Acetaminophen-induced antinociception via central 5-HT_2A receptors

Abstract

Acetaminophen is one of the most widely used analgesic drugs. Although the mechanism of analgesic action of acetaminophen is still not known, the involvement of the central serotonin (5-hydroxytryptamine: 5-HT) system is one possibility. In the present study, we examined the antinociceptive effect of acute and chronic intraperitoneally (i.p.) administered acetaminophen by tail flick latency measurements in the rat. A significantly increased tail flick latency was observed in acute and 15-day acetaminophen-treated rats, but not in 30-day acetaminophen-treated rats, at a dose of 400 mg/kg/day. To investigate the plasticity of receptors at postsynaptic membrane, we conducted a series of experiments by radioligand binding method on frontal cortex and brainstem membrane. The technique involved radioligand binding with [phenyl-4-³H]spiperone and ketanserin for studying 5-HT_2A receptor characteristics. A significant decrease in the maximum number of 5-HT_2A binding sites (B_max) was demonstrated in all treatment groups with acetaminophen 300 and 400 mg/kg on frontal cortex membrane, whereas the value of the dissociation equilibrium constant (K_d) remained unchanged. The down-regulation of 5-HT_2A binding sites in frontal cortex was of a lesser magnitude after 30 days of treatment and the tail flick latency was as in the control animals. These results suggest that down-regulation of 5-HT_2A receptor in response to 5-HT release is a major step in the mechanism underlying analgesia produced by this agent. On the contrary, chronic use of acetaminophen may result in 5-HT depletion, which in turn produces re-adaptation of postsynaptic 5-HT_2A receptors. These data provide further evidence for a central 5-HT-dependent antinociceptive effect of acetaminophen.

Introduction

In spite of the wide use of acetaminophen as an analgesic, its mechanism of action is still unclear. It is still not known whether acetaminophen acts peripherally, centrally or both. Since it is a very poor inhibitor of cyclooxygenase-2, which is involved in inflammation, but a good inhibitor of cyclooxygenase-1, which is not, it apparently exerts its analgesic effects via central actions (Bowman and Rand, 1980, Flower et al., 1980, Jackson et al., 1984). Various mechanisms have been proposed for acetaminophen-induced analgesia, i.e. central inhibition of prostaglandin synthesis, modulation of the central L-arginine-nitric oxide pathway (Bjorkman et al., 1994), modulation of nociceptive transmission in spinal and supraspinal pathways (Hunskaar et al., 1985), etc. as central 5-HT systems may play a role in antinociception.

A relationship between 5-HT system and acetaminophen has been demonstrated previously. The analgesic activity of acetaminophen was reduced in rats in which the 5-HT pathways were lesioned with intrathecal 5,6-dihydroxytryptamine (Tjølsen et al., 1991). A significant increase of 5-HT levels in pons and cerebral cortex was reported in acute administration of acetaminophen in experimental animals (Pini et al., 1996). Chronic use of acetaminophen could deplete 5-HT from platelets and eventually up-regulate the 5-HT_2A receptors on platelet membranes in migraine patients (Srikiatkhachorn and Anthony, 1996). The present study has been conducted to further investigate the acute and chronic effects of acetaminophen on antinociceptive activity and central 5-HT_2A receptors. Frontal cortex and brainstem were selected for study as frontal cortex plays an important role in modification of nociceptive perception and brainstem is a major source of central 5-HT neurons.