Neurological Aspects of Pain

Neurological Aspects of Pain 1.1. Functional Properties of Nerve Fibres 1.1.1. Properties of Peripheral Somatic Nerves Peripheral somatic nerves consists generally of somatic-motor, autonomic-motor and sensible fibres. 1.1.1.1. Somatic-motor fibres for the striated musculature The cell bodys of somatomotor fibres for the striated musculature are always lying in the brainstem (12 pare cerebral nerves) or the fore horn of the whole spinal medulla. The stimulus runs from central to peripheral (efferent). The lateral cutaneous femoral nerve consists of sensible fibres and no motor fibres. The shiatic nerve consists of 20% motor fibres, 30% sensible, and 50% sympathetic fibres. The gluteal nerves consist of pure motor fibres, sympathetic fibres and no sensible fibres. 1,2 1.1.1.2. Autonomic-motor fibres for the smooth muscles of blood- and lymphatic vessels The autonomic-motor fibres for the smooth muscles of the blood and lymphatic vessels are of sympathetic origin. Venes are not innervated. They function by the musculare pump system and in some cases by valves. The cells bodies of the autonomic-motor fibres are situated in the lateral horn between C8-L2. They are termed: the centro-ganglionar neurons. All motor neurons, situated in the spinal medulla go via the fore horn to the peripheral nerve. It must be mentioned that all smooth muscles can contract without external innervation (for example: heart, gut). This is due to the intrinsic nerve system with is influenced by the sympathetic and parasympathetic nervous system. 3-5 1.1.1.3. Sensible fibres for somatic structures The sensible fibres for somatic structures originate from muscles, tendons, capsules, joints, ligaments and bones. Their cell bodies are lying in the spinal ganglions of the corresponding nerve (= afferent). 2,6 1.1.1.4. Sensible fibres for autonomic structures: blood- en lymphatic vessels The cell bodies of the sensible fibres for autonomic structures are situated in the spinal ganglions of the segments where the sympathetic neurons start (SI-joint: T11-L1). The peripheral autonomic nerve contains generally autonomic-motor and sensible fibres and serves for the innervation of organs. Glands are always dubble innervated (sympathetic and parasympathetic), except for the adrenals. 2 Examples: The femoral arterie contains sensible fibres which go to the spinal ganglions and arrive in the dorsal horn where connections exist, via intercalar neurons, with the origins of the sympathethic fibres of the levels T10-T11. Knee joint: is sensible innervated via the sciatic nerve (posterior side of the knee), but in the knee capsule, sensible fibres exist which connect via the femoral arterie the levels T10-T12. 1.1.2. Properties of Peripheral Autonomic Fibres Peripheral autonomic nerves consist of autonomic-motor and sensible fibres. They innervate organs and glands. 1.1.2.1. Viscero-sensible fibres The cell bodies of viscero-sensible nerve fibres are situated in the spinal ganglions of those segments from where the sympathetic and parasympathetic neurons start. Example: the pelvis organs: S2-S4 and/or TLJ (= thoracolumbar junction). The TLJ receives a lot of information. Some of those stimuli go via the nervous supply in the blood vessel wall. 2 1.1.2.2. Motor fibres for smooth muscles The parasympathetic primary cells are situated in the brain stem to the level of C2 and the lateral horn of S2-S4. The sympathetic origin is situated in the lateral horn of C8-L2. 2,7,8 1.1.3. Axoplasma Flow of the Axons Materials and substances are moved within the cytoplasm of all cells. In the axoplasm (= cytoplasm of neurons), structures such as the smooth endoplasmic reticulum, ribosomes, microtubules and neurofilaments likely take part of the axoplasmic transport mechanism. Perhaps the human movement plays a role in this intracellular motility 9. In the cytoplasm of nerve fibres nutrients and transmitters are moved. At the nerve ends vesicles are located, that continue the transport into the gap junction. The transport in the axoplasma is termed antidrome and orthodrome transport. Antidrome (antegrade) transport occurs from central to the periphery and orthodrome (retrograde) transport in the opposite direction.1,10,11 For the sciatic nerve the antidrome transport is rather fast (12 hours), the orthodrome transport is slower (48 hours). 