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Evidence-Based Complementary and Alternative Medicine
Volume 2013, Article ID 563716, 17 pages
Review Article

On the G-Protein-Coupled Receptor Heteromers and Their Allosteric Receptor-Receptor Interactions in the Central Nervous System: Focus on Their Role in Pain Modulation

1Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177 Stockholm, Sweden
2Faculty of Science, University of Malaga, 29080 Malaga, Spain
3Laboratory of Eukaryotic Gene Expression and Signal Transduction (LEGEST), Ghent University-Gent, 9000 Ghent, Belgium
4Russian Academy of Sciences, St. Petersburg Institute for Informatics and Automation, 193167 Saint Petersburg, Russia
5IRCCS, Lido Venice, 41100 Venice, Italy

Received 27 February 2013; Revised 20 May 2013; Accepted 24 May 2013

Academic Editor: Yi-Hung Chen

Copyright © 2013 Dasiel O. Borroto-Escuela et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


The modulatory role of allosteric receptor-receptor interactions in the pain pathways of the Central Nervous System and the peripheral nociceptors has become of increasing interest. As integrators of nociceptive and antinociceptive wiring and volume transmission signals, with a major role for the opioid receptor heteromers, they likely have an important role in the pain circuits and may be involved in acupuncture. The delta opioid receptor (DOR) exerts an antagonistic allosteric influence on the mu opioid receptor (MOR) function in a MOR-DOR heteromer. This heteromer contributes to morphine-induced tolerance and dependence, since it becomes abundant and develops a reduced G-protein-coupling with reduced signaling mainly operating via β-arrestin2 upon chronic morphine treatment. A DOR antagonist causes a return of the Gi/o binding and coupling to the heteromer and the biological actions of morphine. The gender- and ovarian steroid-dependent recruitment of spinal cord MOR/kappa opioid receptor (KOR) heterodimers enhances antinociceptive functions and if impaired could contribute to chronic pain states in women. MOR1D heterodimerizes with gastrin-releasing peptide receptor (GRPR) in the spinal cord, mediating morphine induced itch. Other mechanism for the antinociceptive actions of acupuncture along meridians may be that it enhances the cross-desensitization of the TRPA1 (chemical nociceptor)-TRPV1 (capsaicin receptor) heteromeric channel complexes within the nociceptor terminals located along these meridians. Selective ionotropic cannabinoids may also produce cross-desensitization of the TRPA1-TRPV1 heteromeric nociceptor channels by being negative allosteric modulators of these channels leading to antinociception and antihyperalgesia.