Three decades-old antibiotics could offer an alternative to opioid-based painkillers

Three decades-old antibiotics administered together can block a type of pain triggered by nerve damage in an animal model, UT Southwestern researchers report. The finding, published online today in PNAS, could offer an alternative to opioid-based painkillers, addictive prescription medications that are responsible for an epidemic of abuse in the U.S.

Over 100 million Americans are affected by chronic pain, and a quarter of these experience pain on a daily basis, a burden that costs an estimated $600 billion in lost wages and medical expenses each year. For many of these patients – those with cancer, diabetes, or trauma, for example – their pain is neuropathic, meaning it's caused by damage to pain-sensing nerves.

To treat chronic pain, prescriptions for opioid painkillers have increased exponentially since the late 1990s, leading to a rise in abuse and overdoses. Despite the desperate need for safer pain medications, development of a new prescription drug typically takes over a decade and more than $2 billion according to a study by the Tufts Center for the Study of Drug Development, explains study leader Enas S. Kandil, M.D., associate professor of anesthesiology and pain management at UTSW.

Seeking an alternative to opioids, Kandil and her UT Southwestern colleagues – including Hesham A. Sadek, M.D., Ph.D., professor of internal medicine, molecular biology, and biophysics; Mark Henkemeyer, Ph.D., professor of neuroscience; Mahmoud S. Ahmed, Ph.D., instructor of internal medicine; and Ping Wang, Ph.D., a postdoctoral researcher – explored the potential of drugs already approved by the Food and Drug Administration (FDA).

The team focused on EphB1, a protein found on the surface of nerve cells, which Henkemeyer and his colleagues discovered during his postdoctoral training nearly three decades ago. Research has shown that this protein is key for producing neuropathic pain. Mice genetically altered to remove all EphB1 don't feel neuropathic pain, he explains. Even mice with half the usual amount of this protein are resistant to neuropathic pain, suggesting EphB1's promise as a target for pain-relieving drugs. Unfortunately, no known drugs inactivate EphB1.

Exploring this angle further, Ahmed used computer modeling to scan a library of FDA-approved drugs, testing if their molecular structures had the right shape and chemistry to bind to EphB1. Their search turned up three tetracyclines, members of a family of antibiotics used since the 1970s. These drugs – demeclocycline, chlortetracycline, and minocycline – have a long history of safe use and minimal side effects, Ahmed says.

To investigate whether these drugs could bind to and inactivate EphB1, the team combined the protein and these drugs in petri dishes and measured EphB1's activity. Sure enough, each of these drugs inhibited the protein at relatively low doses. Using X-ray crystallography, Wang imaged the structure of EphB1 with chlortetracycline, showing that the drug fits neatly into a pocket in the protein's catalytic domain, a key portion necessary for EphB1 to function.

In three different mouse models of neuropathic pain, injections of these three drugs in combination significantly blunted reactions to painful stimuli such as heat or pressure, with the triplet achieving a greater effect at lower doses than each drug individually. When the researchers examined the brains and spinal cords of these animals, they confirmed that EphB1 on the cells of these tissues had been inactivated, the probable cause for their pain resistance. A combination of these drugs might be able to blunt pain in humans too, the next stage for this research, says Kandil.

Unless we find alternatives to opioids for chronic pain, we will continue to see a spiral in the opioid epidemic. This study shows what can happen if you bring together scientists and physicians with different experience from different backgrounds. We're opening the window to something new."

Enas S. Kandil, M.D., Associate Professor, Anesthesiology and Pain Management, UT Southwestern

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UT Southwestern Medical Center

Posted in: Medical Science News | Medical Research News | Pharmaceutical News

Tags: Anesthesiology, Animal Model, Antibiotic, Cancer, Cardiology, Chronic, Chronic Pain, Crystallography, Diabetes, Drugs, Education, heat, Medicine, Minocycline, Molecular Biology, Nerve, Neuropathic Pain, Neuroscience, Opioids, Pain, Pain Management, pH, Prescription Drug, Protein, Receptor, Research, Tetracycline, Trauma, X-Ray

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How is RRMS Different from PPMS and SPMS?

Multiple sclerosis is a neurodegenerative disorder that damages the nerves in the brain and spinal cord, leading to problems with muscle movement, balance and vision. The illness is an example of a demyelinating disease, where the protective coating called myelin that surrounds nerve fibres becomes damaged.

