Effects of acetaminophen on monoaminergic systems in the rat central nervous system

Abstract

Although acetaminophen is a well established analgesic, its mechanism of action is still unknown. We investigated whether this drug could affect central monoaminergic neurotransmission in rats. Significant increases in serotonin (5-HT) levels were found in the posterior cortex, hypothalamus, striatum, hippocampus and brain stem, but not spinal cord, 45 min after per os administration of 200-400 mg/kg of acetaminophen. However, this treatment altered neither the levels of 5-hydroxyindoleacetic acid nor the accumulation of 5-hydroxytryptophan after blockade of aromatic L-amino acid decarboxylase. On the other hand, a decrease in both the levels of the dopamine (DA) metabolite, dihydroxyphenylacetic acid, and the accumulation of dihydroxyphenylalanine were noted in the striatum of acetaminophen-treated rats. Finally, acetaminophen administration significantly increased noradrenaline (NA) levels in the posterior cortex. In vitro studies showed that acetaminophen (1 mM) enhanced K+-evoked overflow of [3H]5-HT, but not [3H]DA and [3H]NA, previously taken up in brain slices, and exerted no direct effect on monoamine oxidase A, tyrosine hydroxylase and catechol-O-methyl-transferase activities. These results indicate that acetaminophen affects central monoaminergic neurotransmission, thereby suggesting that monoamines (especially 5-HT) might participate in its analgesic action.

Serotonergic System Does Not Contribute to the Hypothermic Action of Acetaminophen

“…8) Consistent with these findings, depletion of serotonin and central administration of serotonergic antagonists inhibit the antinociceptive effect of AcAP in rats and mice. 5,7,[9][10][11] Also in humans, tropisetron and granisetron block the analgesic effect of AcAP.…”

“…8) However, it also has been shown that serotonin efflux in the hypothalamus of clorgiline-treated mice rises 11-fold when the body temperature is lowered by 5-hydroxytryptophan administration, 28) and thus the increase of brain serotonin by AcAP seems to be far from this level. The serotonin-non-dependence of AcAP-induced hypothermia suggests that the mechanism responsible for the hypothermic action of AcAP differs from that underlying the mechanism responsible for analgesia.…”

Mechanisms of Non-Opioid Analgesics Beyond Cyclooxygenase Enzyme Inhibition

“…In rats, ASA increases 5-HT content in the cerebral cortex and pons [50,51], as does acetaminophen in the striatum, posterior cortex, hypothalamus, hippocampus and brain stem but not the spinal cord of rats [52]; while rofecoxib increases 5-HT in the frontal cortex [53]. Lysine ASA increases concentrations of 5-hydroxyindole acetic acid, in several areas of the brain in rats [54].…”

Development of a Method for a Sensitive Simultaneous Determination of Dopamine and Paracetamol in Biological Samples and Pharmaceutical Preparations

“…For example, PAR can protect primary rat embryonic DA neurons from glutamate toxicity. Also, PAR administration 2 International Journal of Electrochemistry at antinociceptive doses affects serotonin (5-HT) and dopamine levels in various brain areas and the spinal cord in rate [9].…”