Antinociceptive synergy between the cannabinoid receptor agonist WIN 55,212-2 and bupivacaine in the rat formalin test.
BACKGROUND
The analgesic interaction between cannabinoids and local anesthetics has not been investigated. We sought to determine the nature of the interaction between the intrathecal cannabinoid receptor agonist (WIN 55,212-2) and bupivacaine using the formalin test.


METHODS
Lumbar intrathecal catheters were implanted in male Sprague-Dawley rats. After intrathecal administration of WIN 55,212-2, bupivacaine, or their combination, 50 microL of 5% formalin was injected subcutaneously into the hindpaw. Dose-response curves were established and the respective ED50 (50% effective dose) values were determined for each agent alone. Fixed-ratio combinations of WIN 55,212-2 and bupivacaine were tested for combined antinociceptive effects in the formalin test and an isobolographic analysis was performed to characterize the pharmacologic interaction of both drugs.


RESULTS
Intrathecally administered WIN 55,212-2, bupivacaine, or their combination produced a dose-dependent decrease in the number of flinches during Phase 1 and 2 of the formalin test. Isobolographic analysis revealed a synergistic interaction between intrathecal WIN 55,212-2 and bupivacaine in both phases of the formalin test. In combination, the ED50 value was significantly smaller than the theoretical additive value (P < 0.05).


CONCLUSIONS
These results demonstrate that intrathecally coadministered WIN 55,212-2 and bupivacaine provide synergistic antinociceptive interaction in both phases of the formalin test.
Kang
Sinyoung
S
Department of Anesthesiology and Pain Medicine, Ewha Womans University Medical College, Seoul, Korea.
Kim
Chi Hyo
CH
Lee
Heeseung
H
Kim
Dong Yeon
DY
Han
Jong In
JI
Chung
Rack Kyung
RK
Lee
Guie Yong
GY
D000700:Analgesics / Q000008:administration & dosage* / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000008:administration & dosage*; D000818:Animals; D048588:Benzoxazines; D002045:Bupivacaine / Q000008:administration & dosage*; D063386:Cannabinoid Receptor Agonists; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005557:Formaldehyde / Q000494:pharmacology*; D006801:Humans; D007278:Injections, Spinal / Q000379:methods; D008297:Male; D009025:Morpholines / Q000008:administration & dosage*; D009281:Naphthalenes / Q000008:administration & dosage*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley
D000700:Analgesics; D000779:Anesthetics, Local; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D009025:Morpholines; D009281:Naphthalenes; D005557:Formaldehyde; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D002045:Bupivacaine