3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol and Hypoxia

The clinical management of severe pain associated with sickle cell disease (SCD) remains challenging. Development of an optimal therapy would be facilitated by use of murine model(s) with varying degrees of sickling and pain tests that are most sensitive to vaso-occlusion. We found that young (≤3 months old) NY1DD and S+S(Antilles) mice (having modest and moderate sickle phenotype, respectively) exhibited evidence of deep tissue/musculoskeletal pain. Deep tissue pain and cold sensitivity in S+S(Antilles) mice increased significantly with both age and incitement of hypoxia/reoxygenation (H/R). C57/BL6 mice (genetic background strain of NY1DD and S+S(Antilles) ) were hypersensitive to mechanical and heat stimuli, even without the sickle transgene. H/R treatment of HbSS-BERK mice with severe sickle phenotype resulted in significantly decreased withdrawal thresholds and enhanced mechanical, thermal and deep tissue hyperalgesia. Deep hyperalgesia incited by H/R in HbSS-BERK was ameliorated by CP 55940, a cannabinoid receptor agonist. Thus, assessment of deep tissue pain appears to be the most sensitive measure for studying pain mechanisms across mouse models of SCD, and HbSS-BERK mice may be the best model for vaso-occlusive and chronic pain of SCD.

Topics: Age Factors; Analgesics; Anemia, Sickle Cell; Animals; Cannabinoid Receptor Antagonists; Cyclohexanols; Disease Models, Animal; Humans; Hyperalgesia; Hypoxia; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pain; Pain Measurement; Temperature

Cannabinoids (CBs) are implicated in a number of physiological and pathological mechanisms in the central nervous system, but their exact role in post-ischemic brain injury is unclear. The toxic and neuroprotective effects of synthetic and endogenous CBs were evaluated in rat organotypic hippocampal slices exposed to 20 min oxygen-glucose deprivation (OGD) and in gerbils subjected to bilateral carotid occlusion for 5 min. When present in the incubation medium, the synthetic CB agonists WIN 55212-2 and CP 55940 (1-30 μM) and the CB1 agonist ACEA exacerbated CA1 injury induced by OGD, whereas the CB1 receptor antagonists AM 251 and LY 320135 were neuroprotective with maximal activity at 1 μM. AM 251 (at 3 mg/kg, i.p.) also attenuated CA1 pyramidal cell death in gerbils in vivo. The endocannabinoid 2-arachidonoylglycerol (2-AG) reduced OGD injury in hippocampal slices at 0.1-1 μM, whereas anandamide (AEA) was neurotoxic at the same concentrations. The effects of WIN 55212-2, AEA and 2-AG in slices were all dependent on the activation of CB1 but not CB2 receptors, except for the toxic effects of AEA that were also dependent on vanilloid TRPV1 receptors. Our results suggest that exogenous administration of CB1 agonists and the production of endocannabinoids "on demand" may produce different, if not opposite, effects on the fate of neurons following cerebral ischemia.

Topics: Analysis of Variance; Animals; Arachidonic Acids; Benzoxazines; Brain Ischemia; Cannabinoids; Cyclohexanols; Gerbillinae; Glucose; Hippocampus; Hypoxia; Morpholines; Naphthalenes; Neurons; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2