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Study Indicates Pain Signals Can be Transmitted from the Peripheral Sensory Nerves to the CNS

pain, model

A research study of GABAergic communication within rodent peripheral sensory ganglia demonstrated that somatosensory pain signals can be transmitted from the peripheral sensory nerves to the central nervous system (CNS). The study further found that necessary proteins required in GABA synthesis were released by sensory neurons and triggered by depolarization. By infusing the sensory ganglia with GABA or GABA reuptake inhibitors, the researchers could significantly reduce or alleviate acute inflammatory or neuropathic pain and nociception in the rodent subjects. They were also able to cause or exacerbate peripherally-induced nociception by GABA-receptor antagonists to sensory ganglia. The study demonstrated that chronic peripheral-induced nociception could be reduced in vivo by chemogenomic or optogenetic depolarization of the GABAergic root ganglion neurons. This indicates a need for further research into peripheral somatosensory ganglia as a potential site of therapeutic pain remediation.

 

Background

Peripheral nerves create pain to convey information to the brain and central nervous symptoms about damage that may be occurring in the body. Healthy nerves send signals from the origin of the impending damage to the spinal cord. There, peripheral somatosensory signals are analyzed within the synapses. It is believed that, prior to their interaction with the spinal cord, nerve fibers do not receive input from the synapses and that cell bodies are unnecessary to the propagation of action potential (AP) to the spinal cord from its periphery. Some chronic pain conditions could be caused or exacerbated by the somatic sensory neurons stimulating peripheral excitation. The researchers involved in this study examined local GABAergic transmission within the DRG to more fully understand why GABA receptors are present in sensory neuron somata and from where any possible activators of the transmitters may originate.

 

Results

In the in vivo study of rodent peripheral sensory ganglia, the researchers’ data determined that GABA is most likely produced in various sub-types of dorsal root ganglion (DRG) neuron. This observation supports the theory that many different sizes and types of DRG neurons may, upon stimulation, be released. In addition, every type of small-diameter DRG neuron may respond to GABA, which satellite glia will remove from the extra satellite space. This release could also signal and set base GABA levels.

Both GABA and the GABA reuptake inhibitor NO711 produce an antinociceptive effect when administered locally in vivo to DRG. When GABA receptor antagonists are similarly delivered, peripherally-induced pain is exacerbated and a nocifensive behavior occurs—even without applied painful stimuli. The results of this observation indicate a healthy endogenous GABAergic inhibition within DRG, though it is still unknown whether the afferent fiber transmission occurs only within the peripheral segments of the DRG.

Previous evidence of cross-excitation within the sensory ganglia and the abundance of neurotransmitter receptors expressed within the somatic and perisomatic sensory neuron sites could point to complex integration of peripheral somatosensory information within the DRG. This study adds a possible new theory of pain to the previously proposed “gate-control” idea.

The research study indicates a potential for the use of focally-applied GABA mimetics or GAT1 inhibitors targeting DRG as a means of pain relief. This idea corresponds with recent studies that concluded that direct stimulation of DRGs through implanted stimulation devices provided relief in people who suffered from neuropathic pain. The authors of this study postulate that the DRG neuromodulation effect works due to the peripheral ganglionic gate and that peripherally-acting GABA mimetics could be used to affect long-term pain relief in pain sufferers.

 

 

 

 

 

In Vivo MRI Study Examines the Rate of Disc Fluid Loss Over an 8 Hour Day

Disc Fluid Loss Over an 8 Hour Day

Numerous studies have examined disc volume, height, and disc fluid loss to more clearly understand the effects and rate of cellular diffusion and nutrient and waste transfer on IVD. However, to date, there have been no significant measurements of the rate at which discs lose fluids during normal activity throughout the day. We know that IVD fluids are replenished during overnight rest, but understanding how quickly the fluids dissipate during daily activity could be important in the prevention and treatment of disc degeneration.

The Study

To better understand the rate at which discs lose fluids after an overnight gain, researchers conducted a study 1 of five healthy subjects—four women, and one man— between the ages of 21 and 32 years old. Each of the subjects was screened prior to the beginning of the study to determine that they had no pathologies of the spine. The subjects were instructed to remain moderately active and resist sitting for more than 10 minutes at a time during the 10-hour period preceding the study.

On arrival in the evening, each of the subject was instructed to remain in an upright position for one hour, then they were placed into an MRI scanner for the first (PM) scan. The subjects then slept at the study facility and were instructed not to get out of bed except to use the bathroom. After 8 hours of sleep, they were scanned again at approximately 7am (AM).

