Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat.
CT-3 (ajulemic acid) is a synthetic analogue of a metabolite of Delta9-tetrahydrocannabinol that has reported analgesic efficacy in neuropathic pain states in man. Here we show that CT-3 binds to human cannabinoid receptors in vitro, with high affinity at hCB1 (Ki 6 nM) and hCB2 (Ki 56 nM) receptors. In a functional GTP-gamma-S assay CT-3 was an agonist at both hCB1 and hCB2 receptors (EC50 11 and 13.4 nM, respectively). In behavioural models of chronic neuropathic and inflammatory pain in the rat, oral administration of CT-3 (0.1-1 mg/kg) produced up to 60% reversal of mechanical hyperalgesia. In both models the antihyperalgesic activity was prevented by the CB1-antagonist SR141716A but not the CB2-antagonist SR144528. In the tetrad of tests for CNS activity, CT-3 (1-10 mg/kg, po) produced dose-related catalepsy, deficits in locomotor performance, hypothermia, and acute analgesia. Comparison of 50% maximal effects in the tetrad and chronic pain assays produced an approximate therapeutic index of 5-10. Pharmacokinetic analysis showed that CT-3 exhibits significant but limited brain penetration, with a brain/plasma ratio of 0.4 measured following oral administration, compared to ratios of 1.0-1.9 measured following subcutaneous administration of WIN55,212-2 or Delta9-THC. These data show that CT-3 is a cannabinoid receptor agonist and is efficacious in animal models of chronic pain by activation of the CB1 receptor. Whilst it shows significant cannabinoid-like CNS activity, it exhibits a superior therapeutic index compared to other cannabinoid compounds, which may reflect a relatively reduced CNS penetration.
Dyson
Alex
A
Novartis Institutes for Biomedical Research, Chronic Pain unit, 5 Gower Place, London WC1E 6BS, UK.
Peacock
Marcus
M
Chen
Alice
A
Courade
Jean-Philippe
JP
Yaqoob
Mohammed
M
Groarke
Alex
A
Brain
Christopher
C
Loong
Yvonne
Y
Fox
Alyson
A
D000700:Analgesics / Q000493:pharmacokinetics / Q000627:therapeutic use; D000818:Animals; D048588:Benzoxazines; D002186:Cannabinoids / Q000819:agonists*; D002375:Catalepsy / Q000188:drug therapy; D002460:Cell Line; D002845:Chromatography / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D003511:Cyclohexanols / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004347:Drug Interactions; D005620:Freund's Adjuvant; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000493:pharmacokinetics; D006801:Humans; D007035:Hypothermia / Q000188:drug therapy; D007249:Inflammation / Q000139:chemically induced / Q000150:complications / Q000378:metabolism; D008026:Ligation / Q000379:methods; D008297:Male; D009025:Morpholines / Q000627:therapeutic use; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects* / Q000502:physiology; D011869:Radioligand Assay / Q000379:methods; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test / Q000379:methods; D020426:Sciatic Neuropathy / Q000150:complications; D013460:Sulfur Isotopes / Q000493:pharmacokinetics; D013997:Time Factors; D014316:Tritium / Q000493:pharmacokinetics
D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D003511:Cyclohexanols; D009025:Morpholines; D009281:Naphthalenes; D013460:Sulfur Isotopes; D014316:Tritium; D016244:Guanosine 5'-O-(3-Thiotriphosphate); C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; D005620:Freund's Adjuvant; C471849:lenabasum