Perception of pain

Examples of Persistent neuropathic pain

-causalgia (peripheral nerve trauma) -phantom limb pain -entrapment neuropathy (carpel tunnel syndrome) -peripheral neuropathy (widespread nerve damage) -nociceptive pathway damage

Pain modulation methods

1. Gate theory 2. Sensitisation (wind up) 3. Descending analgesia and endogenous opioids

Process of wind up

1. Incoming pain signal 2. Release of Mg block causes NMDA receptor activation 3. Increased intracellular Ca causes a change in cation channel kinetics, the insertion of more Na channels and the blockade of K channels Get increased sensitivity to pain

Chronic pain

1. Nociceptive pain (problem with receptors) 2. Neuropathic pain 3. Central maladaption

Principles of peripheral sensitization

1. Tissue injury causes the release of bradykinin, 5HT, prostaglandins and K+ which stimulate C fibres 2. Active C fibres release CGRP and substance P, which stimulate mast cells, which release histamine 3. CGRP and substance P released by C fibres cause dilation of blood vessels

Hyperalgesia

A decrease in the pain threshold in an area of inflammation such that even trivial stimuli cause pain Increased sensitivity to pain

Dorsal horn sensitisation or 'wind up' summary

A system by which the intensity of signal from C fibres is translated through the WDR neurons into variation in sensitivity The stronger the C fibre (pain) signal the more the dorsal horn post synaptic fibres become sensitive to input The mechanism is quite complex and is based on the special characteristics of the NMDA receptor and Ca ion flow. And induces changes in nuclear expression and membrane channel activity/expression

Activation threshold

All of these processes lower the activation threshold of nociceptors such that they will then be activated by stimuli that would normally not be perceived as painful. Anyone who has had sunburn can relate to the sensitivity of that area of skin. Light touch is perceived as very painful and a warm shower is perceived as painfully hot. This increased sensitivity is due to the heightened activity of the skin nociceptors and a loss of the specificity of the stimulus in that sunburned area of skin. When the response to a normally painful stimulus is heightened (more pain felt than usual), it is referred to as hyperalgesia. When a normally nonpainful stimulus is perceived as painful (light touch on sunburn), it is referred to as allodynia.

Sensitisation of receptors

All these processes increase the sensitivity to pain and non pain stimuli Calcitonin gene related peptide (CGRP) and SP both recruit silent receptors which increase summation in the dorsal horn Histamine causes hyperalgesia through its effects on blood vessels Bradykinin activates pain fibres directly and causes increase in prostaglandins Tissue damage produces H ions which give muscle ache (eg weight lifting) Prostaglandin E2 is made by cyclooxygenase. Aspirin and other NSAIDs act to inhibit this enzyme

Pain matrix overview

Components: -cortex -limbic system - amygdala -hypothalamus -brainstem structures -opioid PAG system -Dorsal horn Brainstem structures can go up or down modulate nociception to provide a saliency (gate system) Electrical stimulation of the PAG induces strong analgesia (blocked by nalaxone) Placebo effect of parental kiss

Pain modulation

Equally important is the ability to modulate pain so that we can react to a potentially hazardous situation and continue to function appropriately. The control of pain is not primarily through a pain suppression system but is part of a broader CNS function in which competing stimuli and needs are prioritized. These descending influences on posterior horn neurons can be both inhibitory and facilitatory. The balance between inhibition and facilitation can be altered to meet different behavioral, emotional, and pathophysiological needs.

Pain transmission and nociceptive fibres

First scratch/pricking pain is from A delta fibres and then have second more prolonged burning or aching pain from C fibres as injury starts to settle down

Cortical pain matrix

Given the multitude of nociceptive pathways and their various targets in the cortex, it is apparent that there is no single "pain center" in the brain. Pain is a multifactorial, multipathway system that projects to many areas of the cortex that are involved in the perception of pain. These cortical areas are collectively referred to as the cortical pain matrix. 1. Somatosensory topographic discrimination 2. Limbic system including the cingulate gyrus (activated when we see others in pain as well as ourselves) and insula -emotional, motivational, modulatory 3. Saliency - the relative potentiation of a specific nociceptive input Damage to one or more of these centres can give a different effect on the detection and perception of pain as well as its modulation

