The human glucocorticoid receptor: molecular basis of biologic function

Abstract:
The characterization of the subfamily of steroid hormone receptors has enhanced our understanding of how a set of hormonally derived lipophilic ligands controls cellular and molecular functions to influence development and help achieve homeostasis. The glucocorticoid receptor (GR), the first member of this subfamily, is a ubiquitously expressed intracellular protein, which functions as a ligand-dependent transcription factor that regulates the expression of glucocorticoid-responsive genes. The effector domains of the GR mediate transcriptional activation by recruiting coregulatory multi-subunit complexes that remodel chromatin, target initiation sites, and stabilize the RNA-polymerase II machinery for repeated rounds of transcription of target genes. This review summarizes the basic aspects of the structure and actions of the human (h) GR, and the molecular basis of its biologic functions.
Steroids (2010), 75(1):1-12

Stress & disorders of the stress system

Chrousos (2009). An excellent article; abstract below:
All organisms must maintain a complex dynamic equilibrium, or homeostasis, which is constantly challenged by internal or external adverse forces termed stressors. Stress occurs when homeostasis is threatened or perceived to be so; homeostasis is re-established by various physiological and behavioral adaptive responses. Neuroendocrine hormones have major roles in the regulation of both basal homeostasis and responses to threats, and are involved in the pathogenesis of diseases characterized by dyshomeostasis or cacostasis. The stress response is mediated by the stress system, partly located in the central nervous system and partly in peripheral organs. The central, greatly interconnected effectors of this system include the hypothalamic hormones arginine vasopressin, corticotropin-releasing hormone and pro-opiomelanocortin-derived peptides, and the locus ceruleus and autonomic norepinephrine centers in the brainstem. Targets of these effectors include the executive and/or cognitive, reward and fear systems, the wake-sleep centers of the brain, the growth, reproductive and thyroid hormone axes, and the gastrointestinal, cardiorespiratory, metabolic, and immune systems. Optimal basal activity and responsiveness of the stress system is essential for a sense of well-being, successful performance of tasks, and appropriate social interactions. By contrast, excessive or inadequate basal activity and responsiveness of this system might impair development, growth and body composition, and lead to a host of behavioral and somatic pathological conditions. Nat Rev Endocrinol 5(7):374-81

Neuroendocrinology of post-traumatic stress disorder

Pervanidou & Chrousos (2010)
Abstract: Dysregulation of the stress system, including the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-sympathetic nervous system (SNS), is involved in the pathophysiology of post-traumatic stress disorder (PTSD), an anxiety disorder that develops after exposure to traumatic life events. Neuroendocrine studies in individuals with PTSD have demonstrated elevated basal cerebrospinal fluid corticotropin-releasing hormone concentrations and contradictory results from peripheral measurements, exhibiting low 24 hours excretion of urinary free cortisol, low or normal circulating cortisol levels or even high plasma cortisol levels. The direction of HPA axis activity (hyper-/or hypo-activation), as evidenced by peripheral cortisol measures, may depend on variables such as genetic vulnerability and epigenetic changes, age and developmental stage of the individual, type and chronicity of trauma, co-morbid depression or other psychopathology, alcohol or other drug abuse and time since the traumatic experience. On the other hand, peripheral biomarkers of the SNS activity are more consistent, showing increased 24h urinary or plasma catecholamines in PTSD patients compared to control individuals. Chronically disturbed hormones in PTSD may contribute to brain changes and further emotional and behavior symptoms and disorders, as well as to an increased cardiometabolic risk. Prog Brain Res. 182:149-60

Positve mood & thinking - the benefits

Ask most people and of course they would agree that positive thinking is going to make life better. Asking people how often they spend time in a positive mood can be an interesting self-reflective exercise. It all seems quite obvious really, but it does seem that in many cases negative thinking and rumination prevails. An increasingly popular method of dealing with this way of living is the Buddhist approach of mindfulness. Maintaining awareness of the present moment without judgement is the essence of this practice underpinned by regular meditation. The argument is that we spend far too much time pondering on the past (it's too late, nothing can be done about that) or the future (that has not happened yet) and not enough in appreciating the now. The mind is blamed for taking us off into past events or into scenarios that have not even occurred (e.g. the argument that you are going to have with the boss). How about reducing this mind activity?

Research shows us that positive moods increase our visual attention aiding the collection of information about the world around us, improves creativity, social skills, ability to deal with criticism, our verbal reasoning and problem-solving ability. Practicing postive thinking regualarly seems to build our resilience and ability to gain benefit. There is likely to be a genetic disposition (accounting for around 50% of the variability) but we also have the ability to change through learning and adaptation.

It is likely that personality type will affect the way in which you create your positive mood. Therefore trying different methods is best. Some ideas to change your mood for the better include challenging your negative thoughts (cognitive restructuring), meditation and developing relationships with family and friends.

