Abstract
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 ED50 value of 137 (S.E. = 23) μg = 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, ED50 = 57 (S.E. = 9) μg, that reverted toward additivity, ED50 = 129 (S.E. = 23) μg, when the opioid antagonist naloxone was given spinally (3.6 μg = 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.
Footnotes
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Send reprint requests to: Robert B. Raffa, Ph.D., Temple University School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA 19140. E-mail:rraffa{at}nimbus.temple.edu
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↵1 The laboratory work was conducted at the R. W. Johnson Pharmaceutical Research Institute in Spring House, PA. R.J.T. was supported in part by National Institute on Drug Abuse Grant DA 09793-03.
- Abbreviations:
- i.t.
- intrathecal
- 5-HT3
- 5-hydroxytryptamine3
- Received April 17, 2000.
- Accepted June 26, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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