期刊
ANESTHESIOLOGY
卷 127, 期 2, 页码 355-371出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/ALN.0000000000001700
关键词
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资金
- Ministry of Education, Culture, Sports, Science, and Technology of Japan, Tokyo, Japan [16K20081]
- Grants-in-Aid for Scientific Research [15K08667, 16K20081] Funding Source: KAKEN
Background: The widely used analgesic acetaminophen is metabolized to N-acylphenolamine, which induces analgesia by acting directly on transient receptor potential vanilloid 1 or cannabinoid 1 receptors in the brain. Although these receptors are also abundant in the spinal cord, no previous studies have reported analgesic effects of acetaminophen or N-acylphenolamine mediated by the spinal cord dorsal horn. We hypothesized that clinical doses of acetaminophen induce analgesia via these spinal mechanisms. Methods: We assessed our hypothesis in a rat model using behavioral measures. We also used in vivo and in vitro whole cell patch-clamp recordings of dorsal horn neurons to assess excitatory synaptic transmission. Results: Intravenous acetaminophen decreased peripheral pinch-induced excitatory responses in the dorsal horn (53.1 +/- 20.7% of control; n = 10; P < 0.01), while direct application of acetaminophen to the dorsal horn did not reduce these responses. Direct application of N-acylphenolamine decreased the amplitudes of monosynaptic excitatory postsynaptic currents evoked by C-fiber stimulation (control, 462.5 +/- 197.5 pA; N-acylphenolamine, 272.5 +/- 134.5 pA; n = 10; P = 0.022) but not those evoked by stimulation of A delta-fibers. These phenomena were mediated by transient receptor potential vanilloid 1 receptors, but not cannabinoid 1 receptors. The analgesic effects of acetaminophen and N-acylphenolamine were stronger in rats experiencing an inflammatory pain model compared to naive rats. Conclusions: Our results suggest that the acetaminophen metabolite N-acylphenolamine induces analgesia directly via transient receptor potential vanilloid 1 receptors expressed on central terminals of C-fibers in the spinal dorsal horn and leads to conduction block, shunt currents, and desensitization of these fibers.
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