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 use d drugs-acetaminophen (paracetamol)-remains largely unknown more than 100 y ears after its original synthesis. Based on the present findings, this elus iveness appears to have resulted from experimental strategies that concentr ated on a single target site or mechanism. Here we report on the use of ana lyses that we previously developed to investigate possible brain/spinal-cor d site-site interaction in acetaminophen-induced antinociception. Spinal (i ntrathecal) administration of acetaminophen to mice produced dose-related, naloxone-insensitive antinociception with an ED50 value of 137 (S.E. = 23) mu g = 907 (S.E. = 153) nmol. In contrast, supraspinal (i.c.v.) acetaminoph en administration had no effect. However, combined administration of acetam inophen in fixed ratios to brain and spinal cord produced synergistic antin ociception, ED50 = 57 (S.E. = 9) mu g, that reverted toward additivity, ED5 0 = 129 (S.E. = 23) mu g, when the opioid antagonist naloxone was given spi nally (3.6 mu g = 10 nmol) or s.c. (3.6 mg/kg). These findings demonstrate for the first time that acetaminophen-induced antinociception involves a "s elf-synergistic" interaction between spinal and supraspinal sites and, furt hermore, that the self-synergy involves an endogenous opioid pathway.