These lipids are synthesized and released on-demand, activate cannabinoid CB1 receptors with high affinity, and are metabolized in vivo by distinct hydrolytic pathways. Within the CNS, 2-AG is present in quantities 170e1000 times greater those of anandamide . 2-AG serves as a full agonist at CB1 and CB2 , whereas anandamide is less efficacious . 2-AG is preferentially degraded by monoacylglycerol lipase , whereas anandamide is preferentially hydrolyzed by fatty-acid amide hydrolase . Mutant mice lacking the FAAH gene are impaired in their ability to degrade anandamide and display reduced pain sensation that is reversed by the CB1 antagonist rimonabant . Immunocytochemical studies have revealed a heterogeneous distribution of FAAH throughout the brain and moderate staining of FAAH-positive cells in the superficial dorsal horn of the spinal cord . In brain, the regional distribution of MGL partially overlaps with that of the CB1 receptor . Inhibition of MGL in the midbrain PAG increases 2-AG accumulation and enhances SIA in a CB1-dependent manner , supporting a physiological role for 2-AG in neural signaling. Thus, the anatomical distributions of FAAH and MGL are consistent with a role for these enzymes in terminating the activity of endocannabinoids. The present studies were conducted to investigate the contribution of endocannabinoids acting at spinal CB1 receptors to nonopioid SIA. We used high-performance liquid chromatography/mass spectrometry to examine the contribution of 2-AG and anandamide at the spinal level to SIA. We examined the time-course of changes in endocannabinoid levels in the lumbar spinal cord of control rats and rats subjected to foot shock stress. Moreover, we used selective inhibitors of MGL and FAAH to further elucidate the roles of these endocannabinoids in SIA. We additionally evaluated effects of intrathecal administration of arachidonoylserotonin ,vertical cannabis farm a FAAH inhibitor that is inactive at phospholipase A2 and CB1 receptors, on SIA. We hypothesized that intrathecal administration of these inhibitors would potentiate nonopioid SIA via a CB1 mechanism. Preliminary results have been reported .

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 LC/MS. Example chromatograms show the coelution of endogenous 2-AG and anandamide with synthetic standards . ANOVA revealed time-dependent changes in 2-AG levels derived from lumbar spinal cord extracts of shocked rats relative to non-shocked rats [F ¼ 21.106, P < 0.001] . Post hoc analyses confirmed that 2-AG levels were significantly increased in rats killed at 2 min post shock and decreased at subsequent time points . By contrast, anandamide levels in the lumbar spinal cords of rats subjected to foot shock did not differ reliably from controls. Planned comparisons failed to reveal a significant elevation in anandamide levels at either 2 min or 5 min post shock . Foot shock also failed to alter either 2-AG or anandamide levels in tissues derived from the occipital cortex , an area enriched in cannabinoid CB1 receptors but not implicated in SIA. A significant correlation was observed between SIA and post-shock levels of 2-AG , but not anandamide , in the lumbar spinal cord over the same interval .We have previously demonstrated that nonopioid SIA is mediated by mobilization of two endocannabinoids, 2-AG and anandamide, in the midbrain PAG . The present results extend those findings and suggest that endocannabinoid actions at spinal CB1 receptors modulate SIA. Foot shock stress induced time-dependent changes in thefindings is that inhibition of MGL or FAAH prevented the deactivation of spinal 2-AG and anandamide, respectively, magnifying nonopioid SIA. Thus, our findings suggest that spinal endocannabinoids regulate, but do not mediate, nonopioid SIA. It is possible that the placement of chronic indwelling intrathecal catheters elevated anandamide levels in the behavioral studies, and that this change in endocannabinoid tone was augmented by the FAAH inhibitors. However, changes in endocannabinoid tone due to catheter placement appear unlikely because intrathecal rimonabant administration did not alter tail-flick latencies in the presence or absence of foot shock. Moreover, Fos immunocytochemical studies suggest that spinal compression induced by catheter placement does not induce appreciable neuronal activation .

