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147 ACETAMINOPHEN PREVENTS HYPERALGESIA IN CENTRAL PAIN CASCADE.
  1. B. K Crawley1,
  2. S. Malkmus1,
  3. B. L. Fitzsimmonds1,
  4. X.-Y. Hua1,
  5. T. L. Yaksh1
  1. 1Department of Anesthesiology, University of California, San Diego, CA.

Abstract

Background Acetaminophen is an analgesic and antipyretic drug believed to exert its effect through interruption of central pain processing pathways, although the means by which this occurs remains unknown. Importantly, its actions are typically limited to pain states wherein there has been an increased sensitivity to painful stimuli secondary to tissue injury or inflammation. Thus, whether this effect is peripheral, occurring at the injury site, or central is not known.

Objective This study addresses the efficacy of acetaminophen delivered orally and intrathecally in preventing the development of hyperalgesia induced through the direct activation of proalgogenic spinal receptors. Here we spinally deliver substance P (sP) and N-methyl-d-aspartic acid (NMDA) to activate neurokinin 1 and NMDA receptors. These receptors are activated under normal circumstances by substance P and glutamate released from nociceptive sensory afferents.

Methods In one experimental group, 300 mg/kg acetaminophen suspended in 5% dimethyl sulfoxide (DMSO) was given orally followed by intrathecal (IT) injection of substance P (n = 8). As a control, 5% DMSO was given orally before injection of intrathecal substance P (n = 7). In a second group, rats received 10 μg, 100 μg, or 200 μg of acetaminophen delivered intrathecally (n = 24) preceding IT NMDA. As a control, 5% DMSO (n = 7) or only saline (n = 6) was given preceding IT NMDA. All rats were tested at 10-minute intervals for response latency to a thermal stimulus.

Results The intrathecal delivery of sP or NMDA produced a significant fall in baseline thermal escape latency in vehicle-treated animals (ie, hyperalgesia). Oral acetaminophen significantly (p = .0122) increased reaction latencies compared with DMSO. In the second group of experimental animals, IT acetaminophen increased reaction latencies when compared with saline at all three dose levels (p = .02, .0001, .0001) and DMSO at 100 μg and 200 μg (p = .0158, .0429). Response latencies following doses 10 μg and 100 μg were significantly different (p = .0429).

Conclusions Results indicate that acetaminophen is effective in attenuating the development of hyperalgesia produced by central pain mediators in a dose-dependent fashion. Oral acetaminophen's ability to reverse this spinally initiated hyperalgesia emphasizes the likely central action and bioavailability of the systemically delivered drug. Jointly, these data argue for an important central antihyperalgesic action of acetaminophen.

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