PST - Pain

The patient can't feel physical pain. It is an extremely dangerous disorder and most individuals with CIP die in childhood due to unnoticed injuries. Pain is a perception created by the brain. Pain, however, is initiated at nociceptors which are specialised receptors that are found in the skin, muscles, joints and organs. It works by picking up on mechanical, chemical and thermal injuries. Nociceptors have a specialised sodium channel called NaV1.7. This allows activation of cells through sodium entry. If there is a fault in this channel, the nociceptor will no longer work. Once activated, the nociceptor sends an electrical signal along the nerves and the spinal cord to the thalamus in the brain. The thalamus is responsible for creating the "pain" experience but cannot tell where its coming from. To find this out, the thalamus sends a signal to the somatosensory cortex of the brain. 

In CIP, a mutation in the SCN9A gene (rare) causes the nociceptor sodium channel NaV1.7 to be abnormal. This prevents sodium from entering the cells and causing activation of the nociceptors. There is no electrical signal being sent through the nerves to the spinal cord and thalamus to create a pain sensation even though damage has been done. CIP is an autosomal recessive disorder. If you only have 1 copy of the mutated gene you will become a carrier of the disorder. Presentation of CIP ca vary but commonly patients will accidently bite off the tip of their tongue, burns, open wounds and even broken bones. If something gets stuck in their eye, it will go unnoticed until it causes damage to the cornea and vision problems. Diagnosis is completed through history and clinical examination. Genetic testing can be used to trace carriers of the disorder. There is no cure for CIP, however, naloxone can be used. Naloxone is an opiate antagonist that increase an individuals sensitivity to pain. It does this by inhibiting naturally occuring opiates in the spinal cord. Gene therapy could be a way of curing CIP in the future. 

If tissue damage occurs, firstly, the ascending paathway is triggered. Pain is identified in the somatosensory cortex which is composed of areas that recognise sensation from different parts of the body. For example, the outer region of the left side of the somatosensory cortex correlates with the leg, hand and face. Below the somatorsensory cortex is the brainstem, made up of the midbrain, pons and medulla from top to bottom. The brainstem follows down into the spinal cord. The spinal cord has nerve coming out from the anterior root and nerves coming in from the posterior route. The spinal cord contains lots of tracts. An important one in the ascending pathway is the spinothalamic tract. When cells are damaged, cytokines are released in that area. Important cytokines in the ascending pathway are prostaglandins. Prostaglandins are produced by almost all cells and are part of the inflammatory reponse. Sensory nerve fibres exist everywhere in the body and respond to prostaglandins. The carry a signal to the dorsal horn of the spinal cord. This neuron is a first order neuron. Within the dorsal horn, the first order neuron will relay or synapse the signal to the second order neuron using Substance P. The second order neuron crosses over to the opposite side of the spinal cord and enetrs the spinothalamic tract. The second order neuron stretches upward and relays the signal through the spinal cord, brainstem and into the thalamus. The second order neuron relays the signal to a third order neuron takes the signal to the correct area of the somatosensory cortex for wherever the tissue damage occurred. The descending pathway mediates the ascending pathway. 2 important areas of the descending pathway are the periaqueductal gray matter of the midbrain and the nucleur raphe magmus of the medulla. When uninhibited the neurons from the periaqueductal gray matter descend and relay the signal to the nucleus raphe magmus in the medulla. The second order neuron in this pathway is a serotonergic/non-adrenergic and will go to the dorsal horn of the spinal cord. This serotonergic/non-adrenergic second order neuron essentially mediates the first order neuron and second order neuron communication of the ascending pathway. This is how it mediates the pain signalling in the ascending pathway.  The dorsal horn is like a control gate for pain signals and is referred to as the substancia gelatinosa. In the ascending pathway, the first order neuron synapses with the second order neuron here. A action potential is brought in by the first order neuron stimulates the release of Sunbstance P by vesicles into the synaptic cleft. Substance P stimulates the second order neuron which will send the signal through the spinothalamic tract and into the brain. In the descending pathway, an inhibitory neuron in the dorsal horn releases serotonin and noradrenaline from its vesicles into the synaptic cleft. This will bind onto receptors on the ascending pathways first order neuron (pre-synaptic) preventing the release of Substance P. The inhibitory neuron also stimulates an inter-neuron in the dorsal horn which is an opioid neuron. When the inter-neuron is activated, it release enkephalin which is an endogenous opioid. In the dorsal horn, enkephalin inhibits the release of Substance P from the ascending pathways first order neuron and prevents depolarisation of the second order neuron in the ascending pathway. This prevents the signal from being relayed into the brain. 

The TrpV1 receptor is responsible for thermoception. This receptor is also sensitive to pain. These receptors are very complex and reside in the cell membrane. If there is a change in temperature or painful stimuli it causes a conformation change in this protein. This works in the same process as discussed using the pain pathways. The sensory fibres come in 3 fibres. The largest myelinated fibres are very fast Aalpha fibres. The medium speed fibres are Abeta with slightly less myelination. Adelta fibres are slightly less myelinated than Abeta fibres and therefore slightly slower. C fibres are the slowest fibres and are unmyelinated. 

This is the same mechanism if you were to heat a jalapeno. The active ingredient in these is capsaicin and thats what gives it that burning sensation. The capcaicin molecules activate the TrpV1 receptors on the tongue and trigger the pain pathway. 

It begins with tissue damage from noxious stimuli e.g. temperature, mechanical pressurre or chemicals. The nociceptors are activated and the pain pathway occurs. This leads to an autonomic response and withdrawal from the stimuli once the signal reaches the spinal cord. This is adaptive, high threshold pain. It acts as an early warning system and protects from further damage. 

Inflammatory pain occurs through tissue damage as damaged cells release cytokines e.g prostaglandins which is an inflammatory mediator. Inflammation is a positive response to damage as it attracts immune cells e.g. macrophages, mast ceells, neutrophils and granulocytes to clear damaged cells away and pomote growth of new cells. This activates the pain pathway and leads to spontaneous pain and pain hypersensitivity when the signal reaches the spinal cord. This is an adaptive low threshold pain. It promotes the healing of tissue by being tender to avoid further damage. 

Allodynia is when a normal touch to damaged cells causes pain such as in inflammation from sun burn or other tissue injury. Hyperalgesia is when the nociceptors are overly excited and cause extreme pain when a normal stimulus occurs like touching a bruised area or broken bone. There is increased and constant signalling in the nociceptor neurons in both these cases. 

In the event of tissue damage, there is primary activation leading to a lower pH due to the increase in hydrogen ions in the area. There is a release of potassium ions in the area. Damage also causes the synthesis of prostaglandins and bradykinin. This causes  more action potentials being fired due to a lower threshold for activation being required. It is the same result if the activation is secondary and the impulse comes from a nerve terminal. 

It is caused by damage in the nervous system which can be peripheral or central. TN is a syndrom that causes severe facial pain that can reoccur and become chronic. It occurs here due to neuropathic pain in the trigeminal nerve. It is a unilateral pain that can ocur in one or more branches of the nerve occsionally causing facial spasms. It tends to favour women more than men and could be caused by an anomalous blood vessel affecting the trigeminal nerve. As a neuropathic pain it is severe, electric shock like and is short lasting. It is often known as Tic doloureauc as the patient moves when an attack of pain occurs causing a tic. It can be treated using pharmacological intervention, percutaneous procedures, micovascular decompression or radiation therapy. Carbamazepine is the best studied drug for TN. Individuals may require further drugs such as lamotrigine and baclofen. Gabapentin has also proved effective for TN, particularly if patients suffer from multiple sclerosis.