Tags

Type your tag names separated by a space and hit enter

AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain.
Br J Pharmacol. 2006 Aug; 148(7):1022-32.BJ

Abstract

An attractive alternative to the use of direct agonists at the cannabinoid receptor type 1 (CB1) in the control of neuropathic pain may be to potentiate the actions of endogenous cannabinoids. Thus, the effects of AM404, an inhibitor of anandamide uptake, were assessed in an experimental model of neuropathic pain in rats. Daily treatment with AM404 prevented, time- and dose-dependently, the development of thermal hyperalgesia and mechanical allodynia in neuropathic rats. Antagonists at cannabinoid CB1 or CB2 receptors, or at the transient receptor potential vanilloid type 1 receptor, each partially reversed effects induced by AM404. A complete reversal was obtained when the three antagonists were given together, suggesting that all three receptors are involved. AM404 treatment affected two pathways involved in the generation and maintenance of neuropathic pain, one mediated by nitric oxide (NO) and the other by cytokines. AM404 completely prevented the overproduction of NO and the overexpression of nNOS, inhibited the increase in tumour necrosis factor alpha (TNFalpha) and enhanced the production of interleukin-10. Both NO and TNFalpha are known to contribute to the apoptotic process, which plays an important role in the establishment of chronic pain states. AM404 treatment prevented the increase in the ratio between pro- and anti-apoptotic gene bax/bcl-2 expression observed in the spinal cord of neuropathic rats. Taken together, these findings suggest that inhibition of endocannabinoid uptake, by blocking the putative anandamide carrier, results in the relief of neuropathic pain and may represent a novel strategy for treating chronic pain.

Authors+Show Affiliations

Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy. barbara.costa@unimib.itNo affiliation info availableNo 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
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16770320

Citation

Costa, Barbara, et al. "AM404, an Inhibitor of Anandamide Uptake, Prevents Pain Behaviour and Modulates Cytokine and Apoptotic Pathways in a Rat Model of Neuropathic Pain." British Journal of Pharmacology, vol. 148, no. 7, 2006, pp. 1022-32.
Costa B, Siniscalco D, Trovato AE, et al. AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. Br J Pharmacol. 2006;148(7):1022-32.
Costa, B., Siniscalco, D., Trovato, A. E., Comelli, F., Sotgiu, M. L., Colleoni, M., Maione, S., Rossi, F., & Giagnoni, G. (2006). AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. British Journal of Pharmacology, 148(7), 1022-32.
Costa B, et al. AM404, an Inhibitor of Anandamide Uptake, Prevents Pain Behaviour and Modulates Cytokine and Apoptotic Pathways in a Rat Model of Neuropathic Pain. Br J Pharmacol. 2006;148(7):1022-32. PubMed PMID: 16770320.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - AM404, an inhibitor of anandamide uptake, prevents pain behaviour and modulates cytokine and apoptotic pathways in a rat model of neuropathic pain. AU - Costa,Barbara, AU - Siniscalco,Dario, AU - Trovato,Anna Elisa, AU - Comelli,Francesca, AU - Sotgiu,Maria Luisa, AU - Colleoni,Mariapia, AU - Maione,Sabatino, AU - Rossi,Francesco, AU - Giagnoni,Gabriella, Y1 - 2006/06/12/ PY - 2006/6/14/pubmed PY - 2006/10/6/medline PY - 2006/6/14/entrez SP - 1022 EP - 32 JF - British journal of pharmacology JO - Br J Pharmacol VL - 148 IS - 7 N2 - An attractive alternative to the use of direct agonists at the cannabinoid receptor type 1 (CB1) in the control of neuropathic pain may be to potentiate the actions of endogenous cannabinoids. Thus, the effects of AM404, an inhibitor of anandamide uptake, were assessed in an experimental model of neuropathic pain in rats. Daily treatment with AM404 prevented, time- and dose-dependently, the development of thermal hyperalgesia and mechanical allodynia in neuropathic rats. Antagonists at cannabinoid CB1 or CB2 receptors, or at the transient receptor potential vanilloid type 1 receptor, each partially reversed effects induced by AM404. A complete reversal was obtained when the three antagonists were given together, suggesting that all three receptors are involved. AM404 treatment affected two pathways involved in the generation and maintenance of neuropathic pain, one mediated by nitric oxide (NO) and the other by cytokines. AM404 completely prevented the overproduction of NO and the overexpression of nNOS, inhibited the increase in tumour necrosis factor alpha (TNFalpha) and enhanced the production of interleukin-10. Both NO and TNFalpha are known to contribute to the apoptotic process, which plays an important role in the establishment of chronic pain states. AM404 treatment prevented the increase in the ratio between pro- and anti-apoptotic gene bax/bcl-2 expression observed in the spinal cord of neuropathic rats. Taken together, these findings suggest that inhibition of endocannabinoid uptake, by blocking the putative anandamide carrier, results in the relief of neuropathic pain and may represent a novel strategy for treating chronic pain. SN - 0007-1188 UR - https://www.unboundmedicine.com/medline/citation/16770320/AM404_an_inhibitor_of_anandamide_uptake_prevents_pain_behaviour_and_modulates_cytokine_and_apoptotic_pathways_in_a_rat_model_of_neuropathic_pain_ L2 - https://doi.org/10.1038/sj.bjp.0706798 DB - PRIME DP - Unbound Medicine ER -