Transient Receptor Potential

Group of ion channels located mostly on the plasma membrane. TRPMs function as intracellular calcium release channels and thus serve an important role in organelle regulation. Generalised, not specific modality Importantly, many of these channels mediate a variety of sensations like the sensations of pain, hotness, warmth or coldness, different kinds of tastes, pressure, and vision. 6 unit protein, with channels going from inside to outside of cell Can change conformation on receipt of pain stimulus Sensitivity can be regulated by regulatory basket on inside of pore When open allows ions like Ca into cell which causes depolarisation

Plasma extravasation

In inflammation, it refers to the movement of white blood cells from the capillaries to the tissues surrounding them

Descending analgesia system

In the spinal cord, showing: 1. Inhibition of incoming pain signals at the cord level 2. Presence of encephalin-secreting neurons that suppress pain signals in the cord -pre and post synaptic Note that this system is exploited by a number of CNS centres to increase salience of selected signals as well as decrease certain prolonged unimportant signals. Can turn down unwanted signals and raise salience of something else.

Hyperaemia

Incresed blood flow to tissue

Function

Is to protect the body Sense of pain only occurs in the brain, prior to that it is just a code. Therefore it is highly subjective and contextual

Ad fibres

Myelinated Sharp 1st pain Mechanical pinching Extreme hot or cold, one temp stimuli

Nociceptive receptors

No receptors for pain the way they exist for other modalities - arent specific, no receptors for burning pain compared to severe cold pain Nociceptive nerves have free unspecialised nerve endings with 'pain' channels inserted in the membrane The most common is the Transient Receptor Potential family of channels (TRP) Sensitive to 02, pH osmolarity and vallinoids (capsicum) and heat Can be sensitised by substance P, bradykinin, serotonin, pH, ATP, NO etc Composed of 6 unit trans-membrane portion and a 'basket' of regulatory complex in the cytoplasm Allows Ca into cell

Gate theory process

Nociceptive fibers have excitatory synapses with the posterior horn neurons, as do mechanosensitive Aβ fibers. The gate control theory involves local circuit neurons, which are inhibitory interneurons that synapse with the posterior horn WDR neurons. These interneurons are inhibited by nociceptive input. This inhibition of the inhibition results in more signaling of the posterior horn neurons. The interneurons also receive excitatory input from the Aβ fibers. In this case, excitation of the inhibition results in more inhibition of the posterior horn neurons and less signaling. Hence, there is a balance: when the Aβ fiber predominates, there is less signaling, and when the nociceptive fiber predominates, there is more signalling. Balance between these 2 systems which determines the pain that gets through to the brain. Rubbing the area around the source of pain activates inhibitory input to the anterolateral system Similar theory behind transcutaneous nerve stimulation TENS and capsaicin treatment

Synaptic targets

Nociceptive fibres synapse in the dorsal horn (quick to cross) with 2 types of ascending axons: 1. Nociceptive specific - C and Ad specific 2. Wide dynamic range neurons (WDR) - any sensory input including pain, can fire in a graded fashion based on C fibre frequency of input (higher the pain higher the input). Monitors all ascending info. Tells brain a lot of activity occuring Whereas NS neurons will encode only for painful stimuli and project to higher centers, the WDR cells can encode for a range of stimuli, both painful and nonpainful. NS and WDR neurons are points of descending pain modulation from PAG in the brainstem Activation of these receptors leads to Na influx, depolarisation of the cells and the generation of APs

Peripheral aspects of pain

Nociceptors 1. Nociceptive receptors 2. Nociceptive activation 3. Sensitization of receptors 4. Nociceptive fibres

