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Antinociceptive effects induced through the stimulation of spinal cannabinoid type 2 receptors in chronically inflamed mice.

Abstract

The stimulation of spinal cannabinoid type 2 (CB(2)) receptors is a suitable strategy for the alleviation of experimental pain symptoms. Several reports have described the up-regulation of spinal cannabinoid CB(2) receptors in neuropathic settings together with the analgesic effects derived from their activation. Besides, we have recently reported in two murine bone cancer models that the intrathecal administration of cannabinoid CB(2) receptor agonists completely abolishes hyperalgesia and allodynia, whereas spinal cannabinoid CB(2) receptor expression remains unaltered. The present experiments were designed to measure the expression of spinal cannabinoid CB(2) receptors as well as the analgesic efficacy derived from their stimulation in mice chronically inflamed by the intraplantar injection of complete Freund's adjuvant 1 week before. Both spinal cannabinoid CB(2) receptors mRNA measured by real-time PCR and cannabinoid CB(2) receptor protein levels measured by western blot remained unaltered in inflamed mice. Besides, the intrathecal (i.t.) administration of the cannabinoid CB(2) receptor agonists AM1241, (R,S)-3-(2-Iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole, (0.03-1 μg) and JWH 133, (6aR,10aR)-3-(1,1-Dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran, (3-30 μg) dose-dependently blocked inflammatory thermal hyperalgesia and mechanical allodynia. The analgesic effects induced by both agonists were counteracted by the coadministration of the selective cannabinoid CB(2) receptor antagonist SR144528, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide, (5 μg) but not by the cannabinoid CB(1) receptor antagonist AM251, N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, (10 μg). The effects induced by AM1241 were also inhibited by the coadministration of the opioid receptor antagonist, naloxone (1 μg). These results demonstrate that effective analgesia can be achieved in chronic inflammatory settings through the stimulation of spinal cannabinoid CB(2) receptors even if this receptor population is not up-regulated.

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  • Authors+Show Affiliations

    ,

    Laboratorio de Farmacología, Facultad de Medicina, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Facultad de Medicina C/ Julián Clavería, 6. 33006 Oviedo, Asturias, Spain. curtoverdad.uo@uniovi.es

    , , ,

    Source

    European journal of pharmacology 668:1-2 2011 Oct 01 pg 184-9

    MeSH

    Analgesics
    Animals
    Cannabinoids
    Chronic Disease
    Freund's Adjuvant
    Gene Expression Regulation
    Hyperalgesia
    Inflammation
    Male
    Mice
    RNA, Messenger
    Receptor, Cannabinoid, CB2
    Spinal Cord
    Temperature

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    21771590

    Citation

    Curto-Reyes, Verdad, et al. "Antinociceptive Effects Induced Through the Stimulation of Spinal Cannabinoid Type 2 Receptors in Chronically Inflamed Mice." European Journal of Pharmacology, vol. 668, no. 1-2, 2011, pp. 184-9.
    Curto-Reyes V, Boto T, Hidalgo A, et al. Antinociceptive effects induced through the stimulation of spinal cannabinoid type 2 receptors in chronically inflamed mice. Eur J Pharmacol. 2011;668(1-2):184-9.
    Curto-Reyes, V., Boto, T., Hidalgo, A., Menéndez, L., & Baamonde, A. (2011). Antinociceptive effects induced through the stimulation of spinal cannabinoid type 2 receptors in chronically inflamed mice. European Journal of Pharmacology, 668(1-2), pp. 184-9. doi:10.1016/j.ejphar.2011.06.057.
    Curto-Reyes V, et al. Antinociceptive Effects Induced Through the Stimulation of Spinal Cannabinoid Type 2 Receptors in Chronically Inflamed Mice. Eur J Pharmacol. 2011 Oct 1;668(1-2):184-9. PubMed PMID: 21771590.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Antinociceptive effects induced through the stimulation of spinal cannabinoid type 2 receptors in chronically inflamed mice. AU - Curto-Reyes,Verdad, AU - Boto,Tamara, AU - Hidalgo,Agustín, AU - Menéndez,Luis, AU - Baamonde,Ana, Y1 - 2011/07/13/ PY - 2011/01/14/received PY - 2011/06/16/revised PY - 2011/06/27/accepted PY - 2011/7/21/entrez PY - 2011/7/21/pubmed PY - 2011/12/28/medline SP - 184 EP - 9 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 668 IS - 1-2 N2 - The stimulation of spinal cannabinoid type 2 (CB(2)) receptors is a suitable strategy for the alleviation of experimental pain symptoms. Several reports have described the up-regulation of spinal cannabinoid CB(2) receptors in neuropathic settings together with the analgesic effects derived from their activation. Besides, we have recently reported in two murine bone cancer models that the intrathecal administration of cannabinoid CB(2) receptor agonists completely abolishes hyperalgesia and allodynia, whereas spinal cannabinoid CB(2) receptor expression remains unaltered. The present experiments were designed to measure the expression of spinal cannabinoid CB(2) receptors as well as the analgesic efficacy derived from their stimulation in mice chronically inflamed by the intraplantar injection of complete Freund's adjuvant 1 week before. Both spinal cannabinoid CB(2) receptors mRNA measured by real-time PCR and cannabinoid CB(2) receptor protein levels measured by western blot remained unaltered in inflamed mice. Besides, the intrathecal (i.t.) administration of the cannabinoid CB(2) receptor agonists AM1241, (R,S)-3-(2-Iodo-5-nitrobenzoyl)-1-(1-methyl-2-piperidinylmethyl)-1H-indole, (0.03-1 μg) and JWH 133, (6aR,10aR)-3-(1,1-Dimethylbutyl)-6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran, (3-30 μg) dose-dependently blocked inflammatory thermal hyperalgesia and mechanical allodynia. The analgesic effects induced by both agonists were counteracted by the coadministration of the selective cannabinoid CB(2) receptor antagonist SR144528, 5-(4-chloro-3-methylphenyl)-1-[(4-methylphenyl)methyl]-N-[(1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]hept-2-yl]-1H-pyrazole-3-carboxamide, (5 μg) but not by the cannabinoid CB(1) receptor antagonist AM251, N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide, (10 μg). The effects induced by AM1241 were also inhibited by the coadministration of the opioid receptor antagonist, naloxone (1 μg). These results demonstrate that effective analgesia can be achieved in chronic inflammatory settings through the stimulation of spinal cannabinoid CB(2) receptors even if this receptor population is not up-regulated. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/21771590/abstract/Antinociceptive_effects_induced_through_the_stimulation_of_spinal_cannabinoid_type_2_receptors_in_chronically_inflamed_mice_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(11)00767-9 DB - PRIME DP - Unbound Medicine ER -