Those suffering pain often present with a negative mindset that is understandable. Working to restructure the beliefs and thoughts and subsequently how the pain is interpreted is an excellent way of improving control. At Specialist Pain Physio we work closely with patients to lessen the impact of pain and suffering with techniques that increase positivity for the aforementioned reasons. Additionally it has a good effect upon the immune system that is very much involved in pain. It takes time and effort as part of the treatment and rehabilitation programme for pain, chronic pain & injury.

Reading
Be Happy, Dan Jones. New Scientist 25th Sept 2010

Using langauge in rehabilitation

One of the most interesting aspects to keeping an on current science is the application of the findings to the rehabilitation process. A recent article in the New Scientist by David Robson discussed the effects of language upon perception. It seems that the words we use have an impact upon what we see. The example used describes words related to up and down movements such as 'climb' and 'drip' have an impact upon the eye's sensitivity to vertical motion. This is based upon the work of Gabriella Vigliocco at UCL who found that individuals were more likely to determine the direction of moving dots when accompanied by a verb that described the movement.

Robson suggests that words prime the visual system, further evidenced by a studies that show when we hear a word we are more able to find obscured images and letters. Creating a mental image from the word may allow us to identify the object more rapidly. It seems that the sounds could also be important and further enhance our perception.

Clearly there is a huge integration and scrutiny of the massive input of information from within and around us to create our sense of self. Many people have spoken about this including Melzack who describes the sentient hub and Bud Craig who discusses interoception. Our representation is known to be altered with pain and injury as demonstrated in many fMRI studies but also from descriptions that patients give of their experience of their body. For example, joints feel 'out of place' and hands feel bigger ('sausage fingers'). Lorimer Moseley has done some interesting work where he asked individuals with chronic low back pain to draw their perception of their trunk and spine. The results demonstrated altered awareness and quite distorted images.

I see a role for perceptual tasks within a rehabilitation programme and most definitely in a multimodal sense. Working with our mental representation of the body whilst performing motor control exercises seems to enhance the quality of the movement. We know about graded motor imagery and imagined movements and how this can be really effective as part of a programme of care for complex regional pain syndrome (CRPS). Applying these principles to altered perception of body shape, size and position with mental imagery is an interesting application and potentially reconfiguring the neuromatrix. Adding language and sounds to the process may enhance this process on the basis that any additional and 'normal' input can reduce the threat value and restore function. Clearly this need to be studied appropriately to discover whether the idea is tangible, however in the meantime, if the individual's perception of their body and its motion can be enhanced with a few simple words, it is a simple application.

The Voice of Reason. Robson, D. New Scientist 4th September 2010

The Pain Neuromatrix

The pain neuromatrix was a concept that came from Ron Melzack who partnered Pat Wall in developing our understanding of pain in a modern sense. Moving on from the Pain Gate Theory, Melzack described a widespread distribution of neurons (brain cells) that imprint a 'neurosignature' upon nerve impulse patterns that pass through the matrix. The neurosignature creates our experience of self including movement and pain. We have an overall neurosignature for our sense of self and subsets of patterns that give us unique experiences such as pain, warmth and other qualities that are produced by these modules.

Melzack (2004) describes four components of this concept including the 'body self' where we have the experience of ourselves as a result of the unification of information from the body, the processing and synthesis of the signature, the sentient neural hub that converts the processes into awareness and the subsequent action to achieve the desired goal. In terms of pain as an output from the brain, this would be the end result of an activation of the pain neuromatrix with a characteristic signature, the pain signature. Pain is part of a multi system response to a perceived threat. There are many inputs to the brain that can trigger the pain neuromatrix including movement, thoughts, emotions, touch, memories, fear and visual stimuli to name but a few. The reason that these stimuli can trigger a pain response is in essence due to a perceived threat but also due to the fact that the widespread neurones that make up the pain matrix are involved in all of the aforementioned activities but are also part of the pain neuromatrix.

The neuromatrix model provides an excellent explanation for higher level parallel processing of information and the output that occurs as a smooth mechanism creating our conscious experience. Melzack points out that the matrix is genetically determined and moulded by sensory input. This makes sense as we continue to learn as we have new experiences, the nervous system being incredibly plastic (Doidge, 2007). Describing this to patients allows them to understand why there are so many influences upon the pain that they suffer, even if they are unaware of the exact stimulus. In many cases of chronic pain the patient describes an increase in symptoms despite no change in their daily routine. The neuromatrix allows us to look at some of the possible reasons for a flare-up and give reassurance that they have done no 'damage' in the case that there has been no further injury. Empowering the individual with the knowledge that hurt does not mean harm can be extremely useful in many cases.

