Cannabinoid system and cyclooxygenases inhibitors

Rationale. The cannabinoid system consists of a complex array of receptors, substances with agonist/antagonist properties for those receptors, biosynthetic machineries and mechanisms for cellular uptake and degradation for endocannabinoids. This system is in interrelation with other systems that comprise lipid mediators like prostaglandins/leukotrienes systems. A clear antagonist, additive or synergic effect of nonsteroidal anti–inflammatory drugs (NSAIDs)–cannabinoid associations was not yet demonstrated. Aim. The present study tried to summarize the existent data on NSAIDS-cannabinoid system interactions. Methods and results A bibliographic research in Medline, Scirus, Embase was made using as keywords cannabinoid, nonsteroidal anti–inflammatory drugs, aspirin, ibuprofen, flurbiprofen, diclofenac, indomethacin, acetaminophen, coxibs, antinociceptive, antinociception, analgesia DiscussionsA systematization of the results focusing on the NSAIDs drugs interaction with the cannabinoid system was presented. Out of all the substances analyzed in the present review, acetaminophen was studied the most regarding its interferences with the cannabinoid system, mainly due to contradictory results. Conclusions Some NSAIDs have additional influences on the cannabinoid system either by inhibiting fatty acid amide hydrolase (FAAH) or by inhibiting a possible intracellular transporter of endocannabinoids. All the NSAIDs that inhibit COX2 can influence the cannabinoid system because a possible important degradative pathway for anandamide and 2–arachidonoyl glycerol might involve COX 2. One of the causes for the variety of experimental results presented might be due to pharmacokinetic mechanisms, depending on the route of administration and the dose Abbreviationsdelta9 THC, (–)–(6aR,10aR)–6,6,9–trimethyl–3–pentyl–6a,7,8,10a–tetrahydro–6H–benzo[c]chromen–1–ol; delta9–THC–11–oic acid, 1–hydroxy–6,6–dimethyl–3–pentyl–6a,7,8,10a–tetrahydrobenzo[c] chromene–9–carboxylic acid; Anandamide, (5Z,8Z,11Z,14Z)–N–(2–hydroxyethyl)icosa–5,8,11,14–tetraenamide; Methanandamide, (5Z,8Z,11Z,14Z)–N–[(2R)–1–hydroxypropan–2–yl]–icosa–5,8,11,14–tetraenamide; 2–AG, 1,3–Dihydroxy–2–propanyl (5Z,8Z,11Z,14Z)–5,8,11,14–eicosatetraenoate; HU 210, (6aR,10aR)– 9–(Hydroxymethyl)–6,6–dimethyl–3–(2–methyloctan–2–yl)–6a,7,10,10a–tetrahydrobenzo [c]chromen–1–ol; SR141716A, 5–(4–Chlorophenyl)–1–(2,4–dichloro–phenyl)–4–methyl–N–(piperidin–1–yl)–1H–pyrazole–3–carboxamide; SR144528, N–[(1S)–endo–1,3,3–trimethyl bicyclo [2.2.1] heptan–2–yl]–5–(4–chloro–3–methylphenyl)–1–(4–methylbenzyl)–pyrazole–3–carboxamide; AM251, 1–(2,4–dichlorophenyl)–5–(4–iodophenyl)–4–methyl–N–(1–piperidyl)pyrazole–3–carboxamide; AM 404, (5Z,8Z,11Z,14Z)–N–(4–hydroxyphenyl)icosa–5,8,11,14–tetraenamide; WIN 55,212–2, (R)–(+)–[2,3–Dihydro–5–methyl– 3–(4–morpholinylmethyl)pyrrolo [1,2,3–de]–1,4–benzoxazin–6–yl]–1–napthalenylmethanone; AM 281, N–(morpholin–4–yl)–5–(4–iodophenyl)–1–(2,4–dichlorphenyl)–4–methyl–1H–pyrazole–3–carboxamide; AM 630, [6–Iodo–2–methyl–1–[2–(4–morpholinyl)ethyl]–1H–indol–3–yl](4–methoxyphenyl)methanone; Ibu Am–5, N–(3–methylpyridin–2–yl)–2–(4'–isobutylphenyl)propionamide; CP 55, 940, 2–[(1R,2R,5R)–5–hydroxy–2–(3–hydroxypropyl) cyclohexyl]–5–(2–methyloctan–2–yl)phenol; NS–398, N–[2–(Cyclohexyloxy)–4–nitrophenyl]methanesulfonamide; SC–560, 5–(4–chlorophenyl)–1–(4–methoxyphenyl)–3–trifluoromethylpyrazole; AM 1241, (3–iodo–5–nitrophenyl)–[1–[(1–methylpiperidin–2–yl)methyl]indol–3–yl]methanone; Met F AEA, 2–methyl–arachidonyl–2'–fluoro–ethylamide; PMSF, Phenylmethylsulfonyl fluoride; URB 597, [3–(3–carbamoylphenyl)phenyl] N–cyclohexylcarbamate; TRPV1, Transient receptor potential vanilloid type 1; CGRP, Calcitonin gene related peptide; COX1, cyclooxygenase type 1; COX2, cyclooxygenase type 2; CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; FAAH, fatty acid amide hydrolase; NSAIDs, nonsteroidal anti–inflammatory drugs; p.o., per os; i.p., intraperitoneally; i.th., intrathecally; s.c. subcutaneously; i.pl., intraplantar; i.v., intravenously; CB cannabinoid.