Discovery of "self-synergistic" spinal/supraspinal antinociception produced by acetaminophen (paracetamol)

The mechanism of the analgesic action of one of the world's most widely used drugs-acetaminophen (paracetamol)-remains largely unknown more than 100 years after its original synthesis. Based on the present findings, this elusiveness appears to have resulted from experimental strategies that con...

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Bibliographic Details
Published in:The Journal of pharmacology and experimental therapeutics 2000-10, Vol.295 (1), p.291-294
Main Authors: Raffa, R B, Stone, Jr, D J, Tallarida, R J
Format: Article
Language:English
Subjects:
Acetaminophen - administration & dosage
Acetaminophen - pharmacology
Analgesics, Non-Narcotic - pharmacology
Animals
Injections, Intraventricular
Injections, Spinal
Male
Mice
Mice, Inbred ICR
Spinal Cord - drug effects
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Summary:The mechanism of the analgesic action of one of the world's most widely used drugs-acetaminophen (paracetamol)-remains largely unknown more than 100 years after its original synthesis. Based on the present findings, this elusiveness appears to have resulted from experimental strategies that concentrated on a single target site or mechanism. Here we report on the use of analyses that we previously developed to investigate possible brain/spinal-cord site-site interaction in acetaminophen-induced antinociception. Spinal (intrathecal) administration of acetaminophen to mice produced dose-related, naloxone-insensitive antinociception with an ED(50) value of 137 (S.E. = 23) microgram = 907 (S.E. =153) nmol. In contrast, supraspinal (i.c.v.) acetaminophen administration had no effect. However, combined administration of acetaminophen in fixed ratios to brain and spinal cord produced synergistic antinociception, ED(50) = 57 (S.E. = 9) microgram, that reverted toward additivity, ED(50) = 129 (S.E. = 23) microgram, when the opioid antagonist naloxone was given spinally (3.6 microgram = 10 nmol) or s.c. (3.6 mg/kg). These findings demonstrate for the first time that acetaminophen-induced antinociception involves a "self-synergistic" interaction between spinal and supraspinal sites and, furthermore, that the self-synergy involves an endogenous opioid pathway.
ISSN:0022-3565