Targeting the endocannabinoid system to reduce nociception

Pain of various etiologies (e.g., visceral, inflammatory) can be a debilitating disorder that presents a problem of clinical relevance. While it is known that ∆9-tetrahydrocannabinol (THC) the primary psychoactive constituent found in marijuana produces analgesia in various rodent models of pain, its pharmacological properties are overshadowed by its psychomimetic effects. THC is the primary phytocannabinoid found in marijuana though other prevalent constituents such as the phytocannabinoids (e.g., cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), tetrahydrocannabivarin (THCV)) may possess antinociceptive actions without the psychomimetic effects associated with THC. Indeed, these phytocannabinoids act upon the endocannabinoid system (ECS) that is comprised of the CB1 and CB2 cannabinoid receptors, endogenous ligands (anandamide (AEA), 2-arachidonoyolglycerol (2-AG)), and endocannabinoid biosynthetic and catabolic enzymes. We hypothesize that phytocannabinoids as well as endocannabinoid catabolic enzyme inhibitors reduce nociception preclinical models of pain. In the first series of studies, the antinociceptive effects of prevalent phytocannabinoids were evaluated in the acetic acid stretching test, a rodent visceral pain model. While CBN and THC both produced antinociceptive effects via a CB1 mechanism of action, CBC, and CBD had no effect on nociception. Conversely, THCV antagonized the antinociceptive effects of THC. These results suggest that various constituents of marijuana may interact in a complex manner to modulate pain. Since the THC and CBN displayed their effects via specific endogenous cannabinoid receptors, we investigated whether increasing endocannabinoids block nociceptive behavior. Blockade of the catabolic enzyme fatty acid amide hydrolase (FAAH) elevates AEA levels and elicits antinociceptive effects, without psychomimetic issues associated with THC. Similarly, blockade of another endocannabinoid catabolic enzyme monoacylglycerol lipase (MAGL) elevates (2-AG) and elicits antinociceptive effects. Therefore, we tested the hypothesis that FAAH and/or MAGL inhibition blocks nociception in the acetic acid abdominal stretching model, and the LPS-induced allodynia (i.e. painful response to a non-noxious stimuli) model of inflammation. Genetic deletion or pharmacological blockade of FAAH or pharmacological blockade of MAGL significantly reduced the total number of abdominal stretches in the visceral pain model. Additionally, blockade of both enzymes simultaneously produced an enhanced antinociceptive effect versus blocking the enzymes individually. These effects were mediated through CB1 receptors. However, in the LPS-induced allodynia model, FAAH inhibited anti-allodynic effects through a CB1 and CB2 receptor mechanismn. In both assays other potential targets of FAA substrates (i.e., mu-opioid, TRPV1, and PPAR-alpha receptors) did not play an apparent role in FAAH inhibited antinociceptive responses. Taken together, these results illustrate that targeting the endocannabinoid system via direct acting agonists such as the phytocannabinoids, or indirect methods (i.e. inhibiting degradative enzymes of the endogenous cannabinoids), represents a promising strategy to treat pain

On white-collar boxing and social class

This article is based on the first sociological research of white-collar boxing in the UK. Grounded in an ethnography of a boxing gym in the Midlands, the article argues that the term ‘white-collar boxing’ in this context is immediately misleading, and entails the term being used in a way with which sociologists are unaccustomed. Whereas white-collar boxing originated in the context of post-industrial New York City as a pastime only for the extremely wealthy, the situation in the UK is different. Participants actively reject this understanding of white-collar boxing. The term white-collar boxing does not signify the social class of participants, but refers to their novice status. Given that boxing is an example through which Bourdieu’s theory of distinction is discussed, and that white-collar boxing is a distinctly late-modern version of the sport containing an erroneous class signifier, this version of the sport is a site through which such discussions of consumption can be furthered. Whilst consumed by actors in various class positions, a logic of distinction is present in white-collar boxing, which becomes recognisable through analysis of the ‘plurality of consumption experiences’. This is proffered as a concept which can aid in the analysis of consumption beyond white-collar boxing

