A new study considers methadone to be most appropriate non-addictive opioid drug to treat chronic pain

The experts Vicent Casadó, Estefanía Moreno and Verònica Casadó-Anguera, from the Molecular Neurobiology Research Group of the Faculty of Biology, the IBUB and the CIBERNED.

The new study describes the molecular action mechanism in cell and animal models brought by the therapeutical benefits of methadone.

Administrating methadone instead of morphine is he most indicated pharmacological treatment in the fight against chronic pain, according to a new article published in the Journal of Clinical Investigation –which counts on the participation of the experts Vicent Casadó, Estefania Moreno and Verònica Casado-Anguera, from the Molecular Neurobiology Research Group of the Faculty of Biology, the Institute of Biomedicine of the University of Barcelona (IBUB) and the Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED).

The new study, which describes the molecular action mechanism in cell and animal models brought by the therapeutical benefits of methadone, counts on the participation of the experts from the National Institute of Health, the University of Maryland, and the Massachusetts General Hospital (United States), among other institutions.

Chronic pain: from opiates to pharmacological addiction

One out of five people in Europe suffers from chronic pain –from moderate to severe pain- and a third part of the affected people face limitations to keep an independent lifestyle due this pain. According to the data, there are about fifty million affected people with this pathology in Spain, the United Kingdom, France, Germany and Italy. In the United States, about between fifty and a hundred million people suffer from constant pain and the pharmacological dependence on opiates has created a serious public health crisis.

Chronic pain responds well to opiates at first, but in the long run, the treatment fails, mainly due the tolerance to prescribed drugs and the risk of addiction. In this context, it is determining to promote new therapeutical alternatives to use the efficiency of opiates and to prevent addiction and tolerance-derived adverse effects.

The great natural brain reward system

Addictive substances affect a nervous system –mesolimbic pathway- which is related to the natural reward mechanisms of the brain. This mesolimbic reward system’s neurological base has the dopaminergic neurons of the ventral tegmental area (VTA), which release dopamine in the nucleus accumbens and are responsible for the addictive response to opioids and other compounds.

Specifically, MOR receptors promote the dopamine release into the nucleus accumbens, and therefore, take part both in the analgesic effects and as addictive action of opiates. The Gal1R receptors confront the MOR receptor effects, since these cause a reduction in the dopamine release.

Both the Gal1R and MOR belong to the family of G protein coupled receptors (GPCR), the biggest group of membrane proteins involved in transduction of cell signals and the control of essential functions of cells (neurotransmission, metabolism, proliferation, differentiation, etc.). Therefore, their role is essential in many dysfunctions that are related to pathologies and in the physiological response of drugs.

Moreover, researchers proved the formation of dimers among GPCR receptors –homodimer and heterodimer- is associated with the acquisition of new pharmacological and functional features different from the ones from their individual compounds, a condition which allows a more precise control of their physiological functions.

In this context, designing drugs to interact with these oligomeric compounds from some receptors –with a specific localization- involved in a certain pathology, could shape new strategies to reduce the adverse effects and to improve efficiency of pharmacological treatments.

Methadone versus morphine

According to the new study, in the analyzed murine models, a high percentage of the Gal1R and MOR receptors are forming MOR-Gal1R heteromers in the ventral tegmental area –but not in the spinal cord.

Since methadone acts preferably on MOR receptors when these do not form heteromers with Gal1R, its effect is mainly peripheral. This is why the methadone’s ability to activate the dopaminergic systems is less compared to morphine and fentanyl, which can indistinctly act on MOR receptors and MOR-Gal1R compounds. This would explain the great proportion of the analgesic effects –and not euphoric- of the administration of methadone, which would be profiled as the most indicated non-addictive opiate to treat chronic pain.

According to the experts, the formation of heteromers could be used as a new therapeutical strategy to counterbalance the opiate addictive dopaminergic effects. In previous studies, the team from the Faculty of Biology and IBUB had already shown the neuropeptide galanin –with neurotrophic and neuroprotection properties- can cause a reduction in the dopamine release in the nucleus accumbens (Journal of Neuroscience, 2016). Therefore, the effects derived from the activation of the MOR receptors in the ventral tegmental area –which generate heteromer with Gal1R receptors- could be counterbalanced with a co-administration of Gal1R ligands with opiates.

Reference articles:

Cai, N. S.; Quiroz, C.; Bonaventura, J.; Bonifazi, A.; Cole, T. O.; Purks, J.; Billing, A. S.; Massey, E.; Wagner, M.; Wish, E. D.; Guitart, X.; Rea, W.; Lam, S.; Moreno, E.; Casadó-Anguera, V.; Greenblatt, A. D.; Jacobson, A. E.; Rice, K. C.; Casadó, V.; Newman, A. H.; Winkelman, J. W.; Michaelides, M.; Weintraub, E.; Volkow, N. D.; Belcher, A. M.; Ferré, S. «Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids», Journal of Clinical Investigation, 2019, 130: 2730-2744. Doi: 10.1172/JCI126912

Moreno, E.; Quiroz, C.; Rea, W.; Cai, N. S.; Mallol, J.; Cortés, A.; Lluís, C.; Canela, E. I.; Casadó, V.; Ferré, S. «Functional μ-opioid-galanin receptor heteromers in the ventral tegmental area». Journal of Neuroscience, 2017, 37(5): 1176-1186. Doi: 10.1523/JNEUROSCI.2442-16.2016

Methadone, non-addictive, Molecular Neurobiology Research Group, Faculty of Biology, the IBUB, CIBERNED, Morphine, Journal of Clinical Investigation
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