Multiple sclerosis follows a different course in every individual but there are three main ways in which the disease can progress depending on which form of the illness a patient has.

Relapsing remitting multiple sclerosis

Around 80% of all individuals with multiple sclerosis have the relapsing remitting form of the disease. These individuals have periods where their symptoms are mild or absent (remission), followed by periods of symptom relapse. Symptoms may occur suddenly and in acute bouts or exacerbations.

During these periods of relapse, symptoms may become worse each time and the relapsing remitting form of this condition may eventually progress to secondary progressive multiple sclerosis, where there are few or no periods of remission. Relapsing remitting multiple sclerosis may be diagnosed when two episodes of relapse are separated by more than 30 days or there has only been one relapse but there is MRI evidence of newly scarred or damaged myelin three months later.

Secondary-progressive multiple sclerosis

Patients with this form of multiple sclerosis often experience phases of relapse followed by remission at first, but this later gives way to progressive disease, characterized by worsening symptoms and few or no periods of remission.

Primary-progressive multiple sclerosis

The least common form of multiple sclerosis is the primary progressive form which occurs in about 10% to 15% of all cases and usually in people aged over 40 years. In this form of the condition, symptoms get worse over time rather than occurring in bouts or as sudden attacks.

Primary progressive multiple sclerosis may be diagnosed if there have been no previous symptoms of relapse but the patient has become increasingly disabled over a period of at least one year.

Sources

  1. http://www.nhs.uk/Conditions/Multiple-sclerosis/Pages/Causes.aspx
  2. www.nlm.nih.gov/medlineplus/tutorials/multiplesclerosis/nr229105.pdf
  3. http://www.who.int/mental_health/neurology/Atlas_MS_WEB.pdf
  4. http://mssociety.ca/en/pdf/ms-effects.pdf
  5. http://www.nice.org.uk/nicemedia/live/10930/29202/29202.pdf

Further Reading

  • All Multiple Sclerosis Content
  • Multiple sclerosis (MS)
  • Multiple Sclerosis Symptoms
  • Multiple Sclerosis Diagnosis
  • Multiple Sclerosis Causes
More…

Last Updated: Aug 23, 2018

Written by

Dr. Ananya Mandal

Dr. Ananya Mandal is a doctor by profession, lecturer by vocation and a medical writer by passion. She specialized in Clinical Pharmacology after her bachelor's (MBBS). For her, health communication is not just writing complicated reviews for professionals but making medical knowledge understandable and available to the general public as well.

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Neuronal Migration Disorder

Neuronal migration disorder refers to a group of disorders that arise from the abnormal migration of nerve cells during embryonic development. If the migration of neuroblasts is disturbed during neurogenesis, neural circuits do not form properly in the correct parts of the brain. This is referred to as cerebral dysgenesis.

The migration commonly takes place in the second month of pregnancy. In cases of migration disorder, only some of the neuroblasts reach the cortical layer or neuroblasts overshoot their path and instead reach the subarachnoid space. In addition, the organization of the neuronal layer in the cortex may be disrupted. Abnormal migration of the neuroblasts leads to abnormal formation of the gyri, the ridges of the cerebral cortex in the brain.

Some examples of neuronal migration disorders include lissencephaly, schizencephaly, porenchephaly, pachygyria, agyria, macrogyria, microgyria, neuronal heterotopias, agenesis of corpus callosum, agenesis of cranial nerves and band heterotopias.

Symptoms

Symptoms of neuronal migration disorder vary according to the type and degree of abnormality. The most common symptoms include:

  • Loss of muscle tone
  • Decreased motor function
  • Seizures
  • Developmental delay
  • Mental retardation and failure to thrive and grow
  • Difficulty feeding
  • Smaller than average head size. This is called microcephaly.
  • Some infants have the characteristic facial features of neuronal migration disorder.

Treatment

A diagnosis is made based on clinical investigations and radiological imaging studies. Treatment is symptomatic and includes the use of antiepileptic medications to prevent and correct seizures, along with physical, occupational and speech therapies to support the child with the various problems associated with the disorder.