Nociceptive receptor activation

Nociceptors can be activated by extreme temperature, intense mechanical stimulation, or an array of chemicals through specific receptors. Activation of nociceptors results in the opening of cation channels (mainly Na+), which will result in membrane depolarization Temperature: -extreme heat and extreme cold open "transient receptor potential vanilloid" (VRPV) channels inserted in the membrane -allows Na and Ca entry and so depolarises the cell to give an action potential -Activation of these thermally sensitive receptors results in behaviors that will either cool the body (in response to heat stimulation) or warm the body (in response to cold stimulation). These behavioral responses are mediated through projections to the hypothalamus Mechanical: -actual mechanism still unknown -presumed to be a form of insensitive mechanoreceptor which allows Na entry when activated -Mechanically activated receptors can be found in both Aδ fibers and C fibers. -These receptors cannot be activated by light touch. They have a high threshold and are activated only when the stimulus is noxious and may result in tissue damage. Chemical: -apart from TPRV receptors (sensitive to O2), its largely unknown but chemical transmission can cause sensitisation of pain receptors -Free nerve endings of C fibers can be activated by a range of chemicals, which can be external irritants or substances released during tissue damage, either by the nociceptors, as discussed above, or through inflammation.

Perception of pain

Nociceptors detect noxious stimuli in the world around us (using free nerve endings) and relay these signals to the brain How we perceive these signals is highly modulated It depends on situation, emotion, genetic susceptibility, previous experience. Signal transmission from periphery which is converted to coded signal which is modulated (turned up or down) to effect perception of pain Manipulation in the vast majority is subconscious - depends on the situation at the time

Pain perception or cause

Not all pain is the same, either in perception nor in its cause Types of pain: -Chronic/Acute -Nociceptive/Neuropathic/Phantom limb -Maladaptive -Visceral (hollow structures) -Referred -Sharp/Ache -Headache -Complex regional pain syndrome

Gate control theory

One of the most basic modulatory systems involves influencing the balance between the nociceptive input (through Aδ and C fibers) and the input through Aβ fibers, which encode for touch. One of the things we do when we hurt ourselves is rub that area or touch it in order to alleviate the pain. The underlying mechanism is that the balance of inputs is shifted toward touch (through Aβ-fiber activation) and away from pain (through Aδ- and C-fiber activation).

Endogenous opioid system

Opioid receptors are activated by a group of neurotransmitters called: -endorphins -encephalins -dynorphins These opioid peptides act as neurotransmitters or neuromodulators and can produce potent analgesic effects. Sensitive to opiates and present at all levels of the pain pathways, therefore doses of opiates can act simultaneously at all levels of the pain pathway, hence their high efficacy

Descending analgesia

Other modulatory systems come from a number of areas in the brainstem, which receive input from the ascending nociceptive pathways. These structures include the PAG and the reticular formation, which includes the locus coeruleus and the raphe nuclei. From these structures, descending fibers project back down to the posterior horn, where they influence NS and WDR neurons through interneurons. These brainstem structures use a wide variety of neurotransmitters including glutamate, norepinephrine, and serotonin. Manipulating these neurotransmitter systems is the basis for some pharmacological approaches to the treatment of pain

Re-experience

Pain can never be re-experienced from memory, it is only intellectualisation of the experience But the fear of pain is very real and therefore important to your future pts

Headache

Pain is only rarely felt when the surface of the brain is cut or electrically stimulated Maj of headaches are due to irritation or destruction of the sensitive areas around the venous sinuses, the dura at the base of the skull or the meninges and the associated blood capillaries Meningitis causes inflammation of all these and results in the worst headaches Hangovers - caused by excessive drinking in extreme cases due to alcohol irritating the meninges, most cases due to dehydration. Low CSF causes the brain to settle onto the base of the skull causing deformation of the dura at the base of the skull and the meninges and so this causes headaches Migraine - nobody knows. Possibly due to vasoconstriction followed by massive vasodilation.

