Why does localized damage or injury caused by trauma lead to chronic, intractable pain in certain patients? What’s in charge of the translation of local injury with acute pain into a chronic pain condition? Why does some pain respond to anti-inflammatory drugs and/or medications, whereas other forms of pain require opiates?
Pain is an intricate process involving both the peripheral nervous system (PNS) and the central nervous system (CNS). Tissue injury triggers the PNS, which transmits signals via the spinal cord into the brain, in which pain perception occurs. However, what causes the intense experience of pain to develop into an unremitting phenomenon? Can anything be done to prevent it? Evidence indicates that chronic pain results from a combination of mechanisms, such as neurological “memories” of preceding pain.
Nociception: The Simplest Pathway
Acute or nociceptive pain is characterized as the regular experience of discomfort which occurs in response to very basic damage or injury. It is protective, warning us to move away from the origin of the insult and take care of the trauma. The mechanisms that create nociceptive pain include transduction, which extends the external traumatic stimulation into electrical activity in specialized nociceptive primary afferent nerves. The afferent nerves then conduct the sensory information from the PNS to the CNS.
In the CNS, the pain data is transmitted by the primary sensory neurons into central projection cells. After the information is transferred to all those areas of the brain which are responsible for our perception, the actual sensory experience happens. Nociceptive pain is a relatively simple reaction to a particularly simple, acute stimulus. But the mechanics in charge of nociceptive pain cannot identify phenomena, such as pain that persists despite removal or healing of the stimulation, such as in the instance of phantom limb pain.
Pain and the Inflammatory Response
In circumstances of more severe injury, such as surgical wounds, tissue damage may stimulate an inflammatory reaction. However, other conditions, especially arthritis, can also be characterized by continuing cases of inflammation associated with intense pain symptoms. The mechanisms for this type of pain related to tissue damage and an inflammatory response are different from early-warning nociceptive pain.
Observing the incision or site of other damage or injury, a cascade of hyperexcitable events occur in the nervous system. This bodily “wind-up” phenomenon begins at the skin, where it is potentiated along the peripheral nerves, and culminates at a hypersensitivity response along the spinal cord (dorsal horn) and the brain. Inflammatory cells then surround the regions of tissue damage and also produce cytokines and chemokines, substances which are intended to mediate the process of healing and tissue regeneration. But, these agents may also be considered irritants and adjust the properties of the primary sensory neurons surrounding the area of trauma.
Thus, the major factors which trigger inflammatory pain include damage to the high-threshold nociceptors, known as peripheral sensitization, changes and alterations of the neurons in the nervous system, and the amplification of the excitability of neurons within the CNS. This represents central sensitization and is accountable for hypersensitivity, where areas adjacent to those of the true injury will experience pain as if these were injured. These tissues can also react to stimulation which normally doesn’t create pain, such as a touch, wearing clothing, light pressure, or even brushing your own hair, as if they were truly painful, referred to as allodynia.
Neuropathic pain results from damage or injury to the nervous system, such as carpal tunnel syndrome, postherpetic neuralgia and diabetic neuropathy. Although some of the mechanisms which seem to cause neuropathic pain overlap with those responsible for inflammatory pain, many of them are different, and thus will need a different approach towards their management.
The process of peripheral and central sensitization is maintained, at least theoretically and experimentally, during the excitatory neurotransmitter, glutamate, which is believed to be released when the N-methyl-D-aspartate (NMDA) receptor is activated.
The nervous system is made up of either inhibitory or excitatory neurotransmitters. Most of what permits our nervous system to respond appropriately to damage or injury is the fine-tuning or inhibition of a variety of processes. The overexcitation of the nervous system is seen to be an issue in a number of different disorders. For instance, overactivation of an NMDA receptor can also be related to affective disorders, sympathetic abnormalities, and even opiate tolerance.
Even ordinary nociceptive pain, to some degree, activates the NMDA receptor and is believed to lead to glutamate release. Nonetheless, in neuropathic pain, oversensitivity to the NMDA receptor is key.
With other types of chronic pain, such as fibromyalgia and tension-type headaches, some of the mechanisms active in inflammatory and neuropathic pain may also create similar abnormalities in the pain system, including central sensitization, higher excitability of the somatosensory pathways, and reductions in central nervous system inhibitory mechanisms.
Peripheral Sensitization
Cyclo-oxygenase (COX) also plays an essential function in both peripheral and central sensitizations. COX-2 is one of the enzymes which are induced during the inflammatory process; COX-2 converts arachidonic acid into prostaglandins, which increase the sensitivity of peripheral nociceptor terminals. Virtually, peripheral inflammation also causes COX-2 to be produced from the CNS. Signals from peripheral nociceptors are partially responsible for this upregulation, but there also seems to be a humoral component to the transduction of the pain signals across the blood-brain barrier.
For instance, in experimental models, COX-2 is generated from the CNS even if animals receive a sensory nerve block prior to peripheral inflammatory stimulation. The COX-2 that is expressed over the dorsal horn neurons of the spinal cord releases prostaglandins, which act on the central terminals, or the presynaptic terminals of nociceptive sensory fibers, to increase transmitter release. Additionally, they act postsynaptically on the dorsal horn neurons to produce direct depolarization. And finally, they inhibit the activity of glycine receptor, and this is an inhibitory transmitter. Therefore, the prostaglandins create an increase in excitability of central neurons.
Brain Plasticity and Central Sensitization
Central sensitization describes changes which happen in the brain in reaction to repeated nerve stimulation. After repeated stimuli, amounts of hormones and brain electric signals change as neurons develop a “memory’ for reacting to those signs. Constant stimulation creates a more powerful brain memory, so the brain will respond more rapidly and effectively when undergoing the identical stimulation in the future. The consequent modifications in brain wiring and reaction are referred to as neural plasticity, which describe the capability of the brain to alter itself readily, or central sensitization. Therefore, the brain is activated or sensitized by previous or repeated stimuli to become more excitable.
