Peripheral and spinal 5-HT receptors participate in the pronociceptive and antinociceptive effects of fluoxetine in rats

• Fluoxetine produces local nociception and spinal antinociception.
• Fluoxetine-induced nociception was prevented by 5-HT2A/2B/2C/3/4/6/7 antagonists.
• Fluoxetine-induced nociception was unaltered by 5-HT1A/1B/1D/5A antagonists.
• Fluoxetine-induced antinociception was prevented by 5-HT1A/1B/1D/5A antagonists.
• Fluoxetine-induced antinociception was unaltered by 5-HT2/3/4/6/7 antagonists.

The role of 5-HT receptors in fluoxetine-induced nociception and antinociception in rats was assessed. Formalin produced a typical pattern of flinching and licking/lifting behaviors. Local peripheral ipsilateral, but not contralateral, pre-treatment with fluoxetine (0.3–3 nmol/paw) increased in a dose-dependent fashion 0.5% formalin-induced nociception. In contrast, intrathecal pretreatment with fluoxetine (0.3–3 nmol/rat) prevented nociception induced by formalin. The peripheral pronociceptive effect of fluoxetine was prevented by the 5-HT2A (ketanserin, 3–10 pmol/paw), 5-HT2B (3-(2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl)-2,4(1H,3H)-quinazolinedione(+) tartrate, RS-127445, 3–10 pmol/paw), 5-HT2C (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulphonamido) phenyl-5-oxopentyl]1,3,8-triazaspiro[4.5] decane-2,4-dione hydrochloride, RS-102221, 3–10 pmol/paw), 5-HT3 (ondansetron, 3–10 nmol/paw), 5-HT4 ([1-[2-methylsulphonylamino ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate, GR-113808, 3–100 fmol/paw), 5-HT6 (4-iodo-N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]benzene-sulfonamide hydrochloride, SB-258585, 3–10 pmol/paw) and 5-HT7 ((R)-3-(2-(2-(4-methylpiperidin-1-yl) ethyl) pyrrolidine-1-sulfonyl) phenol hydrochloride, SB-269970, 0.3–1 nmol/paw), but not by the 5-HT1A (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide maleate, WAY-100635, 0.3–1 nmol/paw), 5-HT1B/1D (N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)-1,1’-biphenyl-4-carboxamide hydrochloride hydrate, GR-127935, 0.3–1 nmol/paw), 5-HT1B (1’-methyl-5-[[2’-methyl-4’-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4’-piperidine hydrochloride, SB-224289, 0.3–1 nmol/paw), 5-HT1D (4-(3-chlorophenyl)-α-(diphenylmethyl)-1-piperazineethanol hydrochloride, BRL-15572, 0.3–1 nmol/paw) nor 5-HT5A ((N-[2-(dimethylamino)ethyl]-N-[[4’-[[(2-phenylethyl)amino]methyl][1,1’-biphenyl]-4-yl]methyl]cyclopentanepropanamide dihydrochloride, SB-699551, 1–3 nmol/paw), receptor antagonists. In marked contrast, the spinal antinociceptive effect of fluoxetine was prevented by the 5-HT1A (WAY-100635, 0.3–1 nmol/rat), 5-HT1B/1D (GR-127935, 0.3–1 nmol/rat), 5-HT1B (SB-224289, 0.3–1 nmol/rat), 5-HT1D (BRL-15572, 0.3–1 nmol/rat) and 5-HT5A (SB-699551, 1–3 nmol/rat), but not by the 5-HT2A (ketanserin, 3–10 pmol/rat), 5-HT2B (RS-127445, 3–10 pmol/rat), 5-HT2C (RS-102221, 3–10 pmol/rat), 5-HT3 (ondansetron, 3–10 nmol/rat), 5-HT4 (GR-113808, 3–100 fmol/rat), 5-HT6 (SB-258585, 3–10 pmol/rat) nor 5-HT7 (SB-269970, 0.3–1 nmol/rat), receptor antagonists. These results suggest that fluoxetine produces nociception at the periphery by activating peripheral 5-HT2A/2B/2C/3/4/6/7 receptors. In addition, intrathecal fluoxetine produces antinociception by activation of spinal 5-HT1A/1B/1D/5A receptors.