Chemokine Receptor Antagonists in Combination with Morphine as a Novel Strategy for Opioid Dose Reduction in Pain Management.

Abstract

INTRODUCTION:

Although opioids are widely prescribed for pain, in many circumstances, they have only modest efficacy. Preclinical studies have shown that chemokines, immune mediators released during tissue injury and inflammation, can desensitize opioid receptors and block opioid analgesia by a process termed "heterologous desensitization." The present studies tested the hypothesis that in evoked pain, certain chemokine receptor antagonists (CRAs), given with a submaximal dose of morphine, would result in enhanced morphine potency.

METHODS:

Three rodent pain assays were used: incisional pain in rats, the cold-water tail flick test in rats, and the formalin test in mice. The FDA-approved, commercially available CRAs, maraviroc and AMD3100, were used. They block the chemokine receptors and ligands, CCR5/CCL5 (RANTES) and CXCR4/CXCL4 (SDF-1α), respectively.

RESULTS:

In the incisional pain assay, it was found that the combination of a single CRA, or of both CRAs, with morphine significantly shifted the morphine dose-response curve to the left, as much as 3.3-fold. In the cold-water tail flick and formalin tests, significant increases of the antinociceptive effects of morphine were also observed when combined with CRAs.

CONCLUSIONS:

These results support the potential of a new "opioid-sparing" approach for pain treatment, which combines CRAs with reduced doses of morphine.

• Authors: Toby K Eisenstein, Xiaohong Chen, Saadet Inan, Joseph J Meissler, Christopher S Tallarida, Ellen B Geller, Scott M Rawls, Alan Cowan, Martin W Adler
• Journal: Military medicine (Mil Med) Vol. 185 Issue Suppl 1 Pg. 130-135 (01 07 2020) ISSN: 1930-613X [Electronic] England
• PMID: 32074321 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © Association of Military Surgeons of the United States 2020. All rights reserved. For permissions, please e-mail: [email protected].

Chemical References

• Analgesics, Opioid
• Benzylamines
• Cyclams
• Drug Combinations
• Heterocyclic Compounds
• Receptors, Chemokine
• Morphine
• Maraviroc
• plerixafor

Topics

• Analgesics, Opioid (pharmacology, therapeutic use)
• Analysis of Variance
• Animals
• Benzylamines
• Cyclams
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Combinations
• Heterocyclic Compounds (pharmacology, therapeutic use)
• Maraviroc (pharmacology, therapeutic use)
• Morphine (pharmacology, therapeutic use)
• Pain Management (methods, standards, statistics & numerical data)
• Pain Measurement (methods)
• Rats
• Rats, Sprague-Dawley
• Receptors, Chemokine (antagonists & inhibitors)
• Surgical Wound (complications, drug therapy)