All the subjects then began a regimen of 40 minute periods of walking, followed by horizontal MR scans. They repeated this protocol over an 8-hour period, until approximately 3pm.

Results

Analysis of all 19 disc scans indicated an average gain of 10.6 % in disc volume overnight, as measured prior to activity in the morning. There was a clear and substantial decrease in this disc volume after the subjects walked during the day, but even after 8 hours of continuous walking (with breaks only for scans), the amount of volume (of fluid) remained higher than the volume that had been measured the previous night, prior to sleeping. This indicates the discs’ ability to retain fluids over an extended period throughout the day.

Researchers noted a large variance between the disc fluid loss of the study participants—from 11.1 % to -3.5 %. Because the volume is determined by the proteoglycan’s fluid-holding ability and by the seepage through the disc collagen, the enormous range in volume decrease between differing discs could be an indication that diverse types of disc and their fluid-retention (and nutrient and waste-dispensing) abilities could be more, or less susceptible to future degeneration. Future study is needed to determine which disc type is more beneficial and less likely to degenerate. Disc fluid loss and gains are important in understanding optimal metabolism.

Research into IVD Cell Mechanobiology and the Role of Genetics in IVD Degeneration Necessary

Role of Genetics in IVD Degeneration

A review 1  of how biochemical and micromechanical events affect the cellular biology and morphology of intravertebral discs (IVD) during physical motion, loading, and compression determined that important interactions between the nucleus pulposus and annular fibrosis altered cells, micromechanical, mechanobiological, and mechanical features. Because previous studies have indicated a strong genetic link in the propensity for disc degeneration, the authors concluded that more information is needed on how these integral biochemical and micromechanical processes may be triggered by genetic factors and contribute to IVD degeneration, annular tears, and endplate or facet damage that can reduce disc height and flexibility, fluid pressurization, and cause stiffness or dissipation of the disc.

 

An Examination of the Intervertebral Disc

The authors of the review emphasized that the three separate anatomic structures of the IVD—namely, the annulus fibrosis, nucleus pulposus, and cartilage endplates, which regulate waste and nutrients and may help pressurize fluids—work together to make the IVD function mechanically.

Negative charges in the gelatinous nucleus pulposus, which is made up of mostly water, glycosomino-glycans, collagens, and other proteins—contribute to pressure and swelling, which helps support spinal loads and distribute forces evenly throughout the annulus fibrosis—a lamellar structure made up of bundles of collagen fibers that help control the tension and stiffness in axial, circumferential, and radial directions during physiologic joint motions.

Pathologic changes in the biochemistry and structure of the extracellular matrix may involve a loss of hydration, decrease in disc height and cell density, disorganization of the lamellar annulus, loss of proteoglycan content, changes in the levels or activity of matrix metalloproteinase, and changes in the proteoglycan structure, leading to degeneration or loss of the negative charge’s fixed density and the swelling pressure that is necessary to assist in spinal loading.

 

Genetic Influence on Degeneration and Cell Morphology

The authors of the review stated that there is much evidence to support the theory that disc degeneration could be genetically-influenced, but emphasized that other factors—including heavy lifting, impact, gait, lifestyle factors, posture, and muscle use— may also be involved in altering the biochemical and mechanical processes within the IVD. Those who are genetically predisposed may be more at risk of disc degeneration triggered by the biochemical and cellular responses to mechanical factors.

 

Intervertebral Cell Morphology

Compressive conditions, tensile stretching, strains, and stresses are all physiologic conditions that contribute to the electro-kinetic, fluid flows, hydrostatic, and osmotic effects of intervertebral disc cell responses.  In adults, the nucleus pulposus is filled with chondrocyte-like cells that may have traversed the endplate or inner annulus fibrosis into the nucleus. Studies have demonstrated that these cells –particularly the innermost cells—contain vimentin filaments that are frequently associated with articular cartilage and other tissues enduring compression. The morphology of examined fibroblast and chondrocyte cells indicate that they are ellipsoidal and contain long axes that are in line with the lamellas’ collagen fibers. Alternatively, the cells normally found in the annulus fibrosis are rounder, with more space in between, and may be surrounded by a type of collagen called chondron.

When IVD degeneration is present, other types of cells are found within the nucleus pulposus, including Schwann cells, nerve fibers, fibroblasts, and endothelial cells. There is also an increase in vasculature –and hydraulic permeability of fluids and proteoglycan contents—associated with the proliferation of array of cells. These factors create electro kinetic effects in the regulation of ion and water movement, as well as the cells’ abilities to send signals to the unit in response to mechanical loading. Similar changes in the annulus fibrosis may be responsible for many of the overt alterations observed in IVD degeneration because of the dependence of the unit upon tissue hydration and negative charge to regulate complex interchanges.