Evolution of the neuromatrix theory of pain. The Prithvi Raj Lecture: Presented at the Third World Congress of World Institute of Pain, Barcelona 2004. Pain Practice, 5(2), 85-94
The brain that changes itself. Doidge, N. (2007)

Pain Medication

Below are some of the common medications that can be prescribed by your doctor or consultant

Paracetemol

This is a simple analgesic that can be beneficial for mild pain. Widely available and safe within prescribed doseages, paracetemol probably works by indirectly inhibiting enzymes known as cyclooxygenases (COX-1 & COX-2). In addition to analgesic effects, there is the well-known antipyretic action (reduces temperature).

NSAIDs (Non-steroidal anti-inflammatory drugs), e.g. neurofen, ibuprofen, diclofenac

Commonly prescribed for inflammatory pain, NSAIDs are active in the inhibition of the COX exnzymes. This has been demonstrated scientifically with both COX-1 and COX-2 enzymes although many anti-inflammatories are not able to be selective and hence inhibit both. This is the reason for the well-documented side-effects such as gastric irritation and renal failure. Your doctor will advise you on the use of these drugs according to your current medical condition.

COX-1 is expressed constitutvely and gives rise to prostaglandins which have a a role in normal cell function. COX-2 is expressed when an inflammatory process is underway to produce more prostanoids. Inhibiting the prostaglandin activity by the use of NSAIDs means that normal physiology is affected and therefore the adverse effects can be experienced.

Prostaglandins are metabolised from arachidonic acid by the COX enzymes following tissue damage. NSAIDs act by inhibiting these enzymes and therefore inhibit prostaglandin production. Prostaglandins have the ability to sensitise nerve endings by altering the membrane excitability, therefore the nerve becomes more likely to send 'danger' signals to the spinal cord. There are other breakdown products that have this action, but prostaglandins are one of the best understood. Following sensitisation, pripheral nerves become more respondant to mechanical, chemical and thermal stimuli, hence the reason for pain when we press on or near injured tissue (mechanical), why it is painful to take a shower with sunburn (temperature) and why exercise can be painful (release of acids, i.e. chemical).

Opioids (e.g. morphine, tramadol, codeine, dihydrocodeine, pethidine)

Opioids have been studied in detail over the last 30 years and now we have a great deal of knowledge about how they work and how they affect the nervous system. The discovery of the opioid receptor (like a lock that a specific key would fit, the key being the opiate drug and the lock being the receptor) and where these receptors are situtated. Knowing that there are receptors in the brain for example, means that we can explain the feelings of drowsiness and cognitive impairment (ability to concentrate).

Once an opiate has bound upon a receptor, it inhibits several channels that cross the nerve membrane (calcium and potassium) because it is linked to these channels. The channels allow for the passing of specific ions which alter the excitability of the nerve (i.e. become more excited and sensitive with a change in the balance of flow of these ions). There are further effects within the cell that reduce excitability of the nerve (inhibition of several pathways of activity that lead to increased excitability; cAMP & MAP kinase cascades).

Anticonvulsants (e.g. carbamazepine, gabapentin, pregabalin)

Anticonvulsants are used to treat neuropathic pain (see page on pain types) that is underpinned by changes in nerve excitability. This is as a result of an alteration in the channel (sodium & calcium) expression upon the nerve membrane (see opioids for brief explanation of channels) that is similar to changes that occur in epilepsy (this does not mean that you have epilepsy just because there are some similarities in channel changes).

Gabapentin decreases the on going firing of signals that are generated through sodium channel activity, inhibits calcium channels and acts with the NMDA receptor. The end result is reduced excitability and less signalling to the spinal cord from the periphery.

Carbamazepine is related to tricyclic antidepressants. It inhibits noradrenaline and has an effect upon sodium channels therefore has inhibitory effects by reducing spontaneous nerve activity (a feature of neuropathic pain) and promoting descending inhibition (signals descend from higher levels, brain & brain stem, to inhibit ascending danger signals).

Pregabalin has a similar action to gabapentin. It has been shown to be effective in diabetic neuropathy and postherpetic neuralgia.

Antidepressants (e.g. tricyclics, SSRIs; amitriptyline, fluoxetine, citalopram, paroxetine)

Antidepressants have been discovered to provide pain relief by activating the descending pain-inhibiting system (brain stem to spinal cord). This includes an endorphin release link between the periaqueductal gray (PAG) and the raphe nucleus and a serotonergic link between the raphe nucleus and the dorsal horn of the spinal cord. There is also a noradrenaline pathway from the locus coeruleus to the spinal cord. The most effective drugs appear to be those that have a combined effect upon both the serotonergic and noradrenaline pathways.

Antidepressants are effective in the treatment of neuropathic pain, relieving the stabbing and steady pains. There are side-effects that can be experienced. Your doctor should tell you about the dosage and how the drug is best taken.