Spinal Serotonin 1A Receptor Contributes to the Analgesia of Acupoint Catgut Embedding by Inhibiting Phosphorylation of the N-Methyl-d-Aspartate Receptor GluN1 Subunit in Complete Freund's Adjuvant-Induced Inflammatory Pain in Rats

J Pain. 2019 Jan;20(1):16.e1-16.e16. doi: 10.1016/j.jpain.2018.07.011. Epub 2018 Aug 10.

Abstract

Acupoint catgut embedding (ACE) is a widely used traditional Chinese medicine method to manage various diseases, including chronic inflammatory pain. We sought to assess the possible analgesic effects of ACE in comparison with electroacupuncture (EA) and to study the analgesic mechanisms of ACE in a rat model of inflammatory pain induced by injection of complete Freund's adjuvant (CFA) into the hind paw of rats. The von Frey, radiant heat, and gait analysis tests were performed to evaluate the analgesic effects of ACE and EA, and Western blot and immunohistochemistry assays were carried out to determine the molecular mechanisms of ACE. ACE treatments were administered every 4 days or every week with different acupoints (ipsilateral, contralateral, or bilateral ST36 and GB30 acupoints). The most effective ACE strategy for attenuating the nocifensive response induced by CFA injection was performing ACE once a week at ipsilateral ST36 in combination with GB30. EA treatment every other day at ipsilateral ST36 and GB30 showed comparable analgesic effects. ACE inhibited the increased activation of the GluN1 subunit of the N-methyl-d-aspartate receptor and the subsequent Ca2+-dependent signals (CaMKII, ERK, and CREB) that take place in response to CFA. The effects of ACE were similar to intrathecal injection of vilazodone (a serotonin 1A receptor [5-HT1AR] agonist) and were blocked by WAY-100635 (a 5-HT1AR antagonist). In summary, we show that ACE attenuates CFA-induced inflammatory pain in rats by activating spinal 5-HT1AR and by inhibiting the phosphorylation of GluN1, thus, inhibiting the activation of Ca2+-dependent signaling cascades. PERSPECTIVE: This article presents the novel evidence concerning the spinal 5-HT1AR activation-related molecular signaling of ACE analgesia in a rat model of CFA-induced inflammatory pain. This work may help clinicians to verify the effectiveness of ACE analgesia and to better understand the underlying mechanism.

Keywords: Acupoint stimulation; Ca(2+)-dependent signal cascade; electroacupuncture; serotonin; spinal cord.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acupuncture Analgesia* / methods
  • Acupuncture Points*
  • Animals
  • Catgut*
  • Disease Models, Animal
  • Electroacupuncture* / methods
  • Freund's Adjuvant / pharmacokinetics
  • Inflammation / chemically induced
  • Inflammation / metabolism*
  • Male
  • Pain / chemically induced
  • Pain / metabolism*
  • Pain Management*
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Serotonin 5-HT1 Receptor Agonists / administration & dosage
  • Serotonin 5-HT1 Receptor Agonists / pharmacology*
  • Serotonin 5-HT1 Receptor Antagonists / pharmacology
  • Spinal Cord / drug effects
  • Vilazodone Hydrochloride / pharmacology

Substances

  • NMDA receptor A1
  • Receptors, N-Methyl-D-Aspartate
  • Serotonin 5-HT1 Receptor Agonists
  • Serotonin 5-HT1 Receptor Antagonists
  • Receptor, Serotonin, 5-HT1A
  • Freund's Adjuvant
  • Vilazodone Hydrochloride