 

Other Changes Noted in IVD Degeneration

High levels of hydrostatic pressure occur with the cells of the IVD during resting and loading. Pressure levels higher or lower than average may inhibit proteoglycan synthesis and create an increase of nitric oxide and MMP-3 production. The cells of the nucleus pulposus and inner annulus fibrosis may be affected by compression, but there is little research to support or disclaim this theory. In addition to fluid movement and mechanically-induced disruptions within the IVD, iron concentrates, Ph, osmolarity, and extracellular hydration also occur.

Many loading conditions may contribute to tensile strains within the IVD. These may include a decrease in the proteoglycan and type 1 and 2 collagen content. High-frequency vibration may increase the release of ATP in the annulus fibrosis cells, and type 3 collagen may be decreased after prolonged exposure to vibration. Studies indicate the release of ATP may help modulate the response to vibration and other mechanical stimuli within the disc cell.

 

Conclusion

Studies of IVD suggest anabolic and catabolic consequences of mechanical stimuli. These responses vary between the inner annulus fibrosis and nucleus pulposus, with higher catabolic responses being evident under significant loading stress and lower magnitude responses occurring with static compression, hydrostatic or osmotic pressures. The studies also suggest a connection between the physiologic range of stimuli and micromechanical consequences that promote cellular repair. These signaling mechanisms, though not sufficiently understood, may involve intracellular Ca transients, remodeling, and ATP release, which act as second messengers to the IVD cells and help regulate genetic expression and subsequent biosynthesis.

Future studies are necessary to fully understand the biologic and chemical signaling devices that serve to regulate the IVD response to mechanical and micromechanical stimuli, as well as the evidently important interactions between genetics, mechanical stresses, cytokines, and the inflammatory responses that appear to play a part in IVD degeneration.

Study Finds Prolapse Injury Influenced by Flexion Degree and Level of Hydration, not Rate of Loading

flexion and hydration

A study 1 of isolated and adapted bovine spinal segments examined the extent to which flexion, hydration, and loading rates were responsible for the breakdown of the nucleus pulpous structure and found that the rate of loading had little effect on disc damage with full annular division. Instead, the degree of flexion and the hydration level of the disc were the most influential biochemical measures of nucleus polyposis disruption, protrusion, and breakdown. The study concluded that the nucleus is most at-risk of damage when fully hydrated and fully flexed.

 

The Study

To ensure the discs being studied were healthy and in no way degenerated, study samples were obtained from recently slaughtered two-year-old cows and frozen, then thawed and fully-hydrated just prior to use. The intervertebral discs were then isolated and all ligaments and muscles were removed. The vertebral segments were sawn partially through and attached to a stainless-steel plate using an adhesive.

The segments were radiographed shortly after collection and prior to freezing using a rubber band to create the flexion state and inverting the tail so that it straightened under its own weight, creating the non-flexed state. After freezing, the tail segments were thawed and hydrated fully or partially. A computer-controlled hydraulic device was used to compress the disc segments. Time, load, and the amount of displacement were recorded as flexion, hydration levels, and loading rates in separate tests with contrasting (flex or non-flexed) conditions.

Following the sectioning and initial compression testing, the nucleus pulposis of each of the 96 samples was split, examined, and photographed to locate any signs of disruption. The researchers concluded that the height of intervertebral discs increases at a slower rate when the disc is more hydrated. Because each of the discs studied had statistically similar hydration levels, the research suggests that the duration of a static load will influence disc height and hydration levels. This means that hydration levels within a disc can be manipulated by static preloads—a finding in agreement with previous studies. For the purposes of this study, the researchers concluded that disc height was stabilized after approximately 20 hours, and the disc was considered fully hydrated at that time.

Following the disc analysis, the study samples were categorized into five groups based upon the amount and type of damage that had occurred to the disc nucleus. The damage was assigned a weighting (W) value between 0-4 (“O” representing no observable damage and “4” representing complete or partial nuclear displacement), and values of 2 percent and 5 percent were used to distinguish between discs that had been moderately or severely impacted and whether they had sustained any disruption or movement of annular materials. An average damage weighting (ADW) scale was then applied to each biochemically-tested sample group.