1.1.3.1. Signal transfer of the peripheral nerve fibres Ion-channels and receptors play an important role in the signal transfer of the peripheral nerve fibres. The ion-channels are located on the extremities of the fibres. They make the transport for the neurotransmitters possible. Receptors are specified. Every cell has ÂÂ ± 1 million receptors. The gates of the ion-channels (mostly proteins) can be inhibitory or excitatory. The Swann-cells are spread over the axon and form de myelin sheet. The myelin sheets are interrupted by the knots of Ranvier. In the CNS they are termed glial cells. The glial cells have several functions. The myelin sheets have a certain thickness. Unmyelinated axons have Schwann-cells as well. In myelinated axons the stimulus progresses salutatory and in unmyelinated axons the stimulus progresses slowly. The signal transfer of the peripheral nerve fibres has 3 kinds of stimulus progress being chemical transport, electric stimuli progression and axoplasm flow. Chemical transport occurs at the nerve ends, and consists of neurotransmitters. The transport depends of the kind of ion-channel, the neurotransmitter and the receptor. Electric stimuli progress over the axon and occur by opening of the ion-channels stimulation the own nerve ends due to production of the neurotransmitters. The speed of transmission depends of the presence of a myelin sheet and the diameter of the fibres. The axoplasm flow of the neurotransmitter in axoplasma (= chemical) occurs in 2 directions. Sometimes the pain can occur 24 hours after injury! It can also be very slow (up to 48 hours) and be resposible for the delayed onset of pain. 1,11 1.1.3.2. Morphologic and functional classification of nerve fibres: Understanding pain phenomen the morphologic and functional properties of nerve fibres is important. In time several classification systems have been investigated and proposed. 1.1.3.3. Classifying axons according to their conduction velocity In the 1920s and 1930s, there was a virtual use of classifying axons according to their conduction velocity 13. Three main categories were discerned, called A, B and C fibres: C fibres are the smallest and slowest. Mechanoreceptors generally fall in category A. The A group is further broken down into subgroups designated: the a fibres: the fastest the b fibres the d fibres: the slowest The muscle afferents axons are usually classified into four additional groups: I: the fastest II, III and IV: the slowest, with subgroups designated by lower case roman letters. 1.1.3.4. Properties of the A-d, A-b sensors or type I en II fibres The A-a and A-b fibres have low threshold properties. They are low threshold afferents/efferents, they have a quick adaptation, are bi- or monosynaptic and unimodal (= mechanosensors: only sensible for mechanical stimuli). They cross the midline in the spinal medulla. The A-b provides information about normal pressure or strain tension and the A-a provides information about position changes of joints in space. They give information about the smooth touch and kinesaesthesis in the skin. 1.1.3.5. Properties of the A-d and C sensors or type III en IV fibres 1.1.3.5.1. The A-d sensors or type III fibres The A-d or type III fibres are selective and have a slightly higher threshold than the A-a and the A-b sensors. They have a longer adaptation time. After a pin prick the pain keeps going on for a time which is a specific property of the A-d sensors. They are multisynaptic and cross the midline in the spinal medulla. A-d sensors are polymodal. They provide information about mechanical stretch and pressure forces from normal to noxious. They give information about temperature from normal to noxious stimuli. From 36,5ÂÂ °C tot 42ÂÂ °C especially C-fibres are involved. From 36,5ÂÂ °C tot 38ÂÂ °C the A-d fibres are responsible. A quantity of those fibres is noxious. They are termed: nocisensors but not all. Some measure only normal temperatures and they become nocisensors in case of tissue injury. 11 1.1.3.5.2. The C sensors or type IV fibres The C or type IV fibres are selective and have a high till very high threshold. They are slow to very slow with a long adaptation time. They have tonic and continuous activity properties. They cross the midline in the medulla medulla and are polymodal. The C fibres measure the chemical consistence of tissues from normal to noxious. They measure temperature from normal till abnormal (= noxious). Some of those fibres are nocisensors but not all of them. Example: the sensibility of the knee consists of 80% normal sensibility sensors and 20% nocisensors. 