The fluctuations of central sensitization occur after repeated encounters with pain. Research in animals indicates that repeated exposure to a painful stimulation will change the animal’s pain threshold and lead to a stronger pain response. Researchers think that these modifications can explain the persistent pain that could occur even after successful back surgery. Although a herniated disc may be removed from a pinched nerve, pain may continue as a memory of the nerve compression. Newborns undergoing circumcision without anesthesia will react more profoundly to future painful stimulation, such as routine injections, vaccinations, and other painful processes. These children haven’t only a higher hemodynamic reaction, known as tachycardia and tachypnea, but they will also develop enhanced crying too.
This neurological memory of pain was studied extensively. In a report on his previous research studies, Woolf noted that the improved reflex excitability following peripheral tissue damage or injury doesn’t rely on continuing peripheral input signals; rather, hours after a peripheral trauma, spinal dorsal horn neuron receptive fields continued to enlarge. Researchers also have documented the significance of the spinal NMDA receptor to the induction and maintenance of central sensitization.
Significance for Pain Management
Once central sensitization is established, bigger doses of analgesics are often required to suppress it. Preemptive analgesia, or therapy before pain progresses, may lower the effects of all of these stimulation on the CNS. Woolf demonstrated that the morphine dose required to stop central hyperexcitability, given before short noxious electrical stimulation in rats, was one tenth the dose required to abolish activity after it had grown. This translates to clinical practice.
In a clinical trial of 60 patients undergoing abdominal hysterectomy, individuals who received 10 mg of morphine intravenously at the time of induction of anesthesia required significantly less morphine for postoperative pain control. Furthermore, pain sensitivity around the wound, referred to as secondary hyperalgesia, was also reduced in the morphine pretreated group. Preemptive analgesia was used with comparable success in an assortment of surgical settings, including prespinal operation and postorthopaedic operation.
A single dose of 40 or 60 mg/kg of rectal acetaminophen has a clear morphine-sparing effect in day-case surgery in children, if administered in the induction of anesthesia. Furthermore, children with sufficient analgesia with acetaminophen experienced significantly less postoperative nausea and vomiting.
NMDA receptor antagonists have imparted postoperative analgesia when administered preoperatively. Various reports exist in the literature supporting the use of ketamine and dextromethorphan in the preoperative period. In patients undergoing anterior cruciate ligament reconstruction, 24-hour patient-controlled analgesia opioid consumption was significantly less in the preoperative dextromethorphan category versus the placebo group.
In double-blind, placebo-controlled research studies, gabapentin was indicated as a premedicant analgesic for patients undergoing mastectomy and hysterectomy. Preoperative oral gabapentin reduced pain scores and postoperative analgesic consumption without gap in side effects as compared with placebo.
Preoperative administration of nonsteroidal anti-inflammatory drugs (NSAIDs) has demonstrated a significant decrease in opioid use postoperatively. COX-2s are preferable due to their relative lack of platelet effects and significant gastrointestinal safety profile when compared with conventional NSAIDs. Celecoxib, rofecoxib, valdecoxib, and parecoxib, outside the United States, administered preoperatively reduce postoperative narcotic use by more than 40 percent, with many patients using less than half of the opioids compared with placebo.
Blocking nerve conduction in the preoperative period appears to prevent the development of central sensitization. Phantom limb syndrome (PLS) has been attributed to a spinal wind-up phenomenon.�Patients with amputation
often have burning or tingling pain in the body part removed. One possible cause is that nerve fibers at the stump are stimulated and the brain interprets the signals as originating in the amputated portion. The other is the rearrangement within the cortical areas so that area say for the hand now responds to signals from other parts of the body but still interprets them as coming for the amputated hand.
However, for patients undergoing lower-extremity amputation under epidural anesthesia, not one of the 11 patients who received lumbar epidural blockade with bupivacaine and morphine for 72 hours before operation developed PLS. For people who underwent general anesthesia without prior lumbar epidural blockade, 5 of 14 patients had PLS at 6 weeks and 3 continued to experience PLS at 1 year.
Woolf and Chong have noted that perfect preoperative, intraoperative, and postoperative treatment comprises of “NSAIDs to reduce the activation/centralization of nociceptors, local anesthetics to block sensory inflow, and centrally acting drugs such as opiates.” Decreasing perioperative pain with preemptive techniques enhances satisfaction, hastens discharge, spares opioid use, along with diminished constipation, sedation, nausea, and urinary retention, and may even stop the development of chronic pain. Anesthesiologists and surgeons should consider integrating these techniques in their everyday practices.
When pain occurs as a result of damage or injury in consequence of surgery, the spinal cord can attain a hyperexcitable state wherein excessive pain reactions occur that may persist for days, weeks or even years.
Why does localized injury resulting from trauma result in chronic, intractable pain in some patients? Tissue injury leads to a constellation of changes in spinal excitability, including elevated spontaneous firing, greater response amplitude and length, decreased threshold, enhanced discharge to repeated stimulation, and expanded receptive fields. The persistence of these changes, which are collectively termed central sensitization, appears to be fundamental to the prolonged enhancement of pain sensitivity which defines chronic pain. Numerous drugs and/or medications as well as local anesthetic neural blockade may limit the magnitude of the central nervous system (CNS) windup, as evidenced by diminished pain and diminished opioid consumption in the preemptive analgesic models.
Dr. Alex Jimenez’s Insight
Chiropractic care is an alternate treatment option which utilizes spinal adjustments and manual manipulations to safely and effectively restore as well as maintain the proper alignment of the spine. Research studies have determined that spinal misalignments, or subluxations, can lead to chronic pain. Chiropractic care is commonly utilized for pain management, even if the symptoms are not associated to an injury and/or condition in the musculoskeletal and nervous system. By carefully re-aligning the spine, a chiropractor can help reduce stress and pressure from the structures surrounding the main component of out body’s foundation, ultimately providing pain relief.
Enteric Nervous System Function and Pain
When it comes to the diminished use of drugs and/or medications, including opioids, in order to prevent side-effects like gastrointestinal health issues, the proper function of the enteric nervous system may be at play.
The enteric nervous system (ENS) or intrinsic nervous system is one of the key branches of the autonomic nervous system (ANS) and consists of a mesh-like system of nerves which modulates the role of the gastrointestinal tract. It’s capable of acting independently of the sympathetic and parasympathetic nervous systems, even though it might be affected by them. The ENS can also be called the second brain.�It is derived from neural crest cells.