Conclusions

 

The disc samples that were fully flexed and fully hydrated had damage that included nuclear sequestration or the formation of a cleft, or both. Discs that had been fully flexed and partially hydrated experienced some, though less severe, damage than those in the fully hydrated/flexed study group. There was little variance between the levels of damage in the non-flexed, fully hydrated and non-flexed, partially hydrated sample groups. The study authors concluded that the degrees of flexion and hydration were significant factors in intervertebral disc damage, but loading rate had little bearing on the severity of nuclear disruption.

While nuclear prolapse is reproducible in healthy disc samples by fully hydrating and flexing them, the compressive loading rate has little or no bearing in nucleus prolapse of discs with annular wall degradation. This study challenges the presumption that disc prolapse is caused by a degenerative process involving repeated mechanical stress. Instead, the healthy disc nucleus is at risk of annular tears or prolapse when fully hydrated and flexed.

Study Finds Understanding their Pain May Help Lesson Fear in Patients

Lesson Fear in Patients

A 2015 study of 36 chronic pain patients sought to explore the causes of pain-related fear in the hopes of contributing to research that might help practitioners develop avoidance models in the future. The study found that the most common cause of pain-related fear is its inexplicability and unpredictability—because patients could not make any reasonable sense of when their pain would occur or how to control it, they experienced the potential of future pain as a threat and limited their physicality in response to their anxiety.

The authors of the study examined three sets of patients: those who were fearful due to diagnostic uncertainty; those who feared their pain symptoms were a sign of damage or impending damage to their bodies and who faced confusion as to how to ‘fix’ their problem and; those who reached out to healthcare providers due to the loss of function (ability to complete tasks) they had experienced because of their pain, but whose treatments had failed to restore their full functionality. These patients were therefore unable to make sensible decisions about how to function to avoid or lesson their pain.

 

The Study

Subjects involved in the study were adult general practitioner, chiropractor, physiotherapy, or pain clinic patients between the ages of 18-65 years. Each of the subjects had experienced intense lower back pain for a minimum of six months. Patients with spondylolisthesis, radicular pain caused by nerve compression, and pregnant women were excluded from the study. Those with particularly high pain-related fear, as determined by their scores on the administered TSK questionnaire, were included in the study. The average age of the study participants was 42 years, and the subjects were 69 percent female. The typical subject had been experiencing pain for around seven years and had high (47/68) TSK scores.

The patients conducted taped interviews in their homes or by telephone, which were immediately transcribed. The researchers sought to identify and understand the overarching theme common to most patients with pain-related fear. Using an agreed-upon system of inductive coding, the study researchers were able to determine a common theme in all three subtypes of pain-related fear subjects: the inability of understand or make sense of their own pain.

Across all three groups of the study’s participants, it was the unpredictability of lower back pain that created the most anxiety and affected the day-to-day physical and psychological existence of patients. Negative past experiences, the fear of suffering and a loss of functionality, and repeated failure of practitioners to control their pain all contributed to the patients’ inability to make sense of their pain, which increased their anxiety and fear. Not knowing when or how the pain might be triggered, how long it would last, what, exactly, was the cause of, or whether they would be able to find sufficient relief from their pain to function caused fear in pain patients and altered how they went about their daily lives. A poor understanding of diagnostic ‘jargon’ also contributed to the patients’ fear of injury and pain, in particular when they were diagnosed with a condition such as disc degeneration from which there was no ‘cure.’

Discussion & Implications

Because people with chronic pain they cannot understand may be more likely to catastrophize their symptoms, which can lead to increased pain-related fear and a possible increase in the pain itself, the study’s authors suggest it could be helpful for practitioners to improve methods of pain control and patient-education about the causes and possible consequences of their pain. Doing so could empower chronic pain-suffering patients by allowing them to better make sense of their pain.

Targeted interventions designed to help patients understand their pain could be effective in reducing pain-related fear. Improvement of pain control measures, a reduction in the pain’s intensity, and better methods of predicting pain could help reduce the vicious cycle of pain-related fear and fear-induced pain. Cognitive functional therapy could help control pain and lesson the anxiety associated with the unpredictability of pain.

The study’s authors suggest practitioners query their pain patients regarding the previous experience with pain to determine appropriate intervention strategies that will replace negative associations with more optimistic expectations regarding therapeutic outcomes.

‘Nocebo’ Response Should be Considered in Doctor-Patient Communication

Nocebo Response

When it comes to pain medication, what you know might hurt you. Research on the nocebo effect 1 suggests that patients who are educated about the potential risks or non-efficacy of the pain drugs they take are at higher risk for developing negative symptoms and less satisfied with the outcome after taking the drug.