11 1.1.3.5.3. Difference between nocisensor- stimulation and pain A nocisensor measures the damage of injured tissue. A nocisensor can but must not necessarily provoke pain. A part of the A-d and C-fibres are nocisensors. They measure the damage or the almost-damage (mechanic, temperature, chemical). Their noxious stimulation does not always lead to pain perception. Here fore the stimulus must attain the thalamus and cerebral cortex, otherwise there is no pain sensation. Not all nociceptory stimuli rise so high to the midbrain or cortex. A lot of stimuli extinguish in the spinal medulla, the ascending pathways or in the brainstem. The stimulus attains the pain centres when the intensity of one stimulus is sufficient or when summation occurs of several stimuli in parts of the dorsal horn. As well reflectory (unconscious) as cognitive (conscious) reactions occur and the nocisensors will provoke pain, in case of severe damage. Thus, not all nocisensors provoke pain but they can be considered as normal pain fibres. It is logic that if a nocisensor is s ufficiently stimulated it will provoke the sensation of pain. A-d en C fibres can give pain thats not only caused by the damage itself, but as a result of the damage as well. A pain feelin which is more intense than normally expected is termed hyperalgesia. For example, when ice is applied on the skin it hurts but ice applied on a burned skin does hurt even more. When punctuated stimuli are applied on the course of the sciatic nerve it normally hurts but in case of sciatica it hurts even more (= hyperalgesia). Hyperalgesia is hypersensitivity on a stimulus that normally hurts, due to over stimulation of the nocisensors. The A-a and A-b fibres normally do not give pain, because they are not nocisensors. They register only normal values. Under certain circumstances they provoke pain. This happens in case of injured tissues or nerves or when the nocisensors become active. When nocisensors already give pain as a result of a decreased threshold, then the A-a and A-b fibres become sensiti ve as well. A light pressure on the pain area will also be painful. A low pressure- or strain force on the skin, tendons or muscles normally provoke no pain, but in case of damage it will well provoke pain. This is termed allodynia. Allodynia is pain that is caused by a stimulus that normally doesnt hurt due to an increased sensitivity of the the A-a and A-b fibres. This phenomon gives an opportunity to test the pain perception of the nervous system by use of pricking or brushing tests on the painfull area. There is a difference between nocisensor stimulation and the pain interpretation. 11 Table 5: Difference between nocicensor stimulation and pain. By use of selective stimulation the A-a and A-b fibres can be stimulated without that the A-d and C-fibres become active. This is caused by the low threshold of the A-a and A-ÃÆ'Ã… ¸ fibres compared with the A-d and C-fibres. A-d en C-fibres cant be stimulated selectively by use of mechanical stimuli because at the moment those fibres are stimulated; already the A-a and A-ÃÆ'Ã… ¸ fibres are active. When those become active, all fibres were stimulated. Also in case of nociception all those fibres are active. Selective stimulation can be used during TENS application or during active en passive mobilisations applied under the pain threshold level. 11 1.1.4. Hierarchy of the Nervous System The information processing in the nervous system happens on 4 levels. As well as the peripheral nerve ends, the dorsal horn, the brainstem and sub cortical and cortical levels are involvend. 1,7,11 1.1.4.1. The peripheral nerve ends The peripheral nerve ends are responsible for the uptake of information. The receptors are modulated by the state of surrounding tissue and the condition of the peripheral nerve. 1.1.4.2. The dorsal horn of the spinal medulla The dorsal horn modulates the incoming signals and is influenced by the state of the dorsal horn and the quantity and kind of gathered stimuli. 1.1.4.3. The brainstem The brainstem provides the primary responses with autonomic and hormonal modulations as a response to stimulation. 1.1.4.4. Sub cortical and cortical levels The sub cortical and cortical area provides the conscious cognitive and psycho-emotional modulation. The processing of the information and response on stimulation depends on the hierarchic manner, but always occurs with a total integration of the whole nerve system. 