Abstract
Recent work in our laboratories has demonstrated that an opioid-independent form of stress-induced analgesia (SIA) is mediated by endogenous cannabinoids [Hohmann et al., 2005. Nature 435, 1108]. Non-opioid SIA, induced by a 3-min continuous foot shock, is characterized by the mobilization of two endocannabinoid lipids—2-arachidonoylglycerol (2-AG) and anandamide—in the midbrain periaqueductal gray (PAG). The present studies were conducted to examine the contributions of spinal endocannabinoids to nonopioid SIA. Time-dependent increases in levels of 2-AG, but not anandamide, were observed in lumbar spinal cord extracts derived from shocked relative to non-shocked rats. Notably, 2-AG accumulation was of smaller magnitude than that observed previously in the dorsal midbrain following foot shock. 2-AG is preferentially degraded by monoacylglycerol lipase (MGL), whereas anandamide is hydrolyzed primarily by fatty-acid amide hydrolase (FAAH). This metabolic segregation enabled us to manipulate endocannabinoid tone at the spinal level to further evaluate the roles of 2-AG and anandamide in nonopioid SIA. Intrathecal administration of the competitive CB 1 antagonist SR141716A (rimonabant) failed to suppress nonopioid SIA, suggesting that supraspinal rather than spinal CB 1 receptor activation plays a pivotal role in endocannabinoid-mediated SIA. By contrast, spinal inhibition of MGL using URB602, which selectively inhibits 2-AG hydrolysis in the PAG, enhanced SIA through a CB 1-selective mechanism. Spinal inhibition of FAAH, with either URB597 or arachidonoyl serotonin (AA-5-HT), also enhanced SIA through a CB 1-mediated mechanism, presumably by increasing accumulation of tonically released anandamide. Our results suggest that endocannabinoids in the spinal cord regulate, but do not mediate, nonopioid SIA.
Highlights
Stress-induced analgesia (SIA) is mediated by the activation of endogenous pain inhibitory systems
To determine whether endocannabinoid release participates in non-opioid SIA, we analyzed 2-AG and anandamide levels in the lumbar spinal cords of rats killed before or at various times after foot shock using liquid chromatography/mass spectrometry (LC/MS)
Anandamide levels in the lumbar spinal cords of rats subjected to foot shock did not differ reliably from controls
Summary
Stress-induced analgesia (SIA) is mediated by the activation of endogenous pain inhibitory systems. Both opioiddependent and opioid-independent forms of SIA have been identified (see Akil et al, 1986 for review). These mechanisms are differentially activated according to stressor parameters and duration (Lewis et al, 1980a,b). SIA elicited by Opioid and nonopioid SIA share similar neuroanatomical substrates. Opioid and cannabinoid receptors populate brain regions regulating nociceptive responding, such as the periaqueductal gray (PAG) (Martin et al, 1995; Lichtman et al, 1996) and the raphe nuclei of the medulla.
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