Sources

  1. http://mcloonlab.neuroscience.umn.edu/8211/papers/Valiente_10.pdf
  2. http://brain.oxfordjournals.org/content/127/6/1458.full
  3. www-cogsci.ucsd.edu/~sereno/201/readings/03.08-NeuralMigration.pdf
  4. http://www.100megspop3.com/chanvinci/01.pdf

Further Reading

  • All Neuronal Migration Disorder Content

Last Updated: Jun 25, 2019

Written by

Dr. Ananya Mandal

Dr. Ananya Mandal is a doctor by profession, lecturer by vocation and a medical writer by passion. She specialized in Clinical Pharmacology after her bachelor's (MBBS). For her, health communication is not just writing complicated reviews for professionals but making medical knowledge understandable and available to the general public as well.

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Neuronopathy and neuropathy: What's the difference?

Neuronopathy and neuropathy are both health conditions that involve abnormalities of the nervous system but are distinguished by a few important differences.

This article will describe the distinctive characteristics of both neuronopathy and neuropathy, in addition to explaining how the two conditions can be differentiated during the diagnostic process.

What is Neuronopathy?

Neuronopathy is a form of polyneuropathy and occurs as a result of neuron degeneration. It is a subgroup of disorders of the peripheral nervous system and involves the destruction of specific neurons in this area.

There are several types of neuronopathy, including sensory neuronopathy, also known as ganglionopathy, motor neuronopathy and autonomic neuronopathy. Each of these types is characterized by damage to particular neurons in the peripheral nervous system and lead to a distinct set of resulting symptoms.

What is Neuropathy?

On the other hand, neuropathy is a broader term used to describe any disease that affects the peripheral nervous system. This includes disorders that affect the cell body of the neurons and neuronopathies.

Image Copyright: Tefi, Image ID: 336895070 via Shutterstock.com

Each neuropathic disorder has specific clinical features that help to differentiate the cause and type. They may be inherited from parents or acquired due to environmental circumstances, including other related medical conditions.

There are several main types of neuropathy, according to the type of nerves that are affected:

  • Sensory neuropathy alters sensation and may cause symptoms of tingling, pain, numbness or weakness of the limbs in affected individuals.
  • Motor neuropathy affects the strength and movement and may cause immobility or weakness of the limbs in affected individuals.
  • Autonomic neuropathy affects the control of smooth muscle in the body, such as in the gastrointestinal tract, the bladder and the cardiovascular system.

Additionally, neuropathic disorders can be categorized as mononeuropathy if a single nerve is affected, or polyneuropathy if several nerves are affected.

Differential Diagnosis

In some cases, it can be difficult to distinguish neuropathy from neuronopathy, both for the motor and sensory types of the condition. However, there are some defining features that can help in the differential diagnosis.

For example, many disorders of the nervous system are characterized by particular electroclinical features, which can be used to identify differences between neuronopathy and neuropathy. For this reason, electrophysiological examinations may be used in the diagnostic process.

Other tests that may be used in the diagnosis of neuronopathy or neuropathy include nerve conduction studies, magnetic resonance imaging (MRI) and pathological analyses. Nerve conduction studies, in particular, are useful to show the changes in the action of the nerves involved in the condition, such as the symmetry of nervous responses.

Although we already have a reasonably good understand of neuropathy and neuropathy, there is a need for further research in the area to classify the differences and improve the differential diagnostic testing methods.

Specific Distinctions

The abnormalities of the nerve conduction and the resulting signs can help in the differentiation between motor neuropathy and motor neuronopathy.

In the reinnervation process, signs of terminal axonal reinnervation are evident in axonal neuronopathies. On the other hand, collateral reinnervation is evident in motor neuronopathies.

Electrophysiological findings that show length-dependent axonal damage is indicative of sensory axonopathy, whereas widespread deficits to the body are usually linked to sensory neuronopathy.

References

  • http://www.ncbi.nlm.nih.gov/pubmed/15244178
  • http://www.hindawi.com/journals/ad/2012/873587/
  • http://www.sciencedirect.com/science/article/pii/S073386191300011X
  • http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3922643/

Further Reading

  • All Neuronopathy Content
  • Sensory Neuronopathy – Sensory Ganglionopathy
  • Neuronopathy and neuropathy: What’s the difference?
  • Sensory neuronopathy and Sjögren’s syndrome

Last Updated: Aug 23, 2018

Written by

Yolanda Smith

Yolanda graduated with a Bachelor of Pharmacy at the University of South Australia and has experience working in both Australia and Italy. She is passionate about how medicine, diet and lifestyle affect our health and enjoys helping people understand this. In her spare time she loves to explore the world and learn about new cultures and languages.

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