Electrophysiological studies have provided evidence both for and against the existence of a tonic endocannabinoid tone at the spinal level. However, in our study, intrathecal rimonabant administration failed to suppress either basal nociceptive thresholds or nonopioid SIA. Hyperalgesic effects of spinal rimonabant may reflect sensitivity of supraspinally-organized relative to spinally organized pain behaviors in measuring lowered nociceptive thresholds. It is also possible that exposure to uncontrolled stress mobilizes endocannabinoids in behavioral studies , thereby resulting in a CB1-dependent apparent hyperalgesia. Although high doses of anandamide activate transient receptor potential vanilloid 1 , several observations suggest that this mechanism is not responsible for the enhancements of SIA observed here. First, systemic administration of the TRPV1 antagonist capsazepine, at a dose that completely blocks capsaicin-induced antinociception, does not alter nonopioid SIA in our paradigm . Second, CB1 and TRPV1 show minimal colocalization at the axonal level in the spinal cord, with CB1 localized predominantly to laminae I and II interneurons and TRPV1 localized primarily to nociceptive primary afferent terminals . Third, anandamide activation of CB1 and TRPV1 typically induces opposing effects with distinct time courses . However, we observed only enhancementsdnot attenuationdof SIA following intrathecal administration of FAAH inhibitors and no change in SIA following antagonist treatment. Fourth, rimonabant completely blocked the potentiation of SIA induced by intrathecal administration of inhibitors of MGL or FAAH, at doses that were insuffificient to reverse SIA when administered alone. Together, these observations suggest that anandamide acts through CB1 rather than TRPV1 at the spinal level to modulate SIA. The foot shock-induced increases in 2-AG levels were smaller than those observed previously in the dorsal midbrain of the same subjects .

This observation is consistent with the inability of spinally administered rimonabant to block nonopioid SIA. By contrast, a tenfold lower dose of rimonabant produced a robust suppression of SIA when micro-injected into the dorsolateral PAG. Our results collectively suggest that supraspinal sites of action play a pivotal role in endocannabinoid-mediated SIA. Our data suggest that spinal inhibition of MGL prolongs the duration of action of 2-AG, thereby enhancing endocannabinoid tone at spinal CB1 receptors to magnify SIA. This enhancement occurred in the absence of reliable changes in spinal anandamide levels. Thus, the antinociceptive effects of MGL inhibitors are not dependent upon concurrent elevations in anandamide that were induced in the midbrain PAG following exposure to the same stressor.However, foot shock did not reliably increase spinal anandamide levels. Our failure to observe enhancements in anandamide accumulation may reflect lower absolute levels of anandamide relative to 2-AG and consequently higher variability in these measurements. Our data are consistent with the ability of FAAH inhibitors to selectively enhance accumulation of anandamide, but not 2-AG . FAAH may regulate both the distance endocannabinoids diffuse to engage CB1 receptors and the duration of endocannabinoid actions to increase accumulation of tonically released anandamide. It is also possible that the extent of on-demand anandamide synthesis may be underestimated in the present work due to the rapid metabolism of this lipid by FAAH. Mapping the distribution of MGL, FAAH and CB1 in the spinal cord could further elucidate the anatomical and functional relationship between cells that degrade 2-AG and those expressing CB1. Cannabinoid receptor agonists such as D9 -tetrahydrocannabinol have limited therapeutic applications at present, mainly because of their undesirable psychoactive effects. However, pharmacological agents that protect endocannabinoids such as 2-AG and anandamide from inactivation may lead to a more circumscribed spectrum of physiological responses than those produced by direct cannabinoid agonists. Ideally,vertical farming growing racks this strategy would enhance endocannabinoid activity only at sites with on-going biosynthesis and release, thereby averting undesirable side effects. The possible use of drugs that inhibit endocannabinoid hydrolysis to treat pain in humans has thus propagated both hope and concern . FAAH is widely distributed throughout the body and implicated in the metabolism of a variety of anandamide analogues . Our data demonstrate that local enhancements of endocannabinoid actions at the spinal level are sufficient to potentiate SIA. Additional experiments will be necessary to determine whether inhibitors of endocannabinoid degradation may find therapeutic applications in the treatment of pain and stress-related disorders.Self-cutting can be understood clinically as a symptomatic behavior, on the one hand, and as a bodily practice embedded in a cultural imaginary and identity on the other. It is present in a variety of ways including the 1993 memoir of Susanna Kaysen “Girl, Interrupted” , the 1995 acknowledgment by Princess Diana that she identified herself as a “cutter,” and the 2011 video “F**kin’ Perfect” by the pop music performer Pink. The Internet has become a massively popular resource for cutters to share information , and one study identified more than 400 message boards about cutting generated via five search engines . Youths may identify with “Emo” or “Goth” culture which lionize depression and cultivate self-cutting as a cultural practice . Popular concern about perceived dangers of self-cutting has at times been heightened to the point that one cultural historian suggested that “Cutting has become a new moral panic about the dangers confronting today’s youth” .