The enteric nervous system in humans is made up of some 500 million neurons, including the numerous types of Dogiel cells, approximately one two-hundredth of the amount of neurons in the brain. The enteric nervous system is inserted into the lining of the gastrointestinal system, beginning at the esophagus and extending down to the anus. Dogiel cells, also known as cells of Dogiel, refers to some kind of multipolar adrenal tissues within the prevertebral sympathetic ganglia.
The ENS is capable of autonomous functions, such as the coordination of reflexes; even though it receives considerable innervation in the autonomic nervous system, it does and can operate independently of the brain and the spinal cord.�The enteric nervous system has been described as the “second brain” for a number of reasons. The enteric nervous system may operate autonomously. It normally communicates with the central nervous system (CNS) via the parasympathetic, or via the vagus nerve, and the sympathetic, that is through the prevertebral ganglia, nervous systems. However, vertebrate studies reveal that when the vagus nerve is severed, the enteric nervous system continues to function.
In vertebrates, the enteric nervous system includes efferent neurons, afferent neurons, and interneurons, all of which make the enteric nervous system capable of carrying reflexes and acting as an integrating center in the absence of CNS input. The sensory neurons report on mechanical and chemical conditions. The enteric nervous system has the ability to change its response based on such factors as nutrient and bulk composition. In addition, ENS contains support cells that are much like astroglia of the brain and a diffusion barrier around the capillaries surrounding ganglia that’s like the blood-brain barrier of blood vessels.
The enteric nervous system (ENS) plays a pivotal role in inflammatory and nociceptive processes. Drugs and/or medications that interact with the ENS have recently raised considerable interest because of their capacity to regulate numerous aspects of the gut physiology and pathophysiology. In particular, experiments in animals have demonstrated that�proteinase-activated receptors (PARs) may be essential to neurogenic inflammation in the intestine. Moreover, PAR2 agonists seem to induce intestinal hypersensitivity and hyperalgesic states, suggesting a role for this receptor in visceral pain perception.
Furthermore, PARs, together with the proteinases that activate them, represent exciting new targets for therapeutic intervention on the ENS. The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .
Curated by Dr. Alex Jimenez
Additional Topics: Sciatica
Sciatica is medically referred to as a collection of symptoms, rather than a single injury and/or condition. Symptoms of sciatic nerve pain, or sciatica, can vary in frequency and intensity, however, it is most commonly described as a sudden, sharp (knife-like) or electrical pain that radiates from the low back down the buttocks, hips, thighs and legs into the foot. Other symptoms of sciatica may include, tingling or burning sensations, numbness and weakness along the length of the sciatic nerve. Sciatica most frequently affects individuals between the ages of 30 and 50 years. It may often develop as a result of the degeneration of the spine due to age, however, the compression and irritation of the sciatic nerve caused by a bulging or herniated disc, among other spinal health issues, may also cause sciatic nerve pain.
Your mother always said don�t slouch – turns out she was right. And she has science to back it up. Your posture can have a profound effect on your health. Walking or sitting with a hunched back has been linked to a variety of health issues.
What�s more, poor posture can cause your body�s structure to change, leading to misalignment. While everyone slips a bit in the posture department now and then, the real damage occurs when it becomes a habit. In fact, you could be damaging your health with bad posture and not even realize it. Here are five ways that posture mistakes can harm your health.
Posture
Pain In The Neck, Back & Shoulders
Sitting in a slouched or hunched over position, drooping your shoulders, or rounding out your spine while standing or sitting can cause pain in your neck, back, and shoulders. Many people who work with computers as a regular part of their jobs experience this to some degree.
That is because the majority of workers do not have their computer monitors at the appropriate height, causing them to spend hours a day hunched over their keyboard. People who spend a lot of time on their smartphone and mobile devices experience text neck, which is caused by this type of poor posture.
Increased Depression & Stress
The connection between posture and mood has long been established. People who walk slouched over tend to feel more depressed and have a poorer self-image.
When you are slouched, you are restricting blood flow throughout your body, inhibiting proper oxygenation of your cells, and crowding your organs so that they are not able to function at an optimum level. If your spine or body is out of alignment, it can slow the neural processes that keep your body functioning as it should. When all these things are going on, your mood will definitely be affected, especially if you aren�t as active as you should be.
Pain/Weakness In The Lower Back, Hips, Knees & Ankles
This posture problem is common in people who are obese and pregnant women. The added weight causes the body to shift in unnatural positions in order to support it.
This postural problem can also be the result of inappropriate footwear. Feet are important! Take care of them by wearing shoes with good support. This can cause flat feet and cause the ankles to roll.
The calf muscles will tighten and your knees may even rotate inward. You can experience plantar fasciitis, pain in your toes, heel spurs, bunions, and hip problems. Weight loss can help and pregnant women can benefit from a pregnancy sling or pregnancy girdle to support the added girth.
Digestion Problems
Sitting in a hunched position crunches up everything inside, including your intestines. This will slow things down considerably, leading to constipation and even hemorrhoids.
The human body was designed to remain in a certain position so that all organs can function as they should. When things are out of alignment it can lead to indigestion, heartburn, and even acid reflux. Practicing good posture can make all the difference in a lot of things. Poor digestion can lead to obesity.
Spinal Misalignment Leading To Many Health Issues
When your spine is out of line it can cause headaches, dizziness, and a host of other issues. It puts your body under stress so even the normal processes like blood flow and organ function are thrown off kilter. When your body isn�t working as it should the risk of serious conditions like heart disease, diabetes, and hypertension are increased.
Many people don�t make the connection between good posture with a properly aligned spine and better health, but it is definitely there. Posture may seem simple, like it�s not that big of a deal, but when it is practiced on an ongoing basis, it can be detrimental to your health. It isn�t worth the risk; not when the fix is as simple as sitting up straight.
Injury Medical Clinic: Fibromyalgia Care & Treatment
Lower Back Injury: Isaiah Delgado, wrestler, began participating in a fitness and nutrition program at Push-as-RX in order to improve his performance in his physical activities. When he suffered a lower back sports injury, Isaiah Delgado once again came to Push for assistance, except this time, the trainers enrolled him in a rehabilitation program to help him return-to-play as soon as possible. Isaiah Delgado describes Push-as-Rx as a lifestyle and he recommends Push to anyone looking for the right type of support when it comes to recovery and increased performance.
