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Increased anandamide uptake by sensory neurons contributes to hyperalgesia in a model of cancer pain.
Neurobiol Dis 2013; 58:19-28ND

Abstract

Opioids do not effectively manage pain in many patients with advanced cancer. Because anandamide (AEA) activation of cannabinoid type-1 receptors (CB1R) on nociceptors reduces nociception, manipulation of AEA metabolism in the periphery may be an effective alternative or adjuvant therapy in the management of cancer pain. AEA is hydrolyzed by the intracellular enzyme fatty acid amide hydrolase (FAAH), and this enzyme activity contributes to uptake of AEA into neurons and to reduction of AEA available to activate CB1R. We used an in vitro preparation of adult murine dorsal root ganglion (DRG) neurons co-cultured with fibrosarcoma cells to investigate how tumors alter the uptake of AEA into neurons. Evidence that the uptake of [(3)H]AEA into dissociated DRG cells in the co-culture model mimicked the increase in uptake that occurred in DRG cells from tumor-bearing mice supported the utility of the in vitro model to study AEA uptake. Results with the fluorescent AEA analog CAY10455 confirmed that an increase in uptake in the co-culture model occurred in neurons. One factor that contributed to the increase in [(3)H]AEA uptake was an increase in total cellular cholesterol in the cancer condition. Treatment with the FAAH inhibitor URB597 reduced CAY10455 uptake in the co-culture model to the level observed in DRG neurons maintained in the control condition (i.e., in the absence of fibrosarcoma cells), and this effect was paralleled by OMDM-1, an inhibitor of AEA uptake, at a concentration that had no effect on FAAH activity. Maximally effective concentrations of the two drugs together produced a greater reduction than was observed with each drug alone. Treatment with BMS309403, which competes for AEA binding to fatty acid binding protein-5, mimicked the effect of OMDM-1 in vitro. Local injection of OMDM-1 reduced hyperalgesia in vivo in mice with unilateral tumors in and around the calcaneous bone. Intraplantar injection of OMDM-1 (5μg) into the tumor-bearing paw reduced mechanical hyperalgesia through a CB1R-dependent mechanism and also reduced a spontaneous nocifensive behavior. The same dose reduced withdrawal responses evoked by suprathreshold mechanical stimuli in naive mice. These data support the conclusion that OMDM-1 inhibits AEA uptake by a mechanism that is independent of inhibition of FAAH and provide a rationale for the development of peripherally restricted drugs that decrease AEA uptake for the management of cancer pain.

Authors+Show Affiliations

Department of Diagnostic and Biological Sciences, Dental School, University of Minnesota, Minneapolis, MN, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

23644187

Citation

Khasabova, Iryna A., et al. "Increased Anandamide Uptake By Sensory Neurons Contributes to Hyperalgesia in a Model of Cancer Pain." Neurobiology of Disease, vol. 58, 2013, pp. 19-28.
Khasabova IA, Holman M, Morse T, et al. Increased anandamide uptake by sensory neurons contributes to hyperalgesia in a model of cancer pain. Neurobiol Dis. 2013;58:19-28.
Khasabova, I. A., Holman, M., Morse, T., Burlakova, N., Coicou, L., Harding-Rose, C., ... Seybold, V. S. (2013). Increased anandamide uptake by sensory neurons contributes to hyperalgesia in a model of cancer pain. Neurobiology of Disease, 58, pp. 19-28. doi:10.1016/j.nbd.2013.04.018.
Khasabova IA, et al. Increased Anandamide Uptake By Sensory Neurons Contributes to Hyperalgesia in a Model of Cancer Pain. Neurobiol Dis. 2013;58:19-28. PubMed PMID: 23644187.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Increased anandamide uptake by sensory neurons contributes to hyperalgesia in a model of cancer pain. AU - Khasabova,Iryna A, AU - Holman,Michelle, AU - Morse,Tim, AU - Burlakova,Natalya, AU - Coicou,Lia, AU - Harding-Rose,Catherine, AU - Simone,Don A, AU - Seybold,Virginia S, Y1 - 2013/05/02/ PY - 2012/12/10/received PY - 2013/04/19/revised PY - 2013/04/24/accepted PY - 2013/5/7/entrez PY - 2013/5/7/pubmed PY - 2014/4/24/medline KW - AEA KW - Anandamide KW - CAY10455 KW - CB1R KW - Cancer KW - DRG KW - Dorsal root ganglion KW - FAAH KW - FABP KW - Fatty acid amide hyrdolase KW - Fatty acid binding protein KW - Hydrolysis KW - Hyperalgesia KW - MβC KW - Neuron KW - PBS KW - PPARα KW - TRPV1 KW - Transport KW - URB597 KW - Uptake KW - anandamide KW - cannabinoid type-1 receptor KW - dorsal root ganglion KW - fatty acid amide hydrolase KW - fatty acid binding protein KW - i.pl KW - intraplantar KW - methyl-β-cyclodextrin KW - peroxisome proliferator-activated receptor alpha KW - phosphate buffered saline KW - transient receptor potential vanilloid-type 1 SP - 19 EP - 28 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 58 N2 - Opioids do not effectively manage pain in many patients with advanced cancer. Because anandamide (AEA) activation of cannabinoid type-1 receptors (CB1R) on nociceptors reduces nociception, manipulation of AEA metabolism in the periphery may be an effective alternative or adjuvant therapy in the management of cancer pain. AEA is hydrolyzed by the intracellular enzyme fatty acid amide hydrolase (FAAH), and this enzyme activity contributes to uptake of AEA into neurons and to reduction of AEA available to activate CB1R. We used an in vitro preparation of adult murine dorsal root ganglion (DRG) neurons co-cultured with fibrosarcoma cells to investigate how tumors alter the uptake of AEA into neurons. Evidence that the uptake of [(3)H]AEA into dissociated DRG cells in the co-culture model mimicked the increase in uptake that occurred in DRG cells from tumor-bearing mice supported the utility of the in vitro model to study AEA uptake. Results with the fluorescent AEA analog CAY10455 confirmed that an increase in uptake in the co-culture model occurred in neurons. One factor that contributed to the increase in [(3)H]AEA uptake was an increase in total cellular cholesterol in the cancer condition. Treatment with the FAAH inhibitor URB597 reduced CAY10455 uptake in the co-culture model to the level observed in DRG neurons maintained in the control condition (i.e., in the absence of fibrosarcoma cells), and this effect was paralleled by OMDM-1, an inhibitor of AEA uptake, at a concentration that had no effect on FAAH activity. Maximally effective concentrations of the two drugs together produced a greater reduction than was observed with each drug alone. Treatment with BMS309403, which competes for AEA binding to fatty acid binding protein-5, mimicked the effect of OMDM-1 in vitro. Local injection of OMDM-1 reduced hyperalgesia in vivo in mice with unilateral tumors in and around the calcaneous bone. Intraplantar injection of OMDM-1 (5μg) into the tumor-bearing paw reduced mechanical hyperalgesia through a CB1R-dependent mechanism and also reduced a spontaneous nocifensive behavior. The same dose reduced withdrawal responses evoked by suprathreshold mechanical stimuli in naive mice. These data support the conclusion that OMDM-1 inhibits AEA uptake by a mechanism that is independent of inhibition of FAAH and provide a rationale for the development of peripherally restricted drugs that decrease AEA uptake for the management of cancer pain. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/23644187/Increased_anandamide_uptake_by_sensory_neurons_contributes_to_hyperalgesia_in_a_model_of_cancer_pain_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(13)00132-0 DB - PRIME DP - Unbound Medicine ER -