Also consistent with past work , ART side-effect severity was significantly negatively associated with ART adherence, as measured by pill counts. In addition to the severity of distress , the degree to which one is able and/or willing to tolerate such distress appears to be further influencing ART medication adherence and viral load status in our sample. Contrary to expectation, no significant relations emerged between distress tolerance measures and CD4 cell counts. The most likely explanation for this null finding is that CD4 cell count is a measure of immune function, sensitive to a host of factors affecting the immune system beyond adherence and response to ART . In concert with this explanation, Ironson et al. found that ART medication adherence was significantly related to viral load changes over time, but not to CD4 cell count changes. Indeed, once patients have started ART, clinical guidelines recommend using viral load as the key biomarker for detecting timely changes in HIV disease progression as viral load may be more immediately responsive to ART than CD4 cell count . In light of these measurement limitations, it is not surprising that psychological measures were not significantly associated with CD4 cell counts. We also found that different measures/aspects of distress tolerance predicted different measures of ART adherence. Perceived capacity or willingness to tolerate affective distress and greater task persistence in the face of distress were related to better ART adherence and viral load, respectively.
Although only replication in future work would determine whether the observed differential associations remain,indoor farming equipment one potential explanation for the observed associations could relate to measurement type/error. Indeed, one could argue that task persistence and viral load are both objective measures with little room for individual error, while self-reported distress tolerance and pill count adherence are more likely subject to individual-level factors and influence . The association between task persistence and viral load also makes conceptual sense as viral load is a reflection of ART response and adherence over a longer duration , which is functionally similar to the MTPT-C, which involves persistence in an effortful task while distressed/frustrated. The lack of relation between MTPT-C and pill count adherence indicates that pill count adherence does not serve as an indirect pathway between MTPT-C persistence and viral load. However, research indicates other potential pathways that might help explain the association between MTPT-C task persistence and viral load, such as problematic substance use. Indeed, substance dependence has been closely linked to both persistence on the MTPT-C , as well as higher viral load . Though the present cross-sectional data do not allow for the examination of these hypothesized temporal associations, future work would benefit from the prospective examination of substance dependence as a potential mediator of the association between distress intolerance, as indexed by the MTPT-C, and heightened viral load. It is important to also note that, consistent with prior studies , we observed self-report distress tolerance not to be significantly associated with the employed behavioral measure of distress tolerance . Here, the contexts in which the two forms of distress tolerance were assessed differ. The behavioral persistence measure was administered in the presence of induced distress; whereas perceived distress tolerance was not.
Moreover, the perceived inability to handle distress is defined as a cognitive factor, broadly, whereas task persistence in the face of distress is defined behaviorally . The absence of significant associations between perceived and objective distress tolerance may be in part due to the different types of distress and measurement contexts . In addition, the measurement of perceived distress tolerance relies on self-report, which presents a challenge because of the difficulty participants have in accurately reflecting upon and discriminating their sensitivity to distress from their tolerance of distress . Indeed, a strength of this study is that the multi-method approach precludes limitations of shared method variance and difficulty in accurately self-reporting by employing a behavioral and self-report measure of distress tolerance. Our findings are largely consistent with past work in the areas of ART adherence and distress tolerance, and underscore the clinically relevant role of distress tolerance in models of adherence and disease status among HIV+ patients. As has been initially shown to be effective among substance-using populations and early-lapse smokers , future interventions for individuals with HIV may benefit from specifically targeting ability/ willingness to tolerate distress through cognitive behavioral treatment approaches so that individuals may remain adherent in the face of treatment related burdens. This intervention development approach is in line with recent endeavors to enhance the impact of CBT for improving ART adherence by treating comorbid depression , and with Blashill and colleagues’ suggestion to develop combination interventions for other psychosocial problems among individuals living with HIV. Yet, our conceptualization of transdiagnostic psychological vulnerability factors, such as distress tolerance, may offer a more parsimonious approach for addressing psychosocial comorbidities.
Although there has been much work developing and testing CBT interventions for promoting ART adherence, there is still room for improvement because traditional multi-component CBT interventions for ART adherence result in small to medium effect sizes . Overall, the current study extends the literature on distress intolerance as a psychological vulnerability factor among people living with HIV. However, there are some limitations that provide opportunities for future research. First, the present study was cross-sectional, limiting inferences that can be made about directionality. Indeed, it is just as likely that low levels of distress tolerance lead to poor adherence as it is that poor adherence is prospectively associated with low levels of distress tolerance. This may be particularly relevant among immuno compromised individuals living with HIV. For instance, if poor adherence leads to an increasing viral load, then one’s immune system is mobilized to contend with the growing viral load. This is a physiological stressor and stress increases one’s drive to escape from unpleasant situations . Thus, it is feasible that stress due to immunological reactivity from an increasing viral load further limits one’s capacity to exercise tolerance of distress. It is plausible that poor adherence resulting in an increasing viral load may subsequently increase one’s vulnerability to distress intolerance. Following, as adherence was measured using pill count at only one time point, we were unable to establish a baseline level of adherence and MEMS caps would have provided a more precise indicator of adherence. Third, as mentioned earlier, though a strength of the study was the multi-method measurement of distress tolerance,hemp drying racks future work would benefit from employing additional objectives and newly refined subjective measures to better understand differential relations between multiple facets of distress tolerance and HIV adherence. Future work would also benefit from assessing tolerance of HIV symptom-related distress, specifically, and the impact of distress tolerance on other clinically relevant HIV outcomes . Finally, though the present study was quite ethnically diverse, a majority of the sample was male. Future work would benefit from recruiting a more gender-diverse sample from different geographic areas. Promoting tolerance of affective distress and distressing tasks associated with the high-adherence demands of ART for HIV management are worthwhile to consider in future research. Future investigations are needed to examine relations prospectively to identify the role of distress intolerance in the development and maintenance of poor HIV management, and then verification of clinical implications through intervention process and outcome studies.Cannabinoid receptors, the molecular targets of the active principle of cannabis 9 -tetrahydrocannabinol, are activated by a small family of naturally occurring lipids that include anandamide and 2-arachidonylglycerol . As in the case of other lipid mediators, these endogenous cannabis-like compounds may be released from cells upon demand by stimulus-dependent cleavage of membrane phospholipid precursors . After release, anandamide and 2-AG may be eliminated by a two-step mechanism consisting of carrier-mediated transport into cells followed by enzymatic hydrolysis . Because of this rapid deactivation process, the endocannabinoids may primarily act near their sites of synthesis by binding to and activating cannabinoid receptors on the surface of neighboring cells .