Lower Back Injury And Chiropractic Care
Sports Therapy is an element of healthcare that’s specifically concerned with the prevention of injury and the rehabilitation of the individual back to optimum levels of practical, occupational and sports specific fitness, regardless of age and capacity. It utilizes the fundamentals of sport and exercise sciences incorporating behavioral and physiological processes to prepare the player for training, competition and where applicable, work. A variety of healthcare professionals are able to provide this type of treatment method.
We are blessed to present to you�El Paso�s Premier Wellness & Injury Care Clinic.
As El Paso�s Chiropractic Rehabilitation Clinic & Integrated Medicine Center,�we passionately are focused treating patients after frustrating injuries and chronic pain syndromes. We focus on improving your ability through flexibility, mobility and agility programs tailored for all age groups and disabilities.
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The aging process can usher in a variety of conditions and health issues that are confined (mostly) to the elderly. Chronic pain, arthritis, loss of mobility, and other issues can occur as a person get older, but senior citizens are finding that chiropractic provides some great benefits for the older demographic.
Senior Citizens
Better Range Of Motion
Regular chiropractic care has been shown to increase spinal range of motion as well as in the extremities. Limited range of motion can occur due to age or inactivity � sometimes a combination of the two.
Having the ability to move easier has many great benefits. It allows seniors to more actively engage with their environment. They can get on their hands and knees to work in the garden, bend down to pick up grandchildren, and improve leisure activities like golfing. Increased range of motion is one of the most common (and appreciated!) benefits of chiropractic treatment.
Decreased Degeneration Of Joints
When the spine is misaligned it can lead to other parts of the body becoming misaligned as well. This can lead to unusual and unnatural wearing of the joints. Over time, the joints can become worn down, painful, and cause difficulty in mobility and flexibility.
Chiropractic care is a very effective treatment for decreasing the degeneration of the spine and even other joints. When the body is in proper alignment it no longer has to adapt through postural compensation. This reduces stress on the spine and joints while relieving pain and restoring mobility.
Pain Relief
Chiropractic has long been recognized for its effectiveness in providing drug free pain relief for everything from back pain to headaches to arthritis. While pain medication and anti-inflammatory drugs only suppress the symptoms, chiropractic addresses the root of the problem.
Spinal alignments and other chiropractic techniques help to relieve pain for a variety of issues, not just back and neck pain. What�s more, chiropractic does not have the undesirable, sometimes dangerous side effects that drugs can.
Overall Better Health & Wellbeing
Proper spinal alignment can greatly benefit a person�s health, wellbeing, and even their mood. It allows them to become more active so they get exercise. They sleep better and have more energy.
An aligned spine also lets them more fully engage with their family, friends, and the world. They can get out and do things they were once unable to do and when they are active and happier the entire body benefits.
Improved Coordination & Balance
The aging process can have a significant impact on a person�s balance and coordination. This can have a variety of causes including degenerative changes to the spine, typically in the neck area. Injury to this area is another culprit.
There are special receptors that reside along the cervical spine in the rear of the joints. These receptors work to send vital messages to the brain regarding coordination and balance. When the spine and especially the neck are out of alignment, it can hinder how these receptors send and receive messages to the brain. The result is a condition called loss of proprioception, or sense of body awareness.
As the condition progresses, the patient relies on vision to determine the location of their feet, legs, and other limbs. The worse it gets, the less able the patient is in compensating and can become prone to falling.
Injuries from falling are one of the most common reasons elderly people visit emergency departments each year. Chiropractic can help realign the neck and spine, allowing the messages to move much easier, thus restoring balance and coordination.
Prevents Seniors From Being Confined To Nursing Homes
Senior citizens who are regular chiropractic patients are more likely to engage in exercise that is more strenuous. They are more active, have fewer injuries, and are basically happier and more positive.
The more active and mobile senior citizens are, the less likely they are to be placed in a nursing home due to medical conditions or the �typical� aging issues. Simply put, chiropractic for seniors changes the way many people look at aging � and places it in a much more positive, active light.
Injury Medical Clinic: Elderly & Geriatric Fitness
Most, if not all, ailments of the body trigger pain. Pain is interpreted and sensed in the brain. Pain is modulated by two key types of drugs which operate on the brain: analgesics and anesthetics. The term analgesic refers to a medication that relieves pain without loss of consciousness. The expression central anesthesia refers to a medication that depresses the CNS. It’s distinguished by the lack of all perception of sensory modalities, for instance, loss of consciousness without loss of critical functions.
Opiate Analgesia (OA)
The most successful clinically used drugs for producing temporary analgesia and relief from pain are the opioid family, which includes morphine, and heroin. There are currently no additional powerful pain therapeutic options to opiates. Several side effects caused by opiate use include tolerance and drug dependence or addiction. In general, these drugs modulate the incoming pain information in the spine and central nervous system, in addition to relieve pain temporarily, and can also be called opiate producing analgesia (OA). Opiate antagonist is a drug that antagonizes the opioid effects, such as naloxone or maltroxone, etc.. They are competitive antagonists of opiate receptors. However, the brain has a neuronal circuit and endogenous substances which modulate pain.
Endogenous Opioids
Opioidergic neurotransmission is located throughout the brain and spinal cord and is believed to influence many functions of the central nervous system, or CNS, such as nociception, cardiovascular functions, thermoregulation, respiration, neuroendocrine functions, neuroimmune functions, food consumption, sexual activity, competitive locomotor behaviour as well as memory and learning. Opioids exert marked effects on mood and motivation and produce a sense of euphoria.
Three classes of opioid receptors are identified: ?-mu, ?-delta and ?-kappa. All 3 classes are widely dispersed in the brain. The genes encoding each one of these have been cloned and found to function as members of the G protein receptors. Moreover, three major types of endogenous opioid peptides that interact with the above opiate receptors have been recognized in the central nervous system, including, ?-endorphins, enkephalins and the dynorphins. These 3 opioid peptides are derived from a large protein receptor by three different genes, such as the proopiomelanocortin, or POMC, gene, the proenkephalin gene and the prodynorphin gene.�The opioid peptides modulate nociceptive input in two ways: first, they block neurotransmitter release by inhibiting Ca2+ influx into the presynaptic terminal, or second, they open potassium channels, which hyperpolarizes neurons and inhibits spike activity. They act on various receptors within the brain and spinal cord.
