The drug could be a less addictive option, helping to combat the drug crisis.
Administering methadone instead of morphine is a more appropriate pharmacological treatment in the fight against chronic pain, as revealed by a new article published in the Journal of Clinical Investigation in which the experts Vicent Casadó, Estefanía Moreno and Verònica Casadó Anguera, from the Instituto of Biomedicine of the University of Barcelona (IBUB) and the Network Biomedical Research Center on Neurodegenerative Diseases (CIBERNED).
Experts from the National Institutes of Health, the University of Maryland and the Massachusetts General Hospital (USA) also participate in the work, which describes in cell and animal models the mechanism of molecular action that produces the therapeutic benefits of methadone. Among other institutions,
Chronic pain responds very well to opiates initially, but long-term treatment fails due to tolerance and the risk of addiction.
Addictive substances affect a nervous circuit – the mesolimbic pathway – related to the brain’s natural reward mechanisms. This mesolimbic reward system is neurologically based on 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 other compounds.
Specifically, MOR receptors promote the release of dopamine in the nucleus accumbens and, therefore, participate in both the analgesic and addictive effects of opiates. In contrast, Gal1R receptors counteract the effects of MOR receptors since they cause a decrease in dopamine release.
The Gal1R and the MOR receptors belong to the family of G protein-coupled receptors (GPCR), the largest group of membrane proteins involved in the transduction of cellular signals and the control of essential cell functions (neurotransmission, metabolism, proliferation, differentiation, etc.). Therefore, its role is critical in many dysfunctions related to pathologies and in the physiological response to drugs.
In addition, it has been shown that the ability to form dimers between GPCR receptors (homodimers or heterodimers) is associated with acquiring new pharmacological and functional properties different from those of their components. This condition allows more refined control of their physiological functions.
In this context, designing drugs that interact with these oligomeric complexes of some receptors –with a specific location– involved in a given pathology would allow outlining new strategies to reduce side effects and improve the effectiveness of pharmacological treatments.
Methadone versus morphine
According to the new work, in the murine models studied, a high percentage of Gal1R and MOR receptors form MOR-Gal1R heteromers in the ventral tegmental area (but not in the spinal cord).
Since methadone acts preferentially on MOR receptors when they do not form heteromers with Gal1Rs, its effect is mainly peripheral. For this reason, the ability of methadone to activate the dopaminergic system is lower than morphine and fentanyl, which can act either on MOR receptors or on MOR-Gal1R complexes. This would explain the more significant proportion of analgesic effects of the administration of methadone. This substance could be outlined as the most indicated non-addictive opiate to treat chronic pain.
According to experts, the ability to form heteromers could also be used as a new therapeutic strategy to counteract the addictive dopaminergic effects of opiates. It should be remembered that, in previous work, the team had already shown that galanin – a neuropeptide with neurotrophic and neuroprotective properties
– is capable of causing a decrease in dopamine release in the nucleus accumbens.
The work describes in cell and animal models the molecular mechanism of action that produces the therapeutic benefits of methadone.
Therefore, the effects generated by activating MOR receptors in the ventral tegmental area
–which form heteromers with Gal1R receptors
–could be counteracted by co-administration of Gal1R ligands with opiates.
Opioids in pharmacological addiction
One in five people in Europe suffer from moderate to severe chronic pain, and a third of those affected find it difficult to maintain an independent lifestyle due to pain. According to the data, there are about fifty million people affected by this pathology between Spain, the United Kingdom, France, Germany and Italy. In the case of the United States, between fifty and one hundred million people suffer from continuous pain, and the pharmacological dependence of many affected on opiates has generated a real public health crisis.
Chronic pain responds very well to opiates initially, but long-term treatment fails, mainly because of tolerance to prescribed medications and the risk of dependence and addiction. For the experts, it is decisive to promote new therapeutic alternatives that take advantage of the efficacy of opiates and avoid the side effects derived from tolerance and addiction.