The nocebo effect, like the placebo effect, is the product of a patient’s suggestibility and expectation. Placebo effect studies have demonstrated that when a patient is conditioned to expect a positive outcome, he is more likely to experience a positive outcome. This is true of the nocebo effect, as well. A patient who is conditioned to anticipate a negative reaction to or inefficacy of pain medication is much more likely to experience the inefficacy or negative physical, physiological, behavioral, or functional response to medication. Patients conditioned to expect that their pain medication will not work receive less pain relief from their pain medications.

Three Types of Nocebo Effects:

  • The positive effects of the pain medication are reduced by the patient’s negative expectation.
  • Patients whose expectations are not met by pain treatment once may have lowered expectation when it comes to the medicine’s efficacy in future treatments and experience less pain relief as a result.
  • Patients whose expectations have been preconditioned and lowered by negative information as to a drug’s efficacy may lose the benefits of the placebo effect, which have been identified as a relevant component of medicinal relief. In other words, believing a medication or procedure is going to improve your pain is an important part of pain relief.

Clinical Trials

During randomized controlled clinical trials, patients were more likely to experience adverse events or pain after being informed of the potential they might occur. Patients who were told they might experience a negative drug effect were more likely to experience the effect, even when the effect was in opposition to the pharmacology of the drug. Disclosing potential serious illnesses—including cancer— associated with a drug was more likely to induce a negative prognosis.

Though the placebo response has been widely studied and verified, the nocebo response remains somewhat of a mystery. Studies of the neurobiology of drug action indicate a similar effect between the molecular changes involved in drug treatment and placebo responses. To date, no such effect has been studied in the case of nocebo effect.

Effects of Doctor-Patient Communication

A recent (2017) review seeks to identify doctor-patient communications that may trigger nocebo reactions and suggests clinicians avoid potential negative outcomes by down-playing negative information and emphasizing positive outcome expectations when counseling patients.

In one study, almost half of the 15 patients who were told their drug might produce headaches developed headaches during the trial. None of the 13 patients in a separate group that was not given the headache information developed headaches. Being told to expect a headache might have produced the headaches, so the authors of the study concluded it was best not to mention the possibility of headaches to patients being prescribed drugs with the potential side-effect.

In a randomized controlled study of epidural procedures, patients who were forewarned to expect a prick of pain were more likely to experience discomfort than patients who were told the medication would make them comfortable during labor. Researchers concluded that framing the experience in a more positive light was beneficial to the patients’ experience.

In another study, patients undergoing prostate surgery were more likely to develop negative side effects over time if they were told in advance they might occur. Roughly 43 percent of a group of patients who had been told about potential negative sexual side effects later developed those side effects, while only 15 percent of those in the group who were not informed of the side effects developed them.

The nocebo effect also discourages potential study subjects from participating in research. When the subjects were informed of the potential negative effects of participating in the study, they were more likely to drop out of the group. Study subjects who were informed about potential gastrointestinal consequences were more 6 times more likely to experience gastrointestinal side effects and drop out of the study prior to its conclusion.

Discussion

Practitioners and researchers should carefully weigh the benefits of informing patients of potential negative effects of medication or procedures against the possibility of inducing the nocebo effect, along with its potential harm. This may be particularly true in cases of pain treatment, as patients who suffer from long-term, chronic pain may be more susceptible to the negative events associated with the nocebo effect. Because the expectation of increased pain can trigger or increase extent anxiety or depression, which may then contribute to further algesia and hyperalgesia and inhibit or produce interactions within the neuropathways that lesson a medication’s effectiveness (or placebo benefits), the nocebo effect should be an important consideration prior to pain-medication counseling.

Concern should also be taken with patients whose health depends upon the medications being prescribed. In one study, breast cancer patients counseled as to the potential negative effects of adjuvant endocrine treatment were more likely to experience long-term side-effects and be less compliant in continuing their treatments.

Studies have shown that a positive doctor-patient experience is more conducive than a negative experience in producing positive long-term health results. The amount, delivery method, and attitude of doctor-patient communications can contribute to placebo or nocebo experiences in patients and should be carefully balanced to minimize negative suggestions and emphasize positive outcome expectations.

Biomechanics Dynamic Spine Model Basics

biomechanics, flexion, extension

Here are a series of labeled Professional LxH model pictures to help in the greater understanding of anatomical pain generators (and relievers) when exploring symptoms as they relate to spinal motion. At Dynamic Disc Designs Corp. we believe that careful evaluation of the quality of motion can help in the diagnosis and treatment of back and neck pain.

 

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