Health & Management / Ruminants Pain Management / Techniques and protocols OVERVIEW:
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Introduction and General Information

A basic understanding of the neurophysiology of pain is important for pain management as it provides information about where and why different pain relieving drugs have their effects. 

  • Treatment of pain can be directed at various points: the site of injury (where pain originates), along the pathways in the spinal cord, or in the brain. (J288.59.w1)

Pain is a conceptual sense which is always subjective and always unpleasant. It is classified as an emotional experience. There is overwhelming scientific evidence that animals can experience or feel pain. (J4.221.w2) 

  • Pain responses may be initiated by insult to tissue, from any part of the body which contains the appropriate number and type of terminal nerve receptors, causing sufficient damage to stimulate the receptors. (J288.59.w1)
  • Pain is usually associated with actual or potential damage to tissue. However in some chronic pain states it is associated with an old insult, for example following nerve injury, as in phantom limb pain, or even with no recognised predisposing event. (B326.5.w5, B327.40.w40)

Pain and nociception

"Pain" and "nociception" are recognised to be distinct entities. The concept of "pain" requires perception by an organism, while the term "nociception" does not imply the requirement for such perception. A variety of definitions of pain have been proposed, both for pain in humans and for pain in animals, together with explanations differentiating nociception from pain. 

Definitions of Nociception :
  • "Nociception is the evoked response to a specific tissue stimulation from mechanical, thermal or chemical irritation applied to receptors on the nerve endings." (J288.59.w1)
  • "Nociception is the detection of a noxious stimulus and the transmission of that information to the brain." (J4.219.w4)
  • "The sensory processes which result, in man, in the perception of pain following a noxious, or damaging, stimulus." Electrical or chemical activity in sensory neurons and receptors, which can be measured. (B322.2.w2)

Defining pain is difficult and various definitions exist (J3.118.w4)

Definitions of pain:
  • The International Association for the Study of Pain has defined pain as: "an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage." (J297.6.w1) the Association has also noted that "pain is always subjective" and that "the inability to communicate in no way negates the possibility that an individual is experiencing pain and is in need of appropriate pain relieving treatment." (J4.219.w4, B323.3.w3)
  • Pain is the perception of the sensual experience induced by a noxious stimulus." (J4.219.w4)
  • "Pain is an aversive sensory experience caused by actual or potential injury which is accompanied by protective somatic and visceral reactions and induces changes in behaviour including social behaviour which can be specific for an individual animal." (B325.w2)
  • In humans pain has been defined as: "a subjective interpretation of nerve impulses that are induced peripherally by a stimulus that is actually or potentially noxious to tissue." (J4.191.w3)

Definitions of pain in animals:

  • "Pain in animals is an aversive sensory and emotional experience (a perception), which elicits protective motor actions, results in learned avoidance, and may modify species-specific traits of behaviour, including social behaviour. Pain depends on the activation of a discrete set of receptors and neural pathways and is usually elicited by stimuli that are actually or potentially noxious, eg, damaging to tissue." (J4.191.w3)
  • "Animal pain is an aversive sensory and emotional experience representing an awareness by the animal of damage or threat to the integrity of its tissues; it changes the animal's physiology and behaviour to reduce or avoid damage, to reduce the likelihood of recurrence and to promote recovery; unnecessary pain occurs when the intensity or duration of the experience is inappropriate for the damage sustained or when the physiological and behavioural responses to it are unsuccessful at alleviating it." (J284.75.w1)
  • Pain in animals is an aversive sensory experience caused by actual or potential injury that elicit protective motor and vegetative actions, results in learned avoidance behaviour, and may modify species specific behaviour, including social behaviour. (P49.1.w2)

Classification of Pain:

It has been recognised that while some pain is appropriate, eliciting responses which protect the organism, other pain is inappropriate.