1.1.4.5. The Archi-, Paleo- and Neo level of the nervous system The nervous system can be ordered depending on a hierarchic manner in an archi, paleo and a neo level. 7 1.1.4.5.1. The Archi level The archi level consists of the gray matter (dorsal horn) of the spinal medulla, the ascending multisynaptic pathways in and around the gray matter, the medial pathways of the anterolateral quadrant, the mid part of the cerebellum and the brainstem (reticular formation). It is responsible for the most automatic movements after Hughlings Jackson. 7 1.1.4.5.2. The Paleo level The paleo level consists of the ascending pathways of the anterolateral quadrant, the descending pathways in the ventro-lateral quadrant, the hormonal and vestibular nuclei in the brainstem, the hypothalamus, certain parts of the cerebellum and the limbic system. Humoral influences from the liquor can influence (endofins) the sensibility of the pain system. 7 1.1.4.5.3. The Neo level The neo level consists of the dorsal ascending pathways, the dorso-lateral and ventral descending pathways, the cerebellar cortex, the lateral thamalus nuclei and the cerebral cortex. It is responsible for the cognitive mental processes, accurate skills and least automatic functions. 7 1.1.4.6. Phylogenetic development of the nervous system The phylogenetic development of the nervous system differs in time for the different levels. The archi-system is the oldest and is identical to that of the lower vertebrates. It is completely developed when born. The paleo-system is younger than the archi-system. It is identical of that of the lower vertebrates but only half developed when born. The neo-system is het youngest system in the phylogenetic evolution. It is much more developed than that of the lower vertebrates and not developed when born. 7 1.1.4.7. Functional properties of the different hierarchic systems of the nervous system Specific properties can be indicated to the different hierarchic levels of the nervous system. 1.1.4.7.1. Functional properties of the Archi level The archi level consists of C and A-d fibres. It is a relatively slow and tonic (continuous) working system that stands for the basic needs of life e.g.: basic survival or most automatic movements and autonomic functions such as basic tonus regulation in the brainstem and medial cerebellum. It is responsible for primary pain modulation e.g.: redraw reflex and increased tonus. 1.1.4.7.2. Functional properties of the Paleo level The paleo level consists especially of A-d, A-b, and C-fibres as well. It is a relative quicker system but also has tonic activity properties. The paleo level supports the archi-level by use of hormonal adaptation and psycho-emotional adaptation. It takes part of the autonomic function (hormonal function), fight/flight reactions in case of stress and pain and posture regulation (static posture balance). 1.1.4.7.3. Functional properties of the Neo level The neo level consists especially of A-a and A-b fibres and is very quick with phasic responses on stimulation. It analyses the information of the archi- and paleosystem and is guided by use of cognitive responses. The least automatic movements are guided and conscious movements. It regulates the dynamic posture balance and automatisation of movements. It is responsible for the organ sense perception and dissociated movement. 1.1.4.7.4. Interaction and control of the different hierarchic systems in the nervous system General principles of interaction among the different hierarchic systems in the nervous system can be summarized as follows. The paleo-system controls the archi-system and guides it. The neo-level controls the archi- and paleo system and guides both. The neo-level surrounds literally the archi and paleo level. The grey matter is situated medially in the nervous system medial in spinal medulla, the white matter laterally. The neo-system keeps the paleo-level and archi-level in harness. The hierarchic construction of the nervous system can be seen as a gate control system that exists on all levels. 7 1.1.4.7.5. Gate-control in the peripheral nerve fibres Axo-axonal connections between lower and higher fibres exist. The A-a and A-b fibres give off collaterals in the dorsal horn. The A-a and A-b attain the spinal medulla faster and prepare it for the arrival of A-d and C-stimuli. Selective stimulation of higher fibres (A-a and A-b fibres) inhibits the working of the fibres of lower order (A-d and C-fibres). 