Enkephalins are considered the putative ligands for the ? receptors, ? endorphins for its ?-receptors, and dynorphins for the ? receptors. The various types of opioid receptors are distributed differently within the peripheral and central nervous system, or CNS. There’s evidence for functional differences in these receptors in various structures. This explains why many undesirable side effects occur after opiate treatments. For instance, mu (?) receptors are widespread in the brain stem parabrachial nuclei, where a respiratory center and inhibition of these neurons may cause what’s known as respiratory depression.
Central or peripheral terminals of nociceptive afferent fibers feature opiate receptors in which exogenous and endogenous opioids could act to modulate the capability to transmit nociceptive information. Additionally, high densities of opiate receptors are found in periaqueductal gray, or PAG, nucleus raphe magnus, or NRM, and dorsal raphe, or DR, from the rostral ventral medulla, in the spinal cord, caudate nucleus, or CN, septal nucleus, hypothalamus, habenula and hippocampus.�Systemically administered opioids at analgesic dosages activate spinal and supraspinal mechanisms via ?, ?, and ? type opioid receptors and regulate pain signals to modulate symptoms.
Neuronal Circuits and Pain Modulation
For many decades it was suggested that somewhere in the central nervous system there is a circuit which can modulate incoming pain details. The gate control theory and the ascending/descending pain transmission system are two suggestions of such a circuit. Below, we will discuss both in further detail.
Gate Control Theory
The initial pain modulatory mechanism known as the gate control theory, has been proposed by Melzack and Wall in the mid 1960’s. The notion of the gate control theory is that non-painful input closes the gates to painful input, which results in avoidance of the pain sensation from travel into the CNS, for example, non-noxious input, or stimulation, suppresses pain.
The theory implies that collaterals of the large sensory fibers carrying cutaneous sensory input activate inhibitory interneurons, which inhibit and regulate pain transmission data carried from the pain fibers. Non-noxious input inhibits pain, or sensory input, and closes the gate to noxious input. The gate control theory demonstrates that in the spinal cord level, non-noxious stimulation will create presynaptic inhibition on dorsal root nociceptor fibers that synapse on nociceptors spinal neurons (T). This presynaptic inhibition will also prevent incoming noxious information from reaching the CNS, for example, it will shut the gate to incoming toxic information.
The gate control theory was the rationale for the idea behind the production and utilization of the transcutaneous electrical nerve stimulation, or TENS, for pain relief. In order to be effective, the TENS unit generates two different present frequencies below the pain threshold that can be taken by the patient. This process has found a degree of achievement in chronic pain treatment.
Evidence for an inherent analgesia system was found by intracranial electrical stimulation of certain discrete brain regions. These areas would be the periaqueductal gray, or PAG, and nucleus raphe magnus, or NRM, dorsal raphe, or DR, caudate nucleus, or CN, septal nucleus, or Spt, along with other nuclei. Such stimulation or sensory signals, inhibits pain, making analgesia without behavioral suppression, while the touch, temperature and pressure sensation stays intact. According to research studies, SPA, or stimulation produced analgesia, is more pronounced and continues for a longer period of time after stimulation in humans than in experimental animals. Additionally, during SPA, the subjects, however, still respond to nonpainful stimulation like temperature and touch within the circumscribed region of analgesia. The most effective CNS, or central nervous system regions for SPA to occur, would be in the PAG and the raphe nuclei, or RN.
Electrical stimulation of PAG or NRM inhibits spinal thalamic cells, or spinal neurons that project monosynaptically to the thalamus, in laminae I, II and V to ensure the noxious information from the nociceptors which are ultimately modulated in the level of the spinal cord. Furthermore, PAG has neuronal connections to the nucleus raphe magnus, or NRM.
The activity of the PAG most likely occurs by activation of the descending pathway from NRM and likely also by activation of ascending connections acting on greater subcortical levels of the CNS. In addition, electric stimulation of PAG or NRM produces behavioral analgesia, or stimulation produced analgesia. Stimulation produced analgesia, or SPA causes the release of endorphins which can be blocked by the opiate antagonist naloxone.
During PAG and/or RN stimulation, serotonin, also medically referred to as 5-HT, can also be discharged from ascending and descending axons from subcortical nuclei, in spinal trigeminal nuclei and in the spinal cord. This release of 5-HT modulates and regulates pain transmission by inhibiting or blocking incoming neural action. Depletion of 5-HT by electrical lesion of the raphe nuclei or with a neurotoxic lesion made by local injection of a chemical agent such as parachlorophenylalanine, or PCPA, results in blocking the power of opiate, both intracranial and systemic, as well as that of electrical stimulation in order to produce analgesia.
To confirm if the electric stimulation produced analgesia via the release of opiate and dopamine, then the region is locally microinjected with morphine or 5-HT. All these microinjections ultimately create analgesia. These processes also provide a way of identifying brain areas related to pain suppression and assist to produce a map of pain centers. The most effective way of producing opiate analgesia, or OA, is by intracerebral injection of morphine into the PAG.
The PAG and RN as well as other brain structures in which analgesia is produced, are also rich in opiate receptors. Intracerebral opioid administration produced analgesia and SPA can be blocked by systemic or from local microinjections of naloxone, the morphine antagonist, into the PAG or RN. For that reason, it’s been suggested that the two, both OA and SPA, operate by a frequent mechanism.
If OA and SPA behave through the same intrinsic system, then the hypothesis that opiates activate a pain-suppression mechanism is much more likely. As a matter of fact, current evidence suggests that microinjections of an opiate into the PAG activate an efferent brainstem system which inhibits pain transmission at segmental spinal cord levels. These observations imply that analgesia elicited from the periaqueductal gray, or PAG, demands a descending pathway into the spinal cord.
Dr. Alex Jimenez’s Insight
Pain modulation occurs through the process of electrical brain stimulation which occurs due to the activation of descending inhibitory fibers, which regulate or inhibit the input and output of certain neurons. What has been described as opioid and serotonergic antagonists, is believed to reverse both local opiate analgesia and brain-stimuli generated analgesia. The sensory signals or impulses in the central nervous system are ultimately controlled by both ascending and descending inhibitory systems, utilizing endogenous opioids or other endogenous substances, such as serotonin as inhibitory mediators. Pain is a complex perception which can also be influenced by a variety of other factors, including emotional state.
