Newly Published
Pain Medicine  |   June 2017
Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn
Author Notes
  • 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.).
  • Submitted for publication October 29, 2016. Accepted for publication April 8, 2017.
    Submitted for publication October 29, 2016. Accepted for publication April 8, 2017.×
  • Research Support: Supported by a Grant-in-Aid for Exploratory Research No. 16K20081 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Tokyo, Japan.
    Research Support: Supported by a Grant-in-Aid for Exploratory Research No. 16K20081 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, Tokyo, Japan.×
  • Competing Interests: The authors declare no competing interests.
    Competing Interests: The authors declare no competing interests.×
  • Correspondence: Address correspondence Dr. Kohno: Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi Dori, Chuo-Ku, Niigata City 951-8510, Japan. kohno-t@umin.net.Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Pain Medicine / Central and Peripheral Nervous Systems / Pain Medicine / Pharmacology
Pain Medicine   |   June 2017
Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn
Anesthesiology Newly Published on June 1, 2017. doi:10.1097/ALN.0000000000001700
Anesthesiology Newly Published on June 1, 2017. doi:10.1097/ALN.0000000000001700
Abstract

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 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.

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.