1.1.4.7.6. Gate control in the dorsal horn At the level of the dorsal horn interaction and control mechanisms exist and this phenomen known as Gate-control in the dorsal horn is also known as the gate theory of Melzack en Wall. The outlets of the A-a en A-b neurons shunt on the outlets of the A-d and C-neurons and their neurotransmitters close the ion-channels of these. The descending pathways of the paleo- and neosystem do the same and work on the interneurons and inhibit the A-d and C-neurons. 11 1.1.4.7.7. Gate-control in the brain The cortical pathways control the sub cortical pathways. They inhibit the brainstem reflexes. Conscious movements and intentions inhibit unconscious tonic reflexes (Example: relaxation). The cortical and sub cortical pathways regulate a directed and conscious life. The brainstem provides the autonomic support. This is all controlled by neurotransmitters. The perception of nociceptive pain not only involves the sensation transmitted and regulated by peripheral and central neurons, but is also affected by higher brain functions. 11 1.1.4.7.8. The uptake of nociception information A-d and C-fibres are the only fibres that can registrate nociception. The A-d fibres are quicker and give epicritic pain when the stimulus is attaining the pain centres. Epicritic pain means precise localisation with immediate redraw reflexes. The kind of pain is described as stabbing, boring, tearing or pulling. The impulses of the C-fibres attain the pain centres much later. They give protopathic pain, which is a continuous pain. That pain is not precisely located. Protopathic pain is burning, booring of a kind and continues much longer. It goes together with autonomic reactions, for expample: oedema. 11 1.1.5. The dorsal horn of the spinal medulla 1.1.5.1. General survey of the classification of the grey matter of the spinal medulla The grey matter is divided in the 10 layers of Rexed. This system is named by Rexed who discovered that the neurons in the dorsal horn where organised in layers depending on their function. Every layer is present in different segments and forms rostro-caudal nuclear columns. The counting happens from the dorsal horn to the anterior horn. Every layer is in contact with another by interneurons and dendrites. Layer I and II: nocisensory outlets of both: musculo-skeletal and visceral structures Layer III: intersegmental ascending pathways (dorsal proprium tract) and outlets to the spinothalamic tract (anterolateral quadrant) Layer IV: exclusive nocisensors from the musculoskeletal system Layer V-VI: fibres arriving from the nocisensors of the skin and viscera Layer VII: lateral horn: interneurons and sympathetic neurons Layer VIII en IX: motoneurons for musculoskeletal system Layer X: hormonal neurons In all levels descending pathways arrive from diverse levels of the brain. 1.1.5.2. Somatotopic ordering of nocisensors in the dorsal horn In layer I-II the nocisensors of viscera and musculo-skeletal structures are laying next to each other. They are ordered in a sagittal way from medial to lateral. The medial structures project medial and lateral structures project laterally. In layer V the nocisensors of certain skin areas are lying next to the nocisensors of viscera. Those are ordered in horizontal layers. For example: the organ-nocisensors under the level of the diafragm are lying next to the skin sensors from Th7-Th10. 1.1.5.3. Segmental interactions in the dorsal horn Normal reactions in musculo-skeletal influence the nocisensoric function. Outlets of nocisensors stimulate interneurons. There exists interaction with the spinothalamic tract and interaction with motoric anterior horn cells (somato-somatic relation). Normal reactions in musculo-skeletal nocisensoric function and influence the outlets of nocisensors stimulate the interneurons causing interaction with spinothalamic tract and with the sympathetic lateral horn cells (viscero-visceral relation). 11 Abnormal reactions can occur when the outlets of nocisensors infect the other nocisensors. Those react in turn causing interaction between motoric and visceral responses. This results in a somato-visceral relation, a somato-sympathetic relation and a viscero-somatic relation. 1.1.5.4. The Importance of Wide Dynamic Range Neurons In layer III, wide dynamic range neurons (WDR-neurons) exist. 