Synergy between Enzyme Inhibitors of Fatty Acid Amide Hydrolase and Cyclooxygenase in Visceral Nociception

The present study investigated whether inhibition of fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide catabolism, produces antinociception in the acetic acid-induced abdominal stretching model of visceral nociception. Genetic deletion or pharmacological inhibition of FAAH reduced acetic acid-induced abdominal stretching. Transgenic mice that express FAAH exclusively in the nervous system displayed the antinociceptive phenotype, indicating the involvement of peripheral fatty acid amides. The cannabinoid receptor 1 (CB1) receptor antagonist, rimonabant, but not the cannabinoid receptor 2 (CB2) receptor antagonist, SR144528, blocked the antinociceptive phenotype of FAAH(-/-) mice and the analgesic effects of URB597 (3′-carbamoyl-biphenyl-3-yl-cyclohexylcarbamate) or OL-135 (1-oxo-1[5-(2-pyridyl)-2-yl]-7-phenyl heptane), respective irreversible and reversible FAAH inhibitors, administered to C57BL/6 mice. The opioid receptor antagonist, naltrexone, did not block the analgesic effects of either FAAH inhibitor. URB597, ED50 [95% confidence interval (CI) = 2.1 (1.5-2.9) mg/kg], and the nonselective cyclooxygenase inhibitor, diclofenac sodium [ED50 (95% CI) = 9.8 (8.2-11.7) mg/kg], dose-dependently inhibited acetic acid-induced abdominal stretching. Combinations of URB597 and diclofenac yielded synergistic analgesic interactions according to isobolographic analysis. It is important that FAAH(-/-) mice and URB597-treated mice displayed significant reductions in the severity of gastric irritation caused by diclofenac. URB597 lost its gastroprotective effects in CB1(-/-) mice, whereas it maintained its efficacy in CB2(-/-) mice, indicating a CB1 mechanism of action. Taken together, the results of the present study suggest that FAAH represents a promising target for the treatment of visceral pain, and a combination of FAAH inhibitors and NSAIDs may have great utility to treat visceral pain, with reduced gastric toxicity

Generalized Additive Mixed-Models for Pharmacology Using Integrated Discrete Multiple Organ Co-Culture

<div><p>Integrated Discrete Multiple Organ Co-culture (IDMOC) is emerging as an in-vitro alternative to in-vivo animal models for pharmacology studies. IDMOC allows dose-response relationships to be investigated at the tissue and organoid levels, yet, these relationships often exhibit responses that are far more complex than the binary responses often measured in whole animals. To accommodate departure from binary endpoints, IDMOC requires an expansion of analytic techniques beyond simple linear probit and logistic models familiar in toxicology. IDMOC dose-responses may be measured at continuous scales, exhibit significant non-linearity such as local maxima or minima, and may include non-independent measures. Generalized additive mixed-modeling (GAMM) provides an alternative description of dose-response that relaxes assumptions of independence and linearity. We compared GAMMs to traditional linear models for describing dose-response in IDMOC pharmacology studies.</p></div

Graphic comparison of alternative models for ticlopedine dose-response.

<p>The AIC preferred model (A, <i>W</i>_<i>i</i> = 0.71) exhibits a non-linear response for both mono and co-cultured fibroblasts, while the less-preferred, yet still competitive model (B, <i>W</i>_<i>i</i> = 0.21) exhibits a linear response.</p

Pearson residuals of A) GAMM, B) ANCOVA and C) ANOVA for cyclophosphamide dose-response.

<p>GAMM exhibits a more even distribution of residuals than does ANCOVA or ANOVA (red trace).</p

Comparison of A) GAMM, B) ANCOVA and C) ANOVA for cyclophosphamide.

<p>ANOCOVA and ANOVA demonstrate insensitivity to the local maximum dose-response indicated by GAMM.</p

AIC comparison for simplification of indicated models.

<p>AIC comparison for simplification of indicated models.</p