  • Physiological pain is a means of detecting a noxious input where the perception of pain is proportional to the intensity of the stimulus. (B322.2.w2)
    • Physiological pain "occurs when a stimulus that induces minimal or no tissue damage activates high-threshold sensory nerve fibers, warning the organism of potentially tissue damaging events. Physiological pain is well localized, transient, and plays a vital role in the body's normal defense mechanisms by initiating protective reflex." (J4.219.w4)
  • Pathological pain or clinical pain occurs when tissue damage occurs (J4.221.w2) and is a perception of pain that is greater than the apparent noxious stimulus. (B322.2.w2)
    • Clinical pain is a type of pain which occurs when stimuli which are excessively intense or prolonged induce tissue damage that results in extended discomfort and abnormal sensitivity. This may arise spontaneously and is characterised by "a low threshold to noxious stimuli, an exaggerated response to noxious stimuli (hyperalgesia), and pain both at the site of injury (primary hyperalgesia) and beyond the area of primary tissue or nerve injury into surrounding uninjured tissue (secondary hyperalgesia and extraterritorial pain). It is caused by tissue damage-associated inflammation (inflammatory pain), or by central or peripheral nerve injury (neuropathic pain) and it may be induced by normally innocuous stimuli (allodynia)." (J4.219.w4)

Pain originating within the peripheral or central nervous system appears to be produced by damage to mechanisms underlying the process of pain and its control. (J284.75.w1)

Other classifications of pain include somatic, visceral, "fast" and "slow" pain, "mild" "moderate" or "severe" and "acute" or "chronic":

  • Somatic pain is pain originating from the periphery, such as skin and muscle. (J4.221.w2)
    • Somatic pain includes superficial pain (from the skin or subcutaneous tissue) and deep pain (from deeper structures of the body wall) . (J4.191.w3)
    • Somatic pain is usually well localised. (J284.75.w1)
  • Visceral pain is pain originating from the abdominal and thoracic cavities. (J4.221.w2) (pain arising from the viscera (J4.191.w3)) 
    • Visceral pain is generally poorly localised, deep and dull and may result from excessive distention. (J9.413.w1)
    • Visceral pain is poorly localised and it may be referred to parts of the body distant from the source of pain. (J284.75.w1)
    • In general, a stimulus which causes diffuse stimulation of large numbers of pain endings throughout a large area of a visceral organ is likely to cause severe pain, while very localised damage, stimulating few pain endings, is unlikely to cause pain. (B332.48.w48)
  • Neurogenic  or neuropathic pain is pain originating from within the nervous system due to disorder in nociceptive processing or generation of abnormal activity in nociceptive pathways. (B325.w3)
  • Fast pain is transmitted at greater than 1 m/s along alpha-delta fast (Aδ) pain fibres (small myelinated fibres). (J3.118.w4, J288.59.w1)
  • Slow pain is transmitted at less than 1 m/s along C- fibres (unmyelinated fibres). (J3.118.w4, J288.59.w1)
  • Pain may be mild, moderate or severe (variation in intensity). (J3.116.w3, J3.118.w4)
  • Pain may be acute or chronic (variation in duration). (J3.116.w3)
    • Acute pain does not outlast the healing process; chronic pain persists beyond the expected healing time for an injury. (J284.75.w1) Acute recurrent pain is defined as prolonged pain (e.g. cancer pain) with a definable cause; this consists of repeated attacks of acute pain. (B325.w3)

Other definitions important in the discussion of pain include:

  • Nociceptor: specific receptors for response to noxious stimuli (J4.191.w3)
  • Hyperalgesia / hyperalgesic state: heightened perception of pain. (B322.2.w2) Increased amount of pain associated with a mild noxious stimulus. (B327.40.w40) Increased perception of pain from a stimulus which would normally be painful. (P61.62.w3)
  • Allodynia: perception as noxious of a stimulus, such as gentle pressure on the skin, normally considered innocuous. (B322.2.w2, P61.62.w3) Pain evoked by a non-noxious stimulus. (B327.40.w40)
  • Pain threshold / pain detection threshold: the point at which stimulation of nociceptors is of sufficient magnitude to be perceived as pain. This is approximately the same in humans and animals (J4.191.w3, B326.14.w14)
  • Pain tolerance level/ pain tolerance threshold: the maximum intensity of experimental pain that an individual human or animal will tolerate. This varies between species and between individuals. It is greatly affected by motivation, stress, previous experience, cultural background and analgesics and is altered by the descending pain-modulation system. (J4.191.w3, B326.14.w14)
  • Pain-sensitivity range: the difference between the pain-detection threshold and the pain-tolerance threshold. (J4.191.w3)
  • Spontaneous pain: pain without any precipitating stimulus. (B327.40.w40)
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Receptors