21 Those WDR-neurons are interneurons that connect all the A-d en C-fibres from the dorsal horn. They project on the spinothalamic tract (antero-lateral quadrant). The ventral pathways go to the reticular formation, medial thalamus and the medial limbic system. The lateral pathways go to the lateral thalamus and cortex. They connect all visceral and motoric stimuli (= summation) with as consequences that motoric and visceral stimuli are sent together to the brain. The brain receives segmental information and no individual information. The brain can project pain to segmental connected structures. This is termed referred pain. Examples are: the stomach ulcer can provoke inter scapular pain or cardiac complaints and can give ulnaris nerve pain. Pain does not always indicate the exact location and origine. Anamnesis, assessment and clinical reasoning are very important. 1.1.5.5. Inhibition and excitation of the dorsal horn Inhibition and excitation of impulses in the dorsal horn can be caused by outlets of peripheral nerves. For example the A-a and A-b can inhibit the A-d and C fibres (pre-synaptic inhibiton). The outlets of the descending pathways can influence the the nerve ends and the interneurons (postsynaptic inhibition/excitation). The interneurons themselves can cause pre- or postsynaptic inhibition/excitation. Summation of stimuli defines the state of the dorsal horn. If a segment is excited or inhibited depends on the som of stimuli. Nocisensory impulses of the peripheral nerves always excite the dorsal horn. Summation of exciting nocisensoric impulses is defined by spatial and temporal facilitation. Temporal facilitation means the timing; spatial facilitation, the diverse structures that are involved. Impulses of A-a and A-b neurons act generally inhibiting. The impulses from the descending pathways can act in both ways. They are also regulated by temporal and spatial factors. The sum of sti mulating and inhibiting stimuli defines the state of the dorsal horn. An excitated dorsal horn provokes a lot of irradiating pain. 1.2. Assessment of Primary and Secondary Hyperalgesia 1.2.1. Definition of primary hyperalgesia Changes in the local sensibility of the afferent neurons as a result of a lesion in the peripheral tissues are termed hyperalgesia. In case of an increased sensibility of the A-a and A-b fibres the primary hyperalgesia is termed allodynia. In case of an increased sensibility of the A-d and C fibres the primary hyperalgesia is termed hyperalgesia. The lesion in the peripheral tissue can be of inflammation or neurogenic origin. 22 1.2.1.1. Pathophysiology of primary hyperalgesia In case of tissue injury bradykinin and ATP is produced at the site of lesion. Those mediators stimulate the blood- and lymphatic vessels, the mast cells and nociceptors. In the circulation inflammatory mediators are released aswell as histamine, serotonin, NGF, leucocytes, trombocytes and others. C-fibres released neuropeptides such as SP and CGRP. Those modulate and stimulate the release of other inflammatory mediators aswell. All those mediators are termed the inflammatory soup. Those mediators also stimulate the C-fibres which causes a vicious circle. The sympathetic nerve terminals are stimulated by inflammation and release noradrenalin which also stimulates the C-fibres. The sympathetic coupling between C-fibres and sympathetic end neurons occurs. The presence of inflammatory mediators decreases the threshold of all types of endneurons with as a result local allodynia and hyperalgesia. The allodynia and hyperalgesia can spread in the surrounding tissue, by stimulating the surro unding neurons. This is termed the flair zone. 22,23 Figure 16: Consequences of tissue injury: the inflammatory soup. 14 1.2.1.2. Primary hyperalgesia and the dorsal horn The A-d mechanoreceptors and nociceptors, and C-nocisensors stimulate the dorsal horn of somatic connected segments. As a consequence a temporary wind-up can occur. A wind-up is an over stimulation that can hold on for 72 hours. A refectory muscular reaction occurs around the lesion aswell. As a result the stimulation via the ascending pathways (antero-lateral quadrant) to the brain increases. Protopatic pain (quick, stabbing pain) followed by epicritical pain (boring, continuous pain) occurs. The brainstem regulates the autonomic reactions further such as sympathetic, hormonal, and emotional. The C-nocisensors give stimuli to the sympathetic connected segments. As a result the sympathetic system stimulates the C-endneurons (= sympathetic coupling) and vasoconstriction on the arterioles and lymphatic vessels. 