Acetaminophen: a central analgesic drug that involves a spinal tropisetron-sensitive, non-5-HT(3) receptor-mediated effect.
The reversal of the antinociceptive effect of systemically administered acetaminophen (paracetamol) by intrathecal administration of the potent 5-HT(3) receptor antagonist tropisetron has been reported in rats subjected to the paw pressure test, suggesting that acetaminophen action is mediated through spinal 5-HT(3) receptors. However, more recent data, showing differences between the pharmacological profiles of various 5-HT(3) receptor antagonists, led us to reconsider the involvement of spinal 5-HT(3) receptors. To address this question, two different approaches were used: 1) electrophysiological recordings to assess whether acetaminophen directly modulates 5-HT(3) receptor activity and 2) pharmacological investigations with various 5-HT(3) receptor antagonists and spinal 5-HT(3) receptors antisense oligodeoxynucleotides (AODNs) to determine how those treatments might affect the antinociceptive action of acetaminophen. Electrophysiological studies demonstrated that acetaminophen had no direct agonist or antagonist effects on 5-HT(3A) receptors. Unlike tropisetron, other 5-HT(3) receptor antagonists, such as ondansetron and granisetron, injected intrathecally were unable to reverse the antinociceptive effect of acetaminophen. Moreover, pretreatment with AODNs did not reverse the acetaminophen-induced antinociceptive effect, although it suppressed the antinociceptive effect of m-chlorophenylbiguanide, a specific agonist of 5-HT(3) receptors, and significantly reduced (30%) the expression of these receptors in the dorsal horn of the spinal cord. These results suggest that acetaminophen-induced antinociceptive action involves a spinal tropisetron-sensitive receptor that is not the 5-HT(3) receptor and that remains to be identified.
INSERM/UdA E9904, Faculté de médecine, Place Henri-Dunant - B.P. 38, 63001 Clermont-Ferrand Cedex 1, France.
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F
Libert
J
J
Bonnefont
E
E
Bourinet
E
E
Doucet
A
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Alloui
M
M
Hamon
J
J
Nargeot
A
A
Eschalier
D000082:Acetaminophen / Q000494:pharmacology*; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D001645:Biguanides / Q000494:pharmacology; D004347:Drug Interactions; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D051381:Rats; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D000077526:Tropisetron
D000700:Analgesics; D001645:Biguanides; D007211:Indoles; D020319:Oligodeoxyribonucleotides, Antisense; D044406:Receptors, Serotonin, 5-HT3; D058831:Serotonin 5-HT3 Receptor Antagonists; D012702:Serotonin Antagonists; D000082:Acetaminophen; D000077526:Tropisetron; C065734:1-(3-chlorophenyl)biguanide