Nociceptors and their Responses

"Physiological pain is initiated by specialized sensory nociceptor fibres innervating peripheral tissues and activated only by noxious stimuli." (J22.288.w1)
  • There are several types of nociceptor. These are all free nerve endings of two types of small nerve fibres: thinly myelinated Aδ fibres and unmyelinated C fibres. Not all Aδ and C fibres are nociceptive fibres; others are receptors for warm, cold or non-noxious mechanical stimuli. (B322.2.w2, J9.413.w1)
  • Aδ fibres, which transmit at 6-30 m/s, are responsible for the first/fast/initial pain, which is described by humans as well-localised sharp or pricking pain, while C fibres, which transmit more slowly at 0.5-2 m/s, are responsible for what humans report as dull, burning and diffusely located pain. The sharp pain is important in giving the organism rapid information about a damaging or potentially damaging influence and making the organism react to remove itself from that influence. The slow pain tends to increase over time, encouraging the organism to continue trying to relieve the cause of the pain. (J4.191.w3, J4.219.w4, B332.48.w48)
  • There are large numbers of nociceptors in the skin and in some other tissues such as bone periosteum and joint surfaces, but in many deep tissues they are quite sparse. (B332.48.w48, J4.191.w3)
  • Different types of nociceptors respond to different noxious stimuli including mechanical (e.g. crushing or cutting) stimuli (for viscera, e.g. distention), thermal stimuli (cold below 4C or below 0C, or heat above 43C or above 53C, depending on the receptor), chemical stimuli and electrical stimuli. (B332.48.w48, J4.191.w3, J9.413.w1, J288.59.w1)
    • Many nociceptors are described as polymodal and respond to all of these types of stimuli. others are more specialised, for example responding to heat but not to mechanical stimuli, or with high thresholds to mechanical stimuli. (B326.1.w1, J4.191.w3, J9.413.w1)
  • A wide variety of chemicals are able to stimulate nociceptors, including bradykinin, serotonin, histamine, potassium ions, acids, acetylcholine and proteolytic enzymes. Bradykinin appears to be particularly important. (B332.48.w48)
  • Ischaemia is known to cause pain; this is probably related to chemicals such as bradykinin and proteolytic enzymes formed due to cell damage. (B332.48.w48)
  • "Silent" or "sleeping" nociceptors become active only after sensitization by tissue injury. (J9.413.w1) SEE BELOW: Peripheral Sensitization
  • Activation of a nociceptor by a stimulus results in transmission of action potentials to the spinal cord. (B322.2.w2, J4.219.w4) SEE BELOW: Peripheral and Spinal Cord Pathways

Analgesic drug action:

  • Pain may be controlled or reduced at the site of injury or inflammation by use of NSAIDs or steroids to reduce inflammation and swelling. (J288.59.w1, J298.75.w1)
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Peripheral and Spinal Cord Pathways 

  • Nociceptive afferent nerve fibres enter the spinal cord via the dorsal roots, with their cell bodies in the dorsal root ganglia. There are several layers or laminae in the dorsal horn, numbered I to V. Aδ fibres terminate mainly in lamina I, some in lamina V, while C fibres terminate mainly in lamina II. From lamina II, short neurons project to laminae I and V. (B322.2.w2, B327.40.w40, J4.219.w4, J9.413.w1)
  • Nociceptive (and other sensory) nerves from the head have their cell bodies in the trigeminal ganglia. (J4.219.w4, J9.413.w1)

Synapses and neurotransmitters

  • The first synapse in the nociceptive pathway occurs in the superficial layers of the grey matter of the dorsal horn of the spinal cord.  (B322.2.w2)
  • All nociceptors use glutamate as their main excitatory neurotransmitter. (J9.413.w1)
    • The transmitter for Aδ fibres synapsing in the spinal cord is believed to be glutamate, which usually has a period of action of only a few milliseconds. (B332.48.w48)
    • C-fibres appear to secrete both glutamate and substance P as transmitters when they synapse in the spinal cord. While the action of glutamate lasts for only a few milliseconds, substance P is released more slowly and builds up over a period of seconds to minutes. (B332.48.w48)
  • NOTE: This is the first major site in the nociceptive/pain pathway involving chemical neurotransmitter agents and therefore is important as a site of drug action. (B322.2.w2)

