Cannabinoid receptor type 1 antagonist, AM251, attenuates mechanical allodynia and thermal hyperalgesia after burn injury.

Abstract

BACKGROUND:

Burn injury causes nociceptive behaviors, and inflammation-related pathologic pain can lead to glial cell activation. This study tested the hypothesis that burn injury activates glial cells, and cannabinoid receptor 1 (CB1R) antagonist, AM251, will decrease burn pain.

METHODS:

Anesthetized rats received 0.75-cm third-degree burn on dorsal hind paw. Vehicle or AM251 30 μg intrathecally (older rats, n=6 per group) or, either vehicle, 0.1 or 1.0 mg/kg intraperitoneally (younger rats, n=6 per group), started immediate postburn, was administered for 7 days. Mechanical allodynia and thermal hyperalgesia were tested on ventral paw for 14 days. Microglial and astroglial activity was assessed by immunocytochemistry.

RESULTS:

Allodynia, observed on burn side from day 1 to 14, was significantly (P<0.05) attenuated by intrathecal and intraperitoneal AM251 (1 mg/kg) starting from 3 to 14 days. Hyperalgesia, observed from day 3 to 12, was completely (P<0.05) reversed by intrathecal and intraperitoneal AM251 (1 mg/kg). AM251 0.1 mg/kg had no effect. Microglial activity (n=3 per time point) increased (P<0.05) 18.5±7.5 and 12.3±1.6 (mean±SD) fold at 7 and 14 days, respectively. Astroglial activity (n=4 per time point) increased 2.9±0.3 fold at day 7 only. Glial activities were unaltered by AM251.

CONCLUSIONS:

AM251 inhibited nociceptive behaviors after burn even beyond 7-day period of administration. Although many studies have documented the utility of CB1R agonists, this study indicates that endogenous cannabinoids may have an unexpected pronociceptive effect during development of burn pain, explaining why CB1R antagonist, AM251, improves nociceptive behaviors. The decreased nociception with AM251 without altering glial activity indicates that AM251 acts further downstream of activated glial cells.

• Authors: Masashi Ueda, Hajime Iwasaki, Shuxing Wang, Eri Murata, K Y Trudy Poon, Jianren Mao, J A Jeevendra Martyn
• Journal: Anesthesiology (Anesthesiology) Vol. 121 Issue 6 Pg. 1311-9 (Dec 2014) ISSN: 1528-1175 [Electronic] United States
• PMID: 25188001 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Analgesics, Non-Narcotic
• Piperidines
• Pyrazoles
• Receptor, Cannabinoid, CB1
• AM 251

Topics

• Aging (physiology)
• Analgesics, Non-Narcotic (therapeutic use)
• Animals
• Burns (complications, pathology)
• Hyperalgesia (drug therapy, etiology, pathology)
• Injections, Spinal
• Male
• Neuroglia (pathology)
• Pain Measurement (drug effects)
• Physical Stimulation
• Piperidines (therapeutic use)
• Pyrazoles (therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (antagonists & inhibitors)
• Spinal Cord (pathology)