Activation of 5-HT_2A receptors potentiates pain produced by inflammatory mediators

Abstract

Previous results from our laboratory indicate that serotonin (5-HT) potentiates pain produced by other inflammatory mediators. To characterize the receptor subtype(s) mediating this synergistic effect of 5-HT, selective 5-HT agonists were injected, alone or with noradrenaline (NA) or prostaglandin E₂ (PGE₂), into the plantar surface of the paws of rats. The behavioural response (favouring, elevation and licking the paw) was recorded using the rating scale developed to quantify formalin-induced pain. The 5-HT_1A and 5-HT₃ agonists, 8-OH-DPAT and 2-methyl-5-HT, respectively, produced only transient responses by themselves and did not interact with PGE₂ or NA. The 5-HT₂ agonists, α-methyl-5-HT and DOI, also produced transient responses alone, but induced lifting and licking of the injected paw lasting more than 30 min when combined with PGE₂ or NA. The lifting and licking response produced by 5-HT plus PGE₂ was not altered by intraplantar pretreatment with the 5-HT_1A and 5-HT₃ antagonists, BMY 7378 and tropisetron, but was attenuated by the 5-$\text{5-}\text{HT}{}_{\mathrm{<mtext>2</mtext><mtext>A</mtext>}}{}_{\mathrm{<mtext>2</mtext><mtext>C</mtext>}}$ antagonist ketanserin. The pain response produced by α-methyl-5-HT plus PGE₂ was blocked by pretreatment with the $\text{5-}\text{HT}{}_{\mathrm{<mtext>2</mtext><mtext>A</mtext>}}{}_{\mathrm{<mtext>2</mtext><mtext>C</mtext>}}$ antagonists ketanserin and ritanserin, and the 5-HT_2A antagonist spiperone (MPE₅₀ values 1.4, 7.7 and 0.06 nmol, respectively). The second phase of the response to intraplantar formalin was also attenuated by ketanserin, ritanserin and spiperone (MPE₅₀ values 11.3, 21.8 and 0.23 nmol, respectively). These data imply that 5-HT_2A antagonists may be effective peripherally acting analgesics or analgesic adjuncts in pain associated with 5-HT release from platelets, such as acute injury and, perhaps, some chronic pain states.