Mechanisms of Pain Modulation
Ascending and Descending Pain Suppression Mechanism
The primary ascending pain fibers, such as the A ? and C fibers, reach the dorsal horn of the spinal cord from peripheral nerve areas in order to innervate the nociceptor neurons in Rexed laminae I & II. Cells from Rexed lamina II make synaptic connections in Rexed layers IV to VII. Cells, particularly within laminae I and VII of the dorsal horn, give rise to ascending spinothalamic tracts. In the spinal level, opiate receptors are located in the presynaptic endings of their nocineurons and in the interneural level layers IV to VII from the dorsal horn.
Activation of opiate receptors at the interneuronal level produces hyperpolarization of the neurons, which lead to the the inhibition of activation as well as the release of substance P, a neurotransmitter involved in pain transmission, thus preventing pain transmission. The circuit which consists of the periaqueductal gray, or PAG, matter in the upper brain stem, the locus coeruleus, or LC, the nucleus raphe magnus, or the NRM, and the nucleus reticularis gigantocellularis, or Rgc,� leads to the descending pain suppression pathway, which inhibits incoming pain data at the spinal cord level.
As stated before, opioids interact with the opiate receptors in distinct central nervous system levels. These opiate receptors are the normal target regions for hormones and endogenous opiates, such as the endorphins and enkephalins. Due to binding at the receptor in subcortical websites, secondary changes which result in some change in the electrophysiological properties of the neurons and regulation of their ascending pain information.
What activates the PAG to exert its consequences? It was discovered that noxious stimulation triggers neurons in the nucleus reticularis gigantocellularis, or RGC. The nucleus Rgc innervates both PAG and NRM. The PAG sends axons into the NRM, and nerves in the NRM send their axons to the spinal cord. Additionally, bilateral dorsolateral funiculus, or DLF, lesions, referred to as DLFX, block the analgesia produced by both electrical stimulation and by microinjection of opiates directly into the PAG and NRM, but they just attenuate the systemic analgesic effects of opiates. These observations support the hypothesis that discrete descending pathways from the DLF are necessary for both OA and SPA.
The DLF is comprised of fibers originating from several brainstem nuclei, which can be serotonergic, or 5-HT, from nerves located inside the nucleus raphe magnus, or NRM; dopaminergic neurons originating from ventral tegmental area, or VTA, and adrenergic neurons originating from the locus coeruleus, or LC. These descending fibers suppress noxious input in the nociceptive spinal cord neurons in laminae I, II, and V.
Opiate receptors have also been discovered in the dorsal horn of the spinal cord, chiefly in Rexed laminae I, II, and V, and such spinal opiate receptors mediate inhibitory effects on dorsal horn neurons transmitting nociceptive information. The action of morphine seems to be exerted equally in the spinal cord and brainstem nuclei, including the PAG and NRM. Systemic morphine acts on both brain stem and spinal cord opiate receptors to produce analgesia. Morphine binds the brainstem opiate receptors, which triggers the brainstem descending serotonergic pathway into the spinal cord as well as the DLF, and these have an opioid-mediated synapse at the level of the spinal cord.
This observation demonstrates that noxious stimuli, instead of non-noxious stimulus, determine the gate control theory, which are critical for the activation of the descending pain modulation circuit where pain inhibits pain via the descending DLF pathway. In addition, there are ascending connections in the PAG and the raphe nuclei into the PF-CM complex. These thalamic regions are a part of the ascending pain modulation at the diencephalon degree.
Stress Induced Analgesia (SIA)
Analgesia may be produced in certain stressful circumstances. Exposure to many different stressful or painful events generates an analgesic response. This phenomenon is known as stress induced analgesia, or SIA. Stress induced analgesia has been believed to give insight into the physiological and psychological factors that trigger endogenous pain control and opiate systems. By way of instance, soldiers injured in battle or athletes hurt in sports sometimes report that they don’t feel pain or discomfort during the battle or game, nevertheless, they will go through the pain afterwards once the specific situation has stopped. It’s been demonstrated in animals that electrical shocks cause stress-induced analgesia. Based on these experiments, it is assumed that the pressure the soldiers and the athletes experienced suppressed the pain which they would later experience.
It’s believed that endogenous opiates are produced in response to stress and inhibit pain by triggering the midbrain descending system. Furthermore, some SIA exhibited cross tolerance with opiate analgesia, which indicates that this SIA is mediated via opiate receptors. Experiments using different parameters of electrical shock stimulation demonstrate such stress induced analgesia and some of those anxieties that produce analgesia could be blocked by the opioid antagonist naloxone, whereas others were not blocked by naloxone. In conclusion, these observations lead to the decision that both opiate and non-opiate forms of SIA exist.
Somatovisceral Reflex
The somatovisceral reflex is a reflex in which visceral functions are activated or inhibited by somatic sensory stimulation. In experimental animals, both noxious and innocuous stimulation of somatic afferents are proven to evoke reflex changes in sympathetic efferent activity and, consequently, effector organ function. These phenomena have been shown in such regions as the gastrointestinal tract, urinary tract, adrenal medulla, lymphatic cells, heart and vessels of the brain and peripheral nerves.
Most frequently, incisions are elicited experimentally by stimulation of cutaneous afferents, even though some work has also been conducted on muscle and articular afferents, including those of spinal cells. The ultimate responses will represent the integration of multiple tonic and reflex influences and might exhibit laterality and segmental trends as well as variable excitability in line with the afferents involved. Given the complexity and multiplicity of mechanisms involved in the last expression of the reflex response, attempts to extrapolate to clinical situations should most likely be conducted in favor of further systematic physiological studies.
The scope of our information is limited to chiropractic as well as to spinal injuries and conditions. To discuss the subject matter, please feel free to ask Dr. Jimenez or contact us at 915-850-0900 .
