Cannabinoids inhibit ATP-activated currents in rat trigeminal ganglionic neurons.

The present study aimed to investigate whether cannabinoids could modulate the response mediated by ATP receptor (P2X purinoceptor). Whole-cell patch-clamp recording was performed on cultured rat trigeminal ganglionic (TG) neurons. The majority of TG neurons were sensitive to ATP (67/75, 89.33%). Extracellular pretreatment with WIN55212-2, a cannabinoid receptor 1 (CB1 receptor) agonist, reduced ATP-activated current (I(ATP)) significantly. This inhibitory effect was concentration-dependent and was blocked by AM281, a specific CB1 receptor antagonist. Pretreatment with WIN55212-2 at 1×10(-13), 1×10(-12), 1×10(-11), 1×10(-10), 1×10(-9) and 1×10(-8) mol/L reduced I(ATP) (induced by 1×10(-4) mol/L ATP) by (8.14±3.14)%, (20.11±2.72)%, (46.62±3.51)%, (72.16±5.64)%, (80.21±2.80)% and (80.59±3.55)%, respectively. The concentration-response curves for I(ATP) pretreated with and without WIN55212-2 showed that WIN55212-2 shifted the curve downward, and decreased the maximal amplitude of I(ATP) by (58.02±4.21)%. But the threshold value and EC(50) (1.15×10(-4) mol/L vs 1.27×10(-4) mol/L) remained unchanged. The inhibition of I(ATP) by WIN55212-2 was reversed by AM281, suggesting that the inhibition was mediated via the CB1 receptor. Pretreatment with forskolin [an agonist of adenylyl cyclase (AC)] or 8-Br-cAMP reversed the inhibition of I(ATP) by WIN55212-2. These results suggest that the inhibitory effect of cannabinoids on I(ATP) is mediated via the CB1 receptors, that lead to inhibition of the AC-cAMP-PKA signaling pathway.

[1]  N. Lozovaya,et al.  The agonists for nociceptors are ubiquitous, but the modulators are specific: P2X receptors in the sensory neurons are modulated by cannabinoids , 2006, Pflügers Archiv.

[2]  D. Simone,et al.  Cannabinoids attenuate depolarization-dependent Ca2+ influx in intermediate-size primary afferent neurons of adult rats , 2002, Neuroscience.

[3]  Zhi-wang Li,et al.  Neurokinin B potentiates ATP-activated currents in rat DRG neurons , 2001, Brain Research.

[4]  G. Burnstock,et al.  P2x Receptors in Peripheral Neurons , 2000 .

[5]  D. Simone,et al.  Cannabinoids attenuate capsaicin-evoked hyperalgesia through spinal and peripheral mechanisms , 2001, Pain.

[6]  P. Schweitzer.  Cannabinoids Decrease the K+ M-Current in Hippocampal CA1 Neurons , 2000, The Journal of Neuroscience.

[7]  W. Welsh,et al.  Signal transduction of eicosanoid CB1 receptor ligands. , 1999, Life sciences.

[8]  D. Simone,et al.  The cannabinoid receptor agonist WIN 55,212-2 mesylate blocks the development of hyperalgesia produced by capsaicin in rats , 1999, Pain.

[9]  M. Herkenham,et al.  Localization of central cannabinoid CB1 receptor messenger RNA in neuronal subpopulations of rat dorsal root ganglia: a double-label in situ hybridization study , 1999, Neuroscience.

[10]  J. Woods,et al.  Local administration of Δ9-tetrahydrocannabinol attenuates capsaicin-induced thermal nociception in rhesus monkeys: a peripheral cannabinoid action , 1999, Psychopharmacology.

[11]  P. Coffin,et al.  Anatomical basis for cannabinoid-induced antinociception as revealed by intracerebral microinjections , 1999, Brain Research.

[12]  D. Piomelli,et al.  Control of pain initiation by endogenous cannabinoids , 1998, Nature.

[13]  E. Mccleskey,et al.  Desensitization, recovery and Ca2+-dependent modulation of ATP-gated P2X receptors in nociceptors , 1997, Neuropharmacology.

[14]  R. Pertwee.  Pharmacology of cannabinoid CB1 and CB2 receptors. , 1997, Pharmacology & therapeutics.

[15]  Zhi-wang Li,et al.  Substance P potentiates ATP-activated currents in rat primary sensory neurons , 1996, Brain Research.

[16]  L. Petrelli,et al.  N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. , 1996, European journal of pharmacology.

[17]  P. Casellas,et al.  Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. , 1995, The Biochemical journal.

[18]  K. Mackie,et al.  Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. , 1995, Molecular pharmacology.

[19]  P. Casellas,et al.  Stimulation of Cannabinoid Receptor CB1 Induces krox-24 Expression in Human Astrocytoma Cells (*) , 1995, The Journal of Biological Chemistry.

[20]  K. Mackie,et al.  Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[21]  S. Childers,et al.  Aminoalkylindoles: actions on specific G-protein-linked receptors. , 1991, The Journal of pharmacology and experimental therapeutics.

[22]  B. Bean,et al.  ATP-activated channels in rat and bullfrog sensory neurons: concentration dependence and kinetics , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.