Persistent neuropathic pain

Pain persists beyond the healing process of damaged tissues and may include: 1. Hyperalgesia (strong reactions to low intensity noxious stimuli) 2. Allodynia (painful reaction to a non noxious stimuli like a light touch on sunburn) 3. Summation (repeated low innocuous stimuli causing increasing intensity of response 4. Paresthesias (tingling without stim) or Dysesthesias (burning or shooting pain without stim) which can sometimes be associated with a thalamic syndrome (thalamic infarct) Type of pain is very hard to treat and is causes by maladaptation of the dorsal horn wind up and sensitisation systems

Ascending pain system

Peripheral pain is transmitted to CNS Anterolateral system Signal processing begins in the dorsal horn

Signs of nociceptor activation (or pain)

Physiological signs of pain Substance P and CGRP release is responsible for 3 local physiological signs of pain 1. Calor (heat) 2. Rubor (redness) 3. Tumor (swelling) 1 and 2 caused by local hyperaemia and the third by plasma extravasation

Nociceptive pain

Results from conditions such as sprains, boen fractures, burns, bumps, bruises, inflammation (from infection or arthritic disorder) Normally pain stops when the problem is healed Normally responds well to painkillers such as opioids Normally responds well to painkillers such as opiods

Signal

Signal transmission --> coded signal --> modulated signal --> perception

Referred pain

Signals of noxious stimuli and normal cutaneous stimuli enter the spinal cord at the same point Cross talk in the dorsal horn between modalities is common Signals from viscera get picked up by ascending nerve fibres that are mapped cortically to dermis

NT of nociceptive fibres

The neurotransmitters used by nociceptive fibers are glutamate, substance P, and calcitonin gene-related peptide (CGRP). These neurotransmitters are produced in the cell body within the spinal ganglion. When the nociceptor is activated, these neurotransmitters are released centrally at the synapse with the second-order neuron in the spinal cord and, interestingly, peripherally at the site of injury. In the periphery, these neurotransmitters lead to redness, swelling, and tenderness, the classic indicators of pain (red flare and tenderness of pain). They also increase the activation of nociceptors and lower their threshold (sensitization). In addition, peripheral neurotransmitters activate so-called "silent" nociceptors, which expand the receptive field for the painful stimulus.

Nociceptors

The perception of pain, or nociception, depends on specialized receptors in the periphery that can respond to extreme temperatures (heat and cold), intense mechanical stimulation, and chemical stimuli. Nociceptors are free nerve endings, whose cell bodies are located in the spinal ganglia for the body and the trigeminal ganglia for the face. Nociceptors are only activated when the stimulus reaches a noxious threshold. They respond progressively, according to the intensity of the stimulus. Whereas other receptors show adaptation, nociceptors do not. Continued stimulation can decrease the threshold at which nociceptors respond. This phenomenon is called sensitization.

Silent nociceptors

The release of inflammatory molecules and neurotransmitters in the periphery also recruits the silent nociceptors. These receptors further amplify the signal to the posterior horn by increasing the temporal and spatial summation of the incoming signal. They only signal in response to the molecules secreted by other activated nociceptors and are not activated by any noxious stimulus per se. Receptors that are normally unresponsive to noxious mechanical stimulation, until activated during inflammation or after tissue damage ONLY activated in presence of inflammation

Substance P

The release of substance P by C fibers also appears to play an important role in the activity of WDR neurons through their NK1 receptors. Activation of the NK1 receptor causes long-lasting depolarization that contributes to the temporal summation of the nociceptive input from C fibers. CGRP contributes to sensitization through its downstream enhancement of NMDA receptor activity.

Posterior Horn synapse

The synapse in the posterior horn is excitatory. The neurotransmitters released by the afferent nociceptive fibers are glutamate, which acts mainly on AMPA and NMDA receptors; substance P, which acts on the NK1 receptor; and CGRP, which also has an excitatory effect via the CGRP receptor.

Central maladaption

The type of sensitisation can lead to long term changes in the structure of the synapses in the dorsal horn or the spinal cord Increases in ionotropic glutamate receptors (NMDA) cause a sensitivity in second order neurons which then more readily send pain signals to the thalamus. Becomes permanent, so pain modulatin is permanently unpregulated to get more ascending info A second component is where descending modulation of the inhibitory interneurons becomes maladapted This can lead to a reduction in the inhibition of WDR neurons and so a disinhibition of the second order neurons. Cant turn down ascending sensitised pain system. Maladapted and cant modulate.

