• Nobuko Ohashi, Daisuke Uta, Mika Sasaki, Masayuki Ohashi, Yoshinori Kamiya, and Tatsuro Kohno.
• Division of Anesthesiology (N.O., T.K.) and Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine (M.O.), Niigata University Graduate School of Medical and Dental Sciences, Niigata City, Japan; Department of Applied Pharmacology, Toyama University Graduate School of Medicine and Pharmaceutical Sciences, Toyama City, Japan (D.U.); and Division of Anesthesiology, Niigata University Medical and Dental Hospital, Uonuma Institute of Community Medicine, Minami-Uonuma City, Japan (M.S., Y.K.).
• Anesthesiology. 2017 Aug 1; 127 (2): 355-371.

BackgroundThe 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.MethodsWe 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.ResultsIntravenous 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 Aδ-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 naïve rats.ConclusionsOur 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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