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Understanding the Molecular Mechanism of Opiate Withdrawal

A clandestine kit containing materials to inje...

A clandestine kit containing materials to inject illicit drugs. (Photo credit: Wikipedia)

In the United States around 24 million people are addicted to drugs, but only 10% of them receive treatment, which often isn’t successful. The poor rate of those having been through addiction therapy that remain drug free may relate to the fact that many programs use unproven methods. The lack of evidence-based treatments available was highlighted by the National Center on Addiction and Substance abuse last year, who published a report demonstrating that only a small fraction of the addiction care available uses interventions backed by scientific evidence. This is despite the fact that addiction treatment is an area of medicine where considerable research is being conducted into both pharmacological and other therapies.

Withdrawal from opiates

Whether it is to prescription drugs such as codeine and morphine or to heroin, opiates are one of the most common classes of drugs to which people develop an addiction. While many addicts wish to break the cycle of drug dependence, this is not easy owing to the symptoms experienced on withdrawal from opiates. The signs include abdominal pain, nausea and vomiting, sweating, increased heart rate and blood pressure, becoming more irritable, experiencing low mood and sleep problems. These typically develop within 24 hours of drug cessation and usually last for up to 10 days, though their severity does decline during this time; however, feelings of low mood often persist far longer than this.

The withdrawal symptoms contribute to opiate addiction, with users maintaining their habit to prevent these feelings; equally they make it very difficult for those wishing to escape drug taking and can lead to relapse. Adaptation of the nervous system as a consequence of opiate use is thought to explain the symptoms seen on withdrawal. Determining the exact mechanism by which this occurs is the focus of research, which will enable the development and use of appropriate medications to increase the chance of success during drug rehabilitation.

Nerve cells

Nerve cells (Photo credit: Wikipedia)

Role of the periaqueductal gray area in withdrawal symptoms

The search for the areas of the nervous system involved in opiate withdrawal has identified the periaqueductal gray area (PAG) of the midbrain as playing an important role with regards to this. Although this region of the brain is rich in opioid receptors, uncoupling of these receptors can’t fully explain the symptoms experienced when addicts try to break their habit; an increase in the number of immune-reactive nerve cells and increased electrical activity in areas of the PAG after opiate withdrawal point towards the nature of its involvement. Activation of glial cells and the resulting production of pro-inflammatory cytokines in the brain’s PAG, which stimulate neuronal activity, has recently been highlighted as an important factor.

The importance of glial cell activity

Until recently the glial cells were only thought to serve the purpose of holding the nerve cells together, but thanks to research they are now known to have a range of active functions and may indeed be involved in opiate dependence and their withdrawal. Glial cells regulate the function of nerve cells by way of the release of substances that aid the communication between the two types of cells. Astrocytes, a type of glial cell, regulate synaptic transmission between nerve cells; their activation stimulates the release of cytokines, which impact on neuronal function.

English: Very basic neural network with glial ...

English: Very basic neural network with glial cells. Version without legends Français : Réseau neural simple avec deux cellules gliales – astrocyte et oligodendrocyte. Version non légendée. (Photo credit: Wikipedia)

When morphine is removed, glial cells in the brain are activated and the production of a pro-inflammatory mediator known as TNFα occurs; further research shows injecting TNFα into the PAG mimics the symptoms of morphine withdrawal. Additional weight for this involvement in the generation of withdrawal symptoms is shown by the fact that administering anti-inflammatory cytokines or a substance that blocks glial cell activation prevents the development of the classic signs of opiate cessation.

Neuronal implications of TNFα

Consequently how does TNFα exert its effects? TNFα has been shown to influence neuronal activity in a number of ways. Firstly it affects the currents in sodium channels of the nerves, which impacts on electrical transmission of impulses. However, TNFα also increases neurotransmitter release and the expression of specific receptors in nerve cells. As a result, an increase in nerve excitation is seen. The release of TNFα by activated glial cells in the brain therefore heightens the neuronal activity in the PAG, which appears responsible for the signs associated with the withdrawal from morphine.

Although further research is required to provide conclusive evidence that the PAG, glial cells and TNFα are primarily responsible for adverse effects experienced on withdrawal from opiates, these recent studies have certainly paved the way towards finding effective therapies to aid successful drug rehabilitation.


Evelyn Graham is an expert in intensive care procedures. Having graduated in International Business and Journalism a few years ago, she has covered everything from science to local news, environment, sustainability issues and a lot in between.

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About Richard Nelson

Freelance science writing all day and night. I'm an expert at writing, marketing, and publishing. Providing writing services nearly everyday, SEO rich articles about science and tech are my specialties. I also love to make money so I'm for hire as an independent communications expert and business consultant with specializations in project management, writing, science, and engineering. With a vast network of professionals in various fields backed by two degrees, 180 credits hours, 6 graduate courses and several awards and recommendations along the way, who could go wrong?



  1. Pingback: Marijuana and its Effect on the Brain – Is Addiction Inevitable? | Freelance Science Writing - December 20, 2013

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