Nociceptive fibres

There are two major classes of fibers associated with nociceptors: Aδ fibers and C fibers. The myelinated Aδ fibers are responsible for the localized, sharp "first" pain and respond to intense mechanical (pinching) and thermal (extreme hot or cold) stimuli. Unmyelinated C fibers, conversely, mediate the poorly localized, diffuse "second" pain. They are polymodal in that they respond to mechanical, thermal, and chemical stimuli.

Descending cortical input

These brainstem nuclei are tightly linked to the thalamus, limbic system, hypothalamus, and cortical areas that are part of the pain matrix. Thus, brainstem center activity depends not only on the ascending nociceptive input from the spinal cord but also on the descending cortical input. The various components of the pain matrix exert influence on the descending brainstem systems as well as on the thalamus, which gates the information to the cortex.

Nociceptive modulation

These descending influences should not be considered an analgesic system that indiscriminately blocks incoming nociceptive signals, but rather a modulator that can both inhibit and facilitate nociception. Together with the cortex, these structures and pathways act as a salience filter. If the signal is deemed important and behavioral responses need to be initiated, nociception is facilitated. If it is deemed as distracting from other more important behavioral needs, nociception is inhibited.

Sensitisation of peripheral receptors

Tissue damage and inflammation result in the release of inflammatory molecules, such as bradykinin and prostaglandins, which sensitize peripheral nociceptors. Bradykinin activates pain fibres directly and causes increase in prostaglandins. In addition, when a noxious stimulus is detected by a nociceptor, free nerve endings will release substance P and CGRP. These two neuropeptides contribute to the inflammatory response at the site of tissue injury by stimulating mast cell release of histamine and bradykinin (recruiting silent receptors). CGRP induces vasodilation, which results in further release of inflammatory molecules.

C fibres

Unmyelinated Secondary slow pain (diffuse) Mechanical pinching, thermal and chemical stimuli (polymodal)

Pain

Unpleasant sensory and emotional experience associated with either actual or potential tissue damage Subjective and not a substantive construct of the real world - perceptual in terms of subject Learning experience

WDR neurons

WDR cells can fire APs in a graded fashion, depending on the stimulus intensity. Stimulus intensity is encoded by the frequency of C-fiber signaling: the more painful the stimulus, the higher the frequency of C-fiber discharge and the greater the WDR neuron response. The WDR neuron can then amplify this signal through a mechanism called "wind-up."

Examples of pain modulation

When we rub a sore spot or when we try to get our mind off pain, we are, effectively, modulating the pain experience. These are examples of descending inhibition of the incoming signal. On the other hand, emotional states, inflammation, and chronic drug use can exacerbate the experience of pain. These are examples of descending facilitation of the incoming signal.

Central sensitisation

Wind up - long term sensitisation of post synaptic neurons in the dorsal horn In the spinal cord is mediated through neurotransmitter release at the postsynaptic neuron in the posterior horn. Wind-up is essentially an amplification system within the spinal cord to respond to the cumulative nociceptive input from C fibers. Wind-up results from the repetitive high frequency excitatory stimulation of the WDR neuron through glutamate acting mainly on AMPA receptors. This increased AP frequency and sustained membrane depolarization result in activation of NMDA receptors. The NMDA receptor is usually inactive due to blockade of channels by Mg2+ ions. Sustained depolarization releases this Mg2+ block, and the NMDA receptor can then be activated by glutamate. Significantly, because the NMDA receptor is Ca2+ permeable, Ca2+ influx into the cell changes the electrophysiological signaling properties of the WDR neuron Net result is a resting potential closer to threshold and a more sensitive cell. This effectively amplifies the pain signal like turning up the amp on a microphone.

Wind up conveys

Wind up can occur in seconds and last for hours (protein turnover is slow), this conveys 1. Priority Salience - in the cortex (you notice it more than normal) 2. Protection from further injury - Continued hyperalgesia of the affected area can protect the injured body part because the person typically shields the injured area from further trauma. 3. Memory - increased duration of stimulation increases the chance of consolidation On the other hand, sensitization can become maladaptive and persist long after an injury has healed.