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

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 295; no. 1; pp. 291 - 294
• Main Authors: Raffa, R B, Stone, Jr, D J, Tallarida, R J
• Format: Journal Article
• Language: English
• Published: United States 01.10.2000
• Subjects: Acetaminophen - administration & dosage; Acetaminophen - pharmacology; Analgesics, Non-Narcotic - pharmacology; Animals; Injections, Intraventricular; Injections, Spinal; Male; Mice; Mice, Inbred ICR; Spinal Cord - drug effects
• ISSN: 0022-3565

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.