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Cited by 39Pain Mechanisms and TreatmentsIon Channels and ReceptorsPain Management and Treatment

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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

Ohashi, Nobuko, Uta, Daisuke, Sasaki, Mika, Ohashi, Masayuki, Kamiya, Yoshinori, Kohno, Tatsuro·2017·Anesthesiology
DOI 10.1097/aln.0000000000001700
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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.

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Metadata

Authors
Ohashi, N., Uta, D., Sasaki, M., Ohashi, M., Kamiya, Y., & Kohno, T.
Affiliations
  • Niigata University (JP)
  • University of Toyama (JP)
  • Niigata University Medical and Dental Hospital (JP)
Corresponding author
Kohno, Tatsuro
ORCID
Venue
Anesthesiology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-08
Volume
127
Issue
2
Pages
355-371
ISSN
0003-3022 (ISSN-L)
DOI
10.1097/aln.0000000000001700
OpenAlex
W2619962806
Cited by
39
References
8
Citations by year
2026: 4 · 2025: 5 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 5 · 2020: 4 · 2019: 6 · 2018: 1
FWCI
2.23
Type
journal article
Language
en
Open access
closed
Locations
  • Anesthesiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
Japan Society for the Promotion of Science (16K20081, 15K08667)
Topics
  • Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
  • Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Treatment
Keywords
paracetamol, TRPV1, cannabinoid 1 receptor, dorsal horn, C-fibers, primary afferent terminals, analgesia, inflammatory pain, excitatory postsynaptic currents, conduction block, shunt current, receptor desensitization, acetaminophen metabolites
MeSH terms
Acetaminophen, Analgesia, Animals, Disease Models, Animal, Male, Neurons, Afferent, Pain, Rats, Wistar, Analgesics, Non-Narcotic, Nerve Fibers, Unmyelinated, TRPV Cation Channels, Rats, Spinal Cord Dorsal Horn

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