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Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis.
Pain. 2017 Sep; 158(9):1711-1722.PAIN

Abstract

Chronic pain and hyperalgesia, as well as pain resulting from episodes of vaso-occlusion, 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, 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 of 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 Aδ- 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.

Authors+Show Affiliations

Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA.Division of Hematology, Oncology and Transplantation, Department of Medicine, Vascular Biology Center, University of Minnesota, Minneapolis, MN, USA.Department of Diagnostic and Biological Sciences, School of Dentistry, University of Minnesota, Minneapolis, MN, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28570479

Citation

Uhelski, Megan L., et al. "Sensitization of C-fiber Nociceptors in Mice With Sickle Cell Disease Is Decreased By Local Inhibition of Anandamide Hydrolysis." Pain, vol. 158, no. 9, 2017, pp. 1711-1722.
Uhelski ML, Gupta K, Simone DA. Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis. Pain. 2017;158(9):1711-1722.
Uhelski, M. L., Gupta, K., & Simone, D. A. (2017). Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis. Pain, 158(9), 1711-1722. https://doi.org/10.1097/j.pain.0000000000000966
Uhelski ML, Gupta K, Simone DA. Sensitization of C-fiber Nociceptors in Mice With Sickle Cell Disease Is Decreased By Local Inhibition of Anandamide Hydrolysis. Pain. 2017;158(9):1711-1722. PubMed PMID: 28570479.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Sensitization of C-fiber nociceptors in mice with sickle cell disease is decreased by local inhibition of anandamide hydrolysis. AU - Uhelski,Megan L, AU - Gupta,Kalpna, AU - Simone,Donald A, PY - 2017/6/2/pubmed PY - 2018/5/3/medline PY - 2017/6/2/entrez SP - 1711 EP - 1722 JF - Pain JO - Pain VL - 158 IS - 9 N2 - Chronic pain and hyperalgesia, as well as pain resulting from episodes of vaso-occlusion, 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, 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 of 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 Aδ- 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. SN - 1872-6623 UR - https://www.unboundmedicine.com/medline/citation/28570479/Sensitization_of_C_fiber_nociceptors_in_mice_with_sickle_cell_disease_is_decreased_by_local_inhibition_of_anandamide_hydrolysis_ L2 - https://doi.org/10.1097/j.pain.0000000000000966 DB - PRIME DP - Unbound Medicine ER -