Anthropology has not been disposed toward addressing cutting as a problematic cultural or clinical phenomenon given the disciplinary propensity to understand body mutilation and modification in terms of rituals and cultural practices. This is perhaps because ritual meaning is not so dependent on distinguishing whether harm is inflicted by others or by oneself or on differentiating cultural practice from psychopathology.One other anthropological observation has been provided by Lester, who notes that current explanations of self-harm can be grouped into four categories: communicating emotional pain, emotional or physiological self-regulation, interpersonal strategy, and cultural trend. She notes that these categories share the idea that self-harm manifests individual pathology or dysfunction, with the cultural assumption of the individual as a rational actor. In contrast, an anthropological perspective emphasizes the “cultural actor who embodies and responds to cultural systems of meaning to internal psychological or physiological states” . Emphasizing the powerful symbolic significance and long cross-cultural record of self-harm and blood shedding as ritual and even therapeutic practices, she suggests that contemporary cutting may be seen as privatized and decontextualized social rituals affecting transformation parallel to collective initiation rituals that operate in a cycle of self-harm and repair, especially in the case of adolescent girls struggling with the aftermath of sexual abuse and/or with contradictory gender messages . Sociocultural characteristics of a typical “self-cutter” emerged in the 1960s as Euro-American, attractive, intelligent, and possibly sexually adventurous teenage girls, that Brickman claimed was partially taken up in medical discourse in a manner that “pathologizes the female body, relying on the notion of ‘femininity as a disease’” . Gilman took exception to assumptions of pathology with the provocative claim that “self-cutting is a reasonable response to an irrational world” . From a clinical vantage point, self-cutting is often viewed as a type of injury or harm to the self. The historical backdrop to this development can be traced to Menninger’s attention to self-mutilation as distinguished from suicidality. The distinction between “delicate” and “coarse” self-cutting was made by Pao , with Weissman focusing on wrist-cutting syndrome and Pattison and Kahan proposing the existence of a deliberate self-harm syndrome. Favazza provided cases of extreme and highly unusual forms of self-mutilation in excruciating detail, with an attempt to classify types based on severity. With the provisional emergence of nonsuicidal self-injury disorder criteria in the fifth version of the Statistical and Diagnostic Manual of Mental Disorders DSM-V ,1 the distinction between self-harm as within a normative or pathological range remains equivocal. This is illustrative of the manner in which conceptualizations of self-cutting continue to be embedded in a complex cultural history of changes in the incidence, popular awareness, and social conditions in which such phenomena occur.While it is possible to find clinical, psychometric, survey, and historical approaches to the phenomenon of self-cutting, we lack an ethnographic account with a substantive locus in the interactions of individuals, grounded in the specificity of bodily experience and the immediacy of struggle in the face of existential precarity . In this article, we take a step toward such an account with a discussion situated at the intersection of two anthropological concerns. First is the ethnographic understanding of experiential specificity through anthropological adaptation of phenomenological method .