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Continuous Intrathecal Infusion of Cannabinoid Receptor Agonists Attenuates Nerve Ligation–Induced Pain in Rats
  1. Sheng-Jie Shiue, PhD*,
  2. Hsien-Yu Peng, PhD,
  3. Chung-Ren Lin, MD, PhD,
  4. Shih-Wei Wang, PhD,
  5. Ruey-Horng Rau, MD* and
  6. Jen-Kun Cheng, MD, PhD*,
  1. *Department of Anesthesiology, MacKay Memorial Hospital, Taipei; †Department of Medicine, MacKay Medical College, New Taipei City; and ‡Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
  1. correspondence: Jen-Kun Cheng, MD, PhD, Department of Anesthesiology, MacKay Memorial Hospital, No. 92, Sec. 2, Zhongshan N Rd, Taipei 10449, Taiwan (e-mail: jkcheng{at}usa.net).

Abstract

Background and Objectives Cannabinoid receptors (CB1R/CB2R) are known to play important roles in pain transmission. In this study, we investigated the effects of continuous intrathecal infusion of CB1/2R agonists in the L5/6 spinal nerve ligation pain model.

Methods Under isoflurane anesthesia, rats received nerve ligation and intrathecal catheter connected to an infusion pump. After surgery, saline (1 μL/h), CB1/2R agonist WIN55,212-2, CB1R agonist ACEA, or CB2R agonist AM1241 (1 μmol/h) was given intrathecally for 7 days. The mechanical and thermal sensitivities of rat hindpaw were determined by von Frey hair and radiant heat tests. The expression of CB1/2R and protein levels of CB1/2R, Iba1, glial fibrillary acidic protein, and tumor necrosis factor α were examined by immunofluorescence study and Western blotting.

Results On postligation day 7, rats that received WIN55,212-2, ACEA or AM1241 had significantly higher mean withdrawal thresholds (6.8, 8.4, and 10.2 g) and latencies (6.3, 7.3, and 9.1 seconds) than did saline-treated rats (1.7 g, 2.2 seconds). Cannabinoid receptors were expressed not only in IB4+ (isolectin B4) and CGRP+ (calcitonin gene–related peptide) dorsal root ganglion neurons, their central terminals, and peripheral axons, but also in neurons, microglia, and astrocytes in spinal cord. Cannabinoid receptor agonists enhanced nerve ligation–induced up-regulation of cannabinoid receptor in spinal cord and dorsal root ganglion. Treatment with WIN55,212-2 or AM1241, but not ACEA, markedly reduced nerve ligation–induced up-regulation of Iba1, glial fibrillary acidic protein, and tumor necrosis factor α in spinal cord.

Conclusions Continuous intrathecal infusion of CB1/2R agonists elicits antinociception in the pain model. The mechanisms might involve their actions on neurons and glial cells. CB2R, but not CB1R, seems to play an important role in the regulation of nerve injury–induced neuroinflammation.

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Footnotes

  • S.-J.S. and H.-Y.P. contributed equally to this work.

    S.-J.S. has received grant (MOST 105-2811-B-195-001) from the Ministry of Science and Technology, Taiwan. H.-Y.P. has received grant (MMH-MM-10403) from MacKay Memorial Hospital, Taipei, Taiwan. J.-K.C. has received grants (MOST 103-2314-B-195-003-MY2 and 105-2314-B-195-003-MY3) from the Ministry of Science and Technology, Taiwan, and grants MMH 10305, 10374, 104100, 10439, 10548, 10575, and 10621 from MacKay Memorial Hospital, Taipei, Taiwan.

    The authors declare no conflict of interest.

    Author Contributions: H.-Y.P., C.-R.L., and J.-K.C. participated in the study design and planning; S.-J.S., H.-Y.P., and J.-K.C. performed the study; S.-W.W., R.-H.R., and J.-K.C. helped analyze the data; S.-J.S., H.-Y.P., and J.-K.C. wrote the manuscript.

    Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.rapm.org).

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