The role of peripheral 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1E and 5-HT_1F serotonergic receptors in the reduction of nociception in rats

This study assessed the possible antinociceptive role of peripheral 5-HT₁ receptor subtypes in the rat formalin test. Rats were injected into the dorsum of the hind paw with 50 μl of diluted formalin (1%). Nociceptive behavior was quantified as the number of flinches of the injected paw. Reduction of flinching was considered as antinociception. Ipsilateral, but not contralateral, peripheral administration of the 5-HT₁ receptor agonists R(+)-UH-301 (5-HT_1A; 0.1-3 μg/paw), CGS-12066A (5-HT_1B; 0.01-0.3 μg/paw), GR46611 (5-HT_1B/1D; 0.3-10 μg/paw), BRL54443 (5-HT_1E/1F; 3-300 μg/paw) or LY344864 (5-HT_1F; 3-300 μg/paw) significantly reduced formalin-induced flinching. The corresponding vehicle was devoid of any effect by itself. The local antinociceptive effect of R(+)-UH-301 (0.3 μg/paw) was significantly reduced by WAY-100635 (30-100 μg/paw; a 5-HT_1A receptor antagonist). Moreover, the antagonists GR55562 (30-100 μg/paw; 5-HT_1B/D) or SB224289 (30-100 μg/paw; 5-HT_1B) dose-dependently reduced the antinociceptive effect of CGS-12066A (0.3 μg/paw) whereas GR55562 (30-100 μg/paw) or BRL15572 (30-100 μg/paw, 5-HT_1D) reduced the antinociceptive effect of GR46611 (0.3 μg/paw). Interestingly, the effects of BRL54443 and LY344864 (300 μg/paw each) were partially reduced by methiothepin, but not by the highest doses of WAY-100635, SB224289 or BRL15572. The above antagonists did not produce any effect by themselves. These results suggest that peripheral activation of the 5-HT_1A, 5-HT_1B, 5-HT_1D, 5-HT_1F and, probably, 5-HT_1E receptor subtypes leads to antinociception in the rat formalin test. Thus, the use of selective 5-HT₁ receptor agonists could be a therapeutic strategy to reduce inflammatory pain.