The development of methods for endocannabinoid analysis and the availability of selective pharmacological probes for cannabinoid receptors have allowed the exploration of the physiopathological functions served by the endocannabinoid system. Although still at their beginnings, these studies indicate that the endocannabinoids may significantly contrib-ute to the regulation of pain processing , motor activity , blood pressure , and tumor cell growth . Furthermore, these investigations point to the endocannabinoid system—with its network of endogenous ligands, receptors, and inactivating mechanisms—as a potentially important arena for drug discovery. In this context, emphasis has been especially placed on the possible roles that CB1 and CB2 receptors may play as drug targets . Here, we focus our attention on another facet of endocannabinoid pharmacology: the mechanisms by which anandamide and 2-AG are deactivated. We summarize current knowledge on how these mechanisms may function, describe pharmacological agents that interfere with their actions, and highlight the potential applications of these agents to medicine.Extracellular anandamide is rapidly recaptured by neuronal and non-neuronal cells through a mechanism that meets four key criteria of carrier mediated transport: fast rate, temperature dependence, saturability, and substrate selectivity . Importantly, and in contrast with transport systems for classical neurotransmitters, [3 H]anandamide reuptake is neither dependent on external Na ions nor affected by metabolic inhibitors, suggesting that it may be mediated by a process of carrier-facilitated diffusion . How selective is anandamide reuptake? Cis-inhibition studies in a human astrocytoma cell line have shown that [ 3 H]anandamide accumulation is not affected by a variety of amino acid transmitters or biogenic amines . Furthermore, [3 H]anandamide reuptake is not prevented by fatty acids , neutral lipids , saturated fatty acyl ethanolamides , prostaglandins, leukotrienes, hydroxyeicosatetraenoic acids, and epoxyeicosatetraenoic acids. Even further, [ 3 H]anandamide accumulation is insensitive to substrates or inhibitors of fatty acid transport , organic anion transport , and P-glycoproteins . By contrast, in the same cells, [3 H]anandamide reuptake is competitively blocked by either of the two endogenous cannabinoids, anandamide or 2-AG . Similar selectivity profiles are observed in primary cultures of rat cortical neurons or astrocytes and rat brain slices . The fact that both anandamide and 2-AG prevent [ 3 H]anandamide transport in cis-inhibition studies suggests that the two compounds compete for the same transport system. This possibility is further supported by three observations: 1) anandamide and 2-AG can mutually displace each other’s transport ; 2) [3 H]anandamide and [3 H]2-AG are accumulated with similar kineticproperties ; and 3) the transports of both compounds are prevented by the endocannabinoid transport inhibitor, N–arachidonylamide. Together, these findings indicate that anandamide and 2-AG may be internalized via a common carrier-mediated process, which displays a substantial degree of substrate and inhibitor selectivity. The molecular structure of this hypothetical transporter remains, however, unknown. Structure-Activity Relationship Studies. The structures of anandamide and 2-AG contain three potential pharmacophores: 1) the hydrophobic carbon chain; 2) the carboxamido/carboxyester group; and 3) the polar head group . Systematic modifications in the carbon chain suggest that the structural requisites for substrate recognition by the putative endocannabinoid transporter may be different from those of substrate translocation. Substrate recognition appears to require the presence of at least one cis double bond in the middle of the fatty acid chain, indicating a preference for substrates whose hydrophobic tail can adopt an extended U-shaped conformation. By contrast, a minimum of four cis non-conjugated double bonds may be required for translocation, suggesting that substrates need to adopt a closed “hairpin” conformation to be transported across the membrane . In agreement with this hypothesis, molecular modeling studies show that transport substrates have both extended and hairpin low-energy conformers . By contrast, extended, but not hairpin, conformations may be thermodynamically favored in pseudosubstrates such as oleylethanolamide , that displace [3 H]anandamide from transport without being themselves internalized . The impact that modifications of the polar head group exert on endocannabinoid transport has also been investigated . The available data suggest that ligand recognition may be favored 1) by a head group of defined stereochemical configuration containing a hydroxyl moiety at its distal end; and 2) by replacing the ethanolamine group with a 4-hydroxyphenyl or 2-hydroxyphenyl moiety. The latter modification leads to compounds, such as AM404 , that are competitive transport inhibitors of reasonable potency and efficacy .Distribution of Endocannabinoid Transport in the CNS.