Hypoactivity of the spinal cannabinoid system results in NMDA-dependent hyperalgesia.
Cannabinoids, such as Delta9-THC, are capable of inhibiting nociception, i.e., pain transmission, at least in part, by interacting with spinal Gi/Go-coupled cannabinoid receptors. What is not known, however, is the antinociceptive role of endogenous spinal cannabinoids. If endogenous cannabinoids modulate basal nociceptive thresholds, then alterations in this system could be involved in the etiology of certain pain states. In this report we provide evidence for tonic modulation of basal thermal nociceptive thresholds by the spinal cannabinoid system. Administration of oligonucleotides directed against CB1 cannabinoid receptor mRNA significantly reduced spinal cannabinoid binding sites and produced significant hyperalgesia when compared with a randomer oligonucleotide control. A second method used to reduce activity of the spinal cannabinoid receptor was intrathecal administration of the cannabinoid receptor antagonist SR 141716A. SR 141716A evoked thermal hyperalgesia with an ED50 of 0.0012 fmol. The SR 141716A-induced hyperalgesia was dose-dependently blocked by the administration of D-AP-5 or MK-801, two antagonists to the NMDA receptor. These results indicate that there is tonic activation of the spinal cannabinoid system under normal conditions. Furthermore, hypoactivity of the spinal cannabinoid system results in an NMDA-dependent hyperalgesia and thus may participate in the etiology of certain chronic pain states.
Richardson
J D
JD
Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Aanonsen
L
L
Hargreaves
K M
KM
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002186:Cannabinoids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003511:Cyclohexanols / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D006358:Hot Temperature; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009619:Nociceptors / Q000187:drug effects / Q000502:physiology; D010147:Pain Measurement; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D000077285:Rimonabant; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects / Q000502:physiology*; D014316:Tritium
D000700:Analgesics; D002186:Cannabinoids; D003511:Cyclohexanols; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011720:Pyrazoles; D016194:Receptors, N-Methyl-D-Aspartate; D014316:Tritium; D016291:Dizocilpine Maleate; D015763:2-Amino-5-phosphonovalerate; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D000077285:Rimonabant