimulation of the dorsal and lateral PAG produced CB1 cannabinoid receptor-mediated analgesia accompanied by a marked increase in the release of anandamide in the PAG, suggesting that endogenous anandamide mediates the behavioral analgesia. Furthermore, pain triggered by subcutaneous injections of the chemical irritant formalin substantially increased the release of anandamide in the PAG. These findings indicate that the endogenous cannabinoid anandamide plays an important role in a cannabinergic pain-suppression system existing within the dorsal and lateral PAG. The existence of a cannabinergic pain-modulatory system may have relevance for the treatment of pain, particularly in instances where opiates are ineffective.analgesia ͉ periaqueductal gray ͉ microdialysis ͉ gas chromatography ͉ mass spectrometry T he components of an elaborate neural system that serves naturally to modulate pain sensitivity have been detailed by Liebeskind and subsequent workers (1, 2). These early studies revealed that electrical stimulation of the periaqueductal gray (PAG) produces analgesia, demonstrating the presence of an analgesia circuit in the brain (1). When elicited from the ventral portion of the PAG, this electrical stimulation-produced analgesia (SPA) is mediated by the release of endogenous opiates (3). However, when elicited from the dorsal or lateral part of the PAG, the analgesic effect of stimulation is mediated by unidentified nonopiate substances (4).Among the prime candidates for these unknown pain modulatory substances are endogenous cannabinoids-compounds similar to the active ingredient in marijuana. Cannabinoids produce analgesia (5) and dampen the spinal and thalamic neuronal responses to noxious stimuli (6, 7). In attempting to understand the neural basis of cannabinoid analgesia, the PAG was a brain region of interest because of its established role in pain-modulation (8) and the presence of the necessary biological machinery for cannabinoid action (9-12). Like opiates, cannabinoids produce analgesia when microinjected in the PAG (13). However, the anatomical subregions of the PAG that support cannabinoid analgesia were the inverse of those supporting morphine analgesia and opiate-mediated SPA (4, 13, 14): cannabinoids were effective in the dorsal and lateral but not the ventral PAG. These findings led us to speculate that endogenous cannabinoids in the dorsal and lateral PAG may be an important component of the nonopiate analgesia system identified earlier. Herein, we show that electrical stimulation of the dorsal and lateral PAG and the dorsal ad...

The elmiric acids: Biologically active anandamide analogs

“…Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Prior reports (Burstein et al 1997;Huang et al, 2001), suggest that NAGly might have analgesic properties similar to those reported for anandamide (Pertwee, 2001;Walker et al, 1999) but would be inactive in assays for psychotropic action such as the "ring test (Pertwee, 1972). The latter was in agreement with a report showing a lack of affinity by NAGly for the cannabinoid receptor, CB1 (Sheskin et al, 1997).…”

Glutamate Spillover Modulates GABAergic Synaptic Transmission in the Rat Midbrain Periaqueductal Grey via Metabotropic Glutamate Receptors and Endocannabinoid Signaling

“…In addition, group I mGluR activation initiates 2-AG biosynthesis (Jung et al, 2005) and endocannabinoid-mediated synaptic plasticity in several other brain regions (Ohno-Shosaku et al, 2002;Zhu and Lovinger, 2005;Grueter et al, 2006;Centonze et al, 2007;Uchigashima et al, 2007). In the present study, we have not identified the endocannabinoid involved; however, anandamide and 2-AG are potential candidates, because they are both produced within the PAG under certain conditions (Walker et al, 1999;Hohmann et al, 2005).…”

Endocannabinoid system and pain: an introduction

“…Later work revealed the role of endogenous ligands by demonstrating mobilisation of AEA (108) , and CB 1 -mediated antinociception, following either electrical stimulation of these regions or a peripheral administration of formalin (109) . Enhancing AEA signalling in these areas via inhibition of FAAH activity is anti-nociceptive in acute pain (110) , probably via disinhibition of descending inhibitory inputs from the brainstem to the spinal cord, inhibiting spinal nociceptive signalling (for a review of the pathways involved, see (38)(39)(40) ).…”