|Pain. 2017 May 31. doi: 10.1097/j.pain.0000000000000966. [Epub ahead of print]|
Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis.
Uhelski ML1, Gupta K, Simone DA.
1Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis MN 55455 2Vascular Biology Center, Division of Hematology, Oncology and Transplantation Department of Medicine, University of Minnesota, Minneapolis MN 55455.
Chronic pain and hyperalgesia, as well as pain resulting from episodes of vasoocclusion, are characteristic features of sickle cell disease (SCD) and are difficult to treat. Since there is growing evidence that increasing local levels of endocannabinoids can decrease hyperalgesia, we examined the effects of URB597, a fatty acid amide hydrolase (FAAH) inhibitor which blocks the hydrolysis of the endogenous cannabinoid anandamide (AEA), on hyperalgesia and sensitization of cutaneous nociceptors in a humanized mouse model of SCD. Using homozygous HbSS-BERK sickle mice, we determined the effects of URB597 on mechanical hyperalgesia and on sensitization of C-fiber nociceptors in vivo. Intraplantar administration of URB597 (10 µg in 10 µl) decreased the frequency of withdrawal responses evoked by a von Frey monofilament (3.9 mN bending force) applied to the plantar hind paw. This was blocked by the CB1 receptor antagonist AM281 but not by the CB2 receptor antagonist AM630. Also, URB597 decreased hyperalgesia in HbSS-BERK/CB2R-/- sickle mice, further confirming the role for CB1 receptors in the effects produced by URB597. Electrophysiological recordings were made from primary afferent fibers of the tibial nerve in anesthetized mice. The proportion of Ad- and C-fiber nociceptors that exhibited spontaneous activity and responses of C-fibers to mechanical and thermal stimuli were greater in HbSS-BERK sickle mice as compared to control HbAA-BERK mice. Spontaneous activity and evoked responses of nociceptors were decreased by URB597 via CB1 receptors. It is suggested that enhanced endocannabinoid activity in the periphery may be beneficial in alleviating chronic pain associated with SCD.
Br J Pharmacol. 2017 May 31. doi: 10.1111/bph.13892. [Epub ahead of print]
Cannabinoid CB1/CB2 receptor agonists attenuate hyperactivity and body weight loss in a rat model of activity-based anorexia.
Scherma M1, Satta V1, Collu R1, Boi MF2, Usai P2, Fratta W1,3, Fadda P1,3.
1Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Italy.
Department of Internal Medicine, University of Cagliari, Italy.
Centre of Excellence "Neurobiology of Dependence", University of Cagliari, Italy.
BACKGROUND AND PURPOSE:
Anorexia nervosa (AN) is a serious psychiatric condition characterized by excessive body weight loss and disturbed perceptions of body shape and size, often associated with excessive physical activity. There is currently no effective drug-related therapy of this disease and this leads to high relapse rate. Clinical data suggest that a promising therapy to treat and reduce reoccurrence of AN may be based on the use of drugs that target the endocannabinoid (EC) system, which appears dysregulated in AN patients.
The activity-based anorexia (ABA) rodent model mimics severe body weight loss and increased physical activity, as well as neuroendocrine disturbances (i.e., hypoleptinemia and hypercortisolemia) in AN. This study investigated whether cannabinoid agonists can effectively modify anorexic-like behaviors and neuroendocrine changes in rats subjected to a repeated ABA regime in order to mimic the human condition in which patients repeatedly undergo recovery and illness cycle.
Our data show that subchronic treatment with both the CB1/CB2 receptor natural agonist ?9-tetrahydrocannabinol and the synthetic CB1/CB2 receptor agonist CP-55,940 significantly reduced body weight loss and running wheel activity in ABA rats. These behavioral effects were accompanied by an increase in leptin signaling and a decrease in plasma levels of corticosterone.
CONCLUSION AND IMPLICATIONS:
Taken together, our results further demonstrate EC system involvement in AN pathophysiology and that strategies which modulate EC signaling are useful to treat this disorder, specifically in patients where physical hyperactivity plays a central role in its progression and maintenance.