Curated by Dr. Alex Jimenez
Additional Topics: Sciatica
Sciatica is medically referred to as a collection of symptoms, rather than a single injury and/or condition. Symptoms of sciatic nerve pain, or sciatica, can vary in frequency and intensity, however, it is most commonly described as a sudden, sharp (knife-like) or electrical pain that radiates from the low back down the buttocks, hips, thighs and legs into the foot. Other symptoms of sciatica may include, tingling or burning sensations, numbness and weakness along the length of the sciatic nerve. Sciatica most frequently affects individuals between the ages of 30 and 50 years. It may often develop as a result of the degeneration of the spine due to age, however, the compression and irritation of the sciatic nerve caused by a bulging or herniated disc, among other spinal health issues, may also cause sciatic nerve pain.
Neurophysiology: There are two ways that nociceptive information reaches the central nervous system. One is the neospinothalamic tract for quick pain and two is the paleospinothalamic tract for slow pain that increases.
Neurophysiology Of Pain Part II
Intensity, Location & Quality of Pain…
… involve Spinothalamic and Trigeminal Pathways
The trigeminal pathway brings information from the face area.
The spinothalamic pathway brings information from the rest of the body.
Both these pathways project to the sensory cortex, which also receives information on innocuous stimuli such as touch, pressure and warmth via a separate pathway.
2 Pain Transmission Pathways For Location Intensity Quality
There is difference between the objective and subjective aspects of injury and pain.
Despite similar injury, people can differ in how much pain they feel.
Depending on the context, pain may not be felt despite injury, e.g. battlefield injury, during intense sports.
This suggests that there is a physiological mechanism that controls the transmission of nociceptive signals to the brain or modifies the interpretation of pain.
The pain control system can also explain the placebo effect.
Pain Modulation Pathway
Nerve signals are sent form the somatic sensory cortex and hypothalamus to the periaqueductal gray matter (PAG).
PAG sends signals to the parabrachial nucleus, medullary reticular formation, locus coeruleus, and Raphe neulei.
These in turn can control the in the transmission of nociceptive signals from the spinal cord to the brain.
This involves different involves different neurotransmitters.
Endogenous Opioids
Internally produced molecules with opioid-like action which regulate transmission of nociceptive signals.
Three classes of these molecules have been identified. All are peptide molecules
Enkephalins
Endorphins
Dynorphins
Despite these being powerful, endogenous modifiers of nociceptive signals, it has been difficult to produce and administer them in a way than can used in clinical practice.
Location Of Nerve Cells With Endogenous Opioid Receptors
In the spinal cord, endogenous opioids can prevent transmission between 1st order nerve cells (bringing signals from the periphery) and 2nd order spinal nerve cells that transmit the signals to the brain.
Also can prevent the increased synaptic efficiency, which plays a role in hyperalgesia.
Knowing the molecules involved in the �inflammatory soup� and how they are synthesized provides possible targets for pain reduction.
e.g. prostaglandins are produced by the COX enzyme. The activity of this enzyme is blocked by non-steroidal anti- inflammatory drugs (NSAIDs) such as ibuprofen, diclofenac.
Allodynia
A condition when normally non- painful stimuli cause pain, e.g., touch, light pressure, cold.
Involves changes in the synaptic sensitivity of the nociceptive neurons in the spinal cord (central sensitization).
Drugs such as ketamine, block NMDA receptors and so reduce transmisison of the nociceptive stimuli.
Gate Control Theory of Pain
Mother says to child, �Come I will rub the area which is painful and this will make it feel better.�
After stubbing a toe, we instinctively rub the area; this reduces the sensation of pain.
Ronald Melzack and Patrick Wall in 1962 provided an possible explanation for this effect.
Ascending Tracts | Pain Modulation: Gate Control Theory
Gate Theory
Rubbing the area that hurts stimulates receptors of innocuous stimuli like touch, pressure and vibration.
These mechano-receptors send signals along the A? nerve fibers that:
(1) stimulate spinal nerves (inhibitory inter-neurons) that in turn inhibit signaling in the 2nd order neurons (projection neuron) and (2) directly inhibit the 2nd order neuron to reduce or stop pain signal from being sent to the brain
Transcutaneous Nerve Stimulation (TENS) is based on the Gate Control Theory. Nerves of the innocuous sensory system are stimulated and they in turn, inhibit transmission of nociceptive stimuli in the spinal cord.
Abnormalities Of Pain System
Phantom Pain
Patients with amputation often have burning or tingling pain in the body part removed.
One possible cause is that nerve fibers at the stump are stimulated and the brain interprets the signals as originating in the amputated portion.
The other is the rearrangement within the cortical areas so that area say for the hand now responds to signals from other parts of the body but still interprets them as coming for the amputated hand.
Peripheral Sensitization
Peripheral sensitization represents a reduction in the threshold and/or an increase in magnitude of responsiveness at the peripheral ends of sensory nerve fibers.
This occurs in response to chemical mediators released by nociceptors and non-neuronal cells (e.g. mast cells, basophils, platelets, macrophages, neutrophils, endothelial cells, keratinocytes and fibroblasts) at the site of tissue injury or inflammation.
Basically, it is an increased sensitivity to an afferent nerve stimuli.
Central Sensitization
Peripheral & Central Sensitisation
A condition of the nervous sytem that is associated with the development and maintenance of chronic pain.
Known as �wind-up� or persistent high reactivity.
�Plastiticity in pain pathways� or the persistence of pain even after an injury has healed.
Is this negative or positive plasticity?
Central Sensitization & C Fibers
Two Main Characteristics Of Central Sensitization:
� Allodynia � occurs when a person experiences pain with things that are normally not painful, ie, soft touch causes pain.
� Hyperalgesia � occurs when a stimulus that is typically painful is perceived as more painful that it should be, ie, a simple bump.
Both are due to hyperreactivity of the nervous system.
Neurophysiology of pain: Pain�defined is the unpleasant sensation that accompanies injury or near injury to tissues, though it can also occur in the absence of such damage if the nociception system is not functioning. Nociception means the system that carries pain signals of injury from the tissues. This is the physiological incident that comes with pain.
Neurophysiology Of Pain
Objectives
Basics of the nervous system
Synaptic function
Nerve impulses
Transduction of peripheral painful stimuli
Central pathways
Central Sensitization
PeripheralSensitization
Control or modulation of pain signals
Pathophysiology of pain signaling pathway
Definition Of Pain
“Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.
