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Mechanism of Pain

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Pain


THE MECHANISMS OF PERIPHERAL NEUROPATHIC PAIN

 

Peripheral neuropathic pain mechanisms vary by underlying causes such as inflammation, compression, and direct injuries to nerve cells (termed neurons).

 

Currently there are five known mechanisms as follows;

 

 

1. Sensitisation:

 

A state of hyperexcitability in primary afferent nociceptors, characterised by a lowered activation threshold and an increased response to a given stimulus.

 

2. Formation of Ectopic Neuronal Pacemaker

 

Peripheral neuropathic pain may arise from the formation of ectopic neuronal pacemakers (sodium channels) by damaged nerves or neurons. Sodium channels are signal systems used by neurons to transmit nerve impulses through a chemical medium. Dysfunctional sodium channels created in damaged cells exhibit different depolarisation characteristics and densities, resulting in abnormal responses to normal stimuli.

 

3. Cross-talking and crossed after-discharge

 

Peripheral neuropathic pain can arise from abnormal electrical connections between axons, also known as “cross-talking”. When the sprouts of primary afferents with damaged axons fire action potentials at abnormally high frequencies in response to stimuli, it is called “crossed after-discharge” These two responses may be the primary source of sympathetically mediated or stimulus provoked pain.

 

4. Neurogenic inflammation

 

Neurogenic inflammation is a process in which inflammatory neuropeptides (substance P and prostaglandins) are released from nociceptors and sympathetic post-ganglionic neurons which in turn, trigger an abnormally high cascade of neural activity.

 

5. Damage to myelin sheath

 

Damage or abnormality of the sheath surrounding peripheral nerves may cause an abnormal pain response because it compromises the proper conduction of pain signals. For example, tumour growth may compress the sheath cells or cause inflammation and disrupt the sheath functionality.

 

  

DISORDERS LEADING TO PERIPHERAL NEUROPATHIC PAIN

 

1. Diabetes

 

Diabetes is one of the major causes or neuropathic pain. Although the exact pathophysiology is still unknown, it is believed that multiple factors are involved in the development of diabetes-related neuropathic pain.

 

2. Herpes Zoster

 

Postherpetic neuralgia is another major cause of peripheral neuropathic pain which advances more prevalently wirh age. Viral infection causes rashes that are followed by chronic pain. It can be common in patients recovering from stress, trauma and surgery and can be exacerbated by medications that suppress the body's immune system such as the corticosteroids (for example prednisolone and dexamethasone).

 

3. Trauma

 

Post-traumatic peripheral neuropathy is caused by direct damage of neurons through external injuries. It can also be caused after the trauma of surgery.

 

4. Tumour

 

Tumour induced neuropathy may be direct, as in the case of a neuroma (new axons sprout up from a damaged nerve ending), or indirect as in the case of solid tumour compression of the myelin sheath surrounding neurons (this occurs when a tumour pushes up against major nerve structures).

 

5. Entrapment

 

The most well known entrapment neuropathy is carpal tunnel syndrome. It is common among office workers and is caused by repetitive hand movements.

 

6. Chemotherapy and Toxic Exposure

 

Medications used in chemotherapy may be toxic and therefore hinder the functionality of neurons. Exposure to toxic materials from the environment on a daily basis can also lead to neuropathic pain.

 

7. Alcoholism

 

Alcoholism may cause neuropathy through nutritional deficiencies. In particular, severe alcoholism can lead to a lack of the B vitamins.

 

 8. Phantom Limb Pain

 

Phantom limb pain is experienced by many amputees, however, its underlying mechanism is not well understood.

 

The mechanism of a painful experience can begin with a noxious stimuli (chemical, mechanical, thermal) causing tissue injury to the skin, muscles or the viscera (internal organs), called nociceptive pain. Electrical impulses are generated and transmitted from the site of injury to specific centres in the brain. This sequence of events, called nociception involves four processes, transduction, transmission, modulation and perception.

When the noxious stimuli results in tissue injury, endogenous (within the body) chemical mediators are released or synthesised and will directly stimulate inflammatory mechanisms which enhance transduction. A chemical soup of the body’s chemicals such as histamine, cytokines, substance P, serotonin and prostaglandins are examples of substances that can be involved in the various inflammatory processes. For example, prostaglandins, which are synthesised by the body from arachidonic acid by the enzyme cyclooxygenase, are associated with an inflammatory response and can induce an enhanced, prolonged response to pain known as hyperalgesia. The class of drugs known as NSAIDS (non-steroidal anti-inflammatory drugs) inhibit prostaglandin synthesis and will relieve this type of pain (the most common NSAID is of course Ibuprofen, the commonly available brand being Nurofen).

Five distinct types of opioid receptors are found in the body: mu (with subtypes mu-1 and mu-2), kappa, delta, sigma, and epsilon. Each receptor type binds differently with the various opioids. The mu receptors are primarily located at sites above the spine including the medial thalamus and brain stem areas. Some are also found in the spinal cord. Research has found that the mu-1 receptors are primarily responsible for analgesia and euphoria, and bind with opiates (codeine, morphine), and opiate type chemicals in the body called beta-endorphins, and enkephalins. Mu-2 receptors, on the other hand, have been associated with side effects such as respiratory depression that is commonly associated with morphine). The opioids also inhibit substance P resulting in pain relief.

Pain resulting from an injury to the peripheral or central nervous system is called neuropathic pain. Neuropathic pain is often described as a sharp, lancinating (stabbing) and burning whereas nociceptive pain is often described as dull and aching and termed somatic pain (originating from the skin, bones or muscles), or visceral pain (coming from the abdominal organs or organs from within the chest).

Another type of pain, termed idiopathic pain, is non specific with an unknown origin. Stress, anxiety and depression can influence this type of pain. Typically this pain is usually located in the head, neck, shoulders, abdominal and pelvic areas.