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BJA Advance Access originally published online on February 18, 2005
British Journal of Anaesthesia 2005 94(5):649-656; doi:10.1093/bja/aei098
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© The Board of Management and Trustees of the British Journal of Anaesthesia 2005. All rights reserved. For Permissions, please e-mail: journal.permissions{at}oupjournals.org

Characterization and comparison of recombinant human and rat TRPV1 receptors: effects of exo- and endocannabinoids{dagger}

P. M. W. Lam, J. McDonald and D. G. Lambert*

Department of Cardiovascular Sciences (Pharmacology and Therapeutics Group), Division of Anaesthesia, Critical Care and Pain Management, University of Leicester, Leicester Royal Infirmary, LE1 5WW, UK

* Corresponding author. E-mail: DGL3{at}le.ac.uk

Background. TRPV1 is a ligand-gated ion channel whose activation by capsaicin increases intracellular Ca2+ ([Ca2+]i). TRPV1 and cannabinoid CB1 receptor activation are capable of eliciting analgesia. In this study, using recombinant human (h) and rat (r) TRPV1 receptors expressed in HEK293 cells, we have performed a comparison of both TRPV1 species at 22 and 37°C and compared endo- and exocannabinoid activity at both receptors.

Methods. [Ca2+]i was measured in Fura-2-loaded HEK293hTRPV1 and HEK293rTRPV1 cells. To assess native CB1 receptor activity, [35S]GTP{gamma}S binding to membranes prepared from rat cerebellum was measured.

Results. Both capsaicin (pEC50 rat ~6.9 and pEC50 human ~6.8 at 37°C) and anandamide (pEC50 rat ~5.3 and pEC50 human ~5.8 at 37°C) produced a concentration-dependent increase in [Ca2+]i in rat and human systems and at 22 and 37°C. In HEK293rTRPV1 cells, anandamide appeared to be a partial agonist. Capsazepine demonstrated competitive antagonism at both human and rat TRPV1 receptors and at both temperatures studied. Capsazepine effects were not temperature dependent: pKB at rTRPV1 was 5.98 at 22°C and 6.02 at 37°C, and pKB at hTRPV1 was 6.76 at 22°C and 6.75 at 37°C. However, there was a consistent 6-fold increase in capsazepine potency for hTRPV1 relative to rTRPV1. The exocannabinoid {Delta}9-tetrahydrocannabinol failed to increase [Ca2+]i, although its solvent ethanol was an effective TRPV1 activator. In the [35S]GTP{gamma}S binding assay using rat cerebellar membranes, anandamide (pEC50 ~5.8) and {Delta}9-tetrahydrocannabinol (pEC50 ~7.1), but not capsaicin, stimulated binding. {Delta}9-tetrahydrocannabinol was a partial agonist. pEC50 values for anandamide at rTRPV1 and rCB1 were similar.

Conclusions. There were small differences in the pharmacology of rat and human TRPV1 receptors. Whilst capsaicin activated TRPV1 and {Delta}9-tetrahydrocannabinol activated CB1, anandamide is an endogenous agonist for both receptor systems.

{dagger} Presented in abstract form in the following publications: Lam PMW, Smart D, Lambert DG. Anandamide but not {Delta}9-tetrahydrocannabinol activates recombinant human vanilloid receptors. Br J Anaesth 2003; 90: 418P; Lam PMW, Smart D, Lambert DG. Differences in the affinity of capsazepine at recombinant rat and human VR1 receptors. Br J Pharmacol 2003; 138: 220P.


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