It is important to know the basic structure of the nervous system.
This will help in:
� Understanding the mechanism by which nociceptive signals are produced.
� Know the different regions of the nervous system involved in processing these signals.
� Learn how the different medications and treatment for pain management work.
Nervous System
Central nervous system (CNS)
Brain and Spinal Cord
Peripheral Nervous System (PNS)
Nerve fibers go to all parts of the body.
Send signals to the different tissues and send signals back to the CNS.
Nerve Cells
The nervous system is made up of nerve cells which send long processes (axons) to make contact with other cells.
Nerve Cell-To-Nerve Cell Communication
Nerve cells communicate with other cells by releasing a chemical from the nerve endings � Neurotransmitters
Basic Steps In Synaptic Transmission
Synaptic Transmission
Steps in the passage of signal from one nerve cell to other.
Drugs are used to block the transmission of signals from one nerve cell to other.
These drugs can effect:
Ca2+ ion channel to prevent Ca2+ inflow which is essential for neurotransmitter (NT) release, e.g., the action of gabapentin.
Release of NT.
Prevent NT from binding to its receptor so stop further transmission of the signal.
Electrical Impulse
Signals move along a nerve process (axon) as a wave of membrane depolarization called the Action Potential.
The inside of all nerve cells has a negative electrical potential of around � 60 mV.
When stimulated this negative electrical potential becomes positive and then negative again in milliseconds.
The action potential moves along the nerve process (axon) to the nerve ending where it cause release of NT.
Action Potential
When there is no stimulation the membrane potential is at its Resting Potential.
When stimulated, channels in the nerve membrane open allowing the flow of sodium ions (Na+) or calcium ions (Ca2+) into the nerve or cell. This makes the inside less negative and in fact positive -the peak of the action potential (+40 mV).
These channels than close and by the opening of K+ channels the membrane potential returns to its resting level.
Stopping Action Potentials To Stop Nociceptive Stimuli
Nociceptive stimuli are those that will create a sensation of pain after they are processed in the CNS.
Nociceptive signals can be prevented from reaching the CNS by blocking the action of the channels that control the movement of ions across the nerve membrane.
A number of anesthetic agents stop Na+ channel from working and hence stop the generation of actions potentials and transmission of signals to the CNS.
Sensory Systems
The sensory system that can be divided into two divisions:
A Sensory System that transmits innocuous stimuli such as touch, pressure, warmth.
A System that transmits stimuli that indicate that tissues have been damaged = nociceptive .
These two systems have different receptors and pathways in the PNS & CNS
Nociceptors are free nerve endings that respond to stimuli that can cause tissue damage or when tissue damage has taken place.
Present in membrane of free nerve endings are receptors (protein molecules) whose activity changes in the presence of painful stimuli.
(Note the use of the same term receptor is used for cell or organs or molecules that involved in transduction of a stimuli.)
Transduction
Transduction is the process of converting the stimuli into a nerve impulse.
For this to occur the flow of ions across the nerve membrane has to change to allow entry of either Na+ or Ca2+ ions to cause depolarization of the membrane potential.
This involves a receptor molecule that either directly or indirectly opens the ion channels.
Chemical Agents…
… which can cause the membrane potential at the free nerve ending (nociceptor) to produce an action potential.
Many stimuli � mechanical, chemical and thermal � give rise to painful sensation making transduction a complex process.
Recently receptor molecules have been identified�� Transient Receptor Potential (TRP) channels � that respond to a number of strong stimuli.
TRP receptors are also involved in transmitting the burning sensation of chili pepper.
In time, drugs that act on these receptors will be developed to control pain.
Different TRP Channels
Capsasin, the active ingredient in chili pepper, is used in patches for relief of pain.
Menthol and peppermint gels are used to relieve muscle pain.
Motor Output & Sensory Input To Spinal Cord
Sensory nerves have their cell body outside the spinal cord in the dorsal root ganglia ( = 1st order neurons).
One process goes to the periphery, the other goes to the spinal cord where it makes synaptic contact with nerve cells in the spinal cord ( = 2nd order neurons).
The 2nd order neuron sends processes to other nerve cells in the spinal cord and to the brain.
2nd Order Nerve Cells Send Nerve Fibers In The Spinal Cord White Matter
Transmission Of Nociceptive Signals From The Periphery To The Brain
Silverthorn
A Delta (?) & C Nerve Fibers
Nerve fibers are classified according to the:
� (1) diameter of the nerve fiber and
� (2) whether myelinated or not.
A? and C nerve fiber endings respond to strong stimuli.
A? are myelinated and C are not.
Action potentials are transmitted 10 times faster in the A?
(20 m/sec) fibers than in C fibers (2 m/sec).
A? & C fibers
A? fibers respond mainly to mechanical and mechno-thermal stimuli.
C fibers are polymodal, i.e. the nerve ending responds to several modalities � thermal, mechanical and chemical
This polymodal ability is due to the presence of different receptor molecules in a single nerve ending.
Fast & Slow Pain
Most people when they are hit by an object or scrape their skin, feel a sharp first pain (epicritic) followed by a second dull, aching, longer lasting pain (protopathic).
The first fast pain is transmitted by the myelinated A? fibers and the second pain by the unmyelinated C fibers.
Central Pain Pathways
Nociceptive signals are sent to the spinal cord and then to different parts of the brain where sensation of pain is processed.
There are a pathways/regions for assessing the:
Location, intensity, and quality of the noxious stimuli
Unpleasantness and autonomic activation (fight-or-flight response, depression, anxiety).
Dr. Sletten Discussing Central Sensitization Syndrome (CSS)
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Pain/Weakness In The Lower Back, Hips, Knees & Ankles
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Brain Areas Involved In Processing Of Nociceptive Signals
The Anterior Cingulate & Insula Cortex Are Activated In Human Subjects
Inflammatory Soup – Hyperalgesia
Gate Control Theory of Pain
Abnormalities Of Pain System
Peripheral Sensitization
Somatosensory Cortex Organization
Cortical Reorganization
Nerve Cell-To-Nerve Cell Communication
Nerve cells communicate with other cells by releasing a chemical from the nerve endings � Neurotransmitters
TRP Channels