20,24 1.2.1.3. Primary hyperalgesia and nerve injury When compressed inflammation occurs as prescribed above. In case of long standing injury, an ectopic injury occurs. This can be located on different locations on the peripheral nerve with the result that hyperalgesia and allodynia occurs on the course of the nerve, the connected dermatomes and this from the nerve root! In the spinal ganglion of the nerve, the sympathetic endneurons grow round the nerve cells with the occurrence of basket formations as a result. Consequently sympathetic maintained pain (SMP) occurs, also termed causalgia. This phenomon can continue for 7 to 10 weeks after the lesion but can also continue afterwards. 10 25 To summarize we can state that inflammation provokes a local hyperalgesia and allodynia, which spreads over the flair zone. Locally a vicious circle between the inflammatory soup and C-fibres takes place and sympathetic coupling between sympathetic end-neurons and C-fibres occurs. This continues until the tissue heals. Normally the medulla reacts with a temporary wind-up and a normal stimulus-response reaction. In case of neurogenic injury, causalgia may occur and sensitisation of the dorsal horn is possible. 22 1.2.1.4. Clinical pain assessment in case of primary hyperalgesia During the pain assessment, in case of primary hyperalgesia, when brushing or by use of punctuate stimuli the following properties are local allodynia and hyperalgesia restricted to the flair zone. In case of a nerve injury the flair zone is restricted to the course of the nerve root. Local sympathetic reactions occur when inflamed but are restricted in time. In case of allodynia and hyperalgesia when brushing and applying punctuated stimuli on the course of the nerve or a part of it, sympathetic reactions in the dermatome of the nerve can occure aswell. 22 1.2.2. Definition of Secondary Hyperalgesia An increased sensibility of all types of nerve fibres that continues outside the flair zone of the original lesion, linked to the course of the hyperalgesia and allodynia around the tissue, is termed secondary hyperalgesia. 22 1.2.2.1. Pathophysiology of secondary hyperalgesia When tissue is injured, nociceptors stimulate the interneurons by use of neurotransmitters such as SP, CGRP, NO, Ca, etc. The A-a and A-b neurons provide inhibiting neurotransmitters and the descending pathways give exciting or inhibiting mediators. The WDR-neurons receive al those impulses and send them to the spino-thalamic tract. WDR-neuron receptors differ. Some open ion-channels using inhibiting neurotransmitters, others open ion-channels using exciting neurotransmitters depending on the kind of receptor. If the stimulus acts inhibiting or exciting depends on the quantity of the opened inhibiting- or exciting ion-channels. In case of secondary hyperalgesia, more excitatory stimuli exist and insufficient inhibiting ways are activated. The WDR-neurons will work exiciting as well because of the fact they do not only activate the spino-thalamic pathways but also on the incoming stimulating neurons. As a result a vicious circle occurs in the dorsal horn. This provokes a decreased thr eshold of the present neurons. The sensors are also stimulated by the dorsal horn and not only by the local lesion. They become sensitized over their whole course with the consequence that the central hyperalgesia is linked to the lesion. When the local lesion is healing, the central allodynia will also disappear. Hyperalgesia is not as much linked to the course of the lesion but can last longer. Its origin is mostly caused by temporal and spatial summation of exciting stimuli. 22 1.2.2.2. Clinical pain assessment in case of secondary hyperalgesia During the pain assessment, when touching (brushing) and applying punctuate stimuli local hyperalgesia en allodynia and extending hyperalgesia and allodynia can be observed. When the pain occurs outsite the spinal column area the touching (brushing) and applied punctuate stimuli starting from the lesion and over the dermatome near by. The application must be enlarged to the neighbouring dermatomes and also to the corresponding segments of the spine. Always compare with the opposite side. Differentiate allodynia and hyperalgesia. 22 In case of primary hyperalgia the allodynia and/or hyperalgesia is restricted to the lesion area and flair zone. The allodynia disappears before the hyperalges