Interaction with other sensory neurons:

  • Stimulation of large Aβ sensory fibres (from peripheral tactile receptors) can depress pain signal transmission, presumably due to local lateral inhibition in the spinal cord. This may explain pain relief due to rubbing the skin near a painful area. (B332.48.w48)
  • Acupuncture may act by local lateral inhibition (B332.48.w48), i.e. by A fibre input stimulating inhibitory interneurons which then reduce nociceptive signals in the transmission neurons. (B322.2.w2); excitation of the central inhibitory system may also be involved (SEE BELOW: Central control. (B332.48.w48)

Afferent pathways

  • There are one or more short neurons in the dorsal horn with the last of these having a long axon which passes up the spinal cord. (B332.48.w48)
  • The main projections from the dorsal horn arise from laminae I and V. (B327.40.w40)
  • Two main types of spinal dorsal horn neurons transmit nociceptive signals. One type is nociceptor-specific, that is, receives afferent inputs only from nociceptors; the other type of neurons are known as multireceptive or wide dynamic range neurons and these have inputs not only from nociceptors but also from mechanoreceptors. (J4.191.w5)
  • The nerve fibres generally cross to the contralateral side of the spinal cord and up to the brain stem. (B327.40.w40, B332.48.w48, J4.191.w4)
    • There are species differences in pathways: in cats bilateral ascending pathways are involved in response to a stimulus. (J4.191.w4)
  • Pathways in which nociceptive information is transmitted include the spinothalamic tract, the spinoreticular tract and the spinomesencephalic tract. (B322.2.w2, B327.40.w40, B332.48.w48)
    • Which spinal white matter tract or tracts is/are most important in transmitting nociceptive information to the brain varies between species. (B325.w3, J4.191.w4, J4.219.w4)
    • Localisation of pain transmitted in the paleospinothalamic tract (mainly C-fibres) is very poor, allowing localisation for example to a given limb. (B332.48.w48)
  • NOTE: It is important to realize that the afferent pathways do not relay information received from nociceptors in a one-to-one fashion. Information transmitted upward to the brain is a synthesis of information from activity of nociceptors and, in pathways which also receive information from other types of receptor, information passed on to the brain is a synthesis of nociceptive information with information from the other receptors. (B325.w3)

Reflex (withdrawal) arc

  • "Acute stimuli may result in a rapid transmission by sensory fibres and an immediate motor response to both recognize and avoid the source of irritation." (J288.59.w1)
  • The reflex arc or motor reflex (usually the flexion reflex), which acts to remove the point at which a pain stimulus has occurred away from the source of the stimulus, involves connections within the grey matter, to the ventral horn. (B322.2.w2, B323.3.w3)
  • This reflex does not depend on conscious perception of pain and can be elicited even in an anaesthetised or paraplegic individual. (B323.3.w3)
  • Control mechanisms act even on the withdrawal reflex: withdrawal happens only once, even though the pain may continue, and, if required, this response can be overridden. (B322.2.w2, B323.3.w3)

Other local responses

  • Synapses in other spinal cord regions may produce other responses such as local cardiovascular effects. (B322.2.w2)

Gate theory:

  • At the level of the spinal cord, modification of the signal takes place before action potentials are relayed to the brain for final processing. (J4.219.w4)
  • The gate theory proposes that the signal passed up to the brain is a summation of the excitatory inputs from the afferent fibres and inhibitory descending inputs (see below: Descending control). (J22.150.w1, B327.40.w40) 
    • There are at least two levels of gating in the spinal cord, at the level of entry to the dorsal horn and at the level of afferent input to the ascending dorsal columns (B322.2.w2, B323.3.w3)

Aberrant pain perception in the absence of painful stimuli may occur if lesions are present within the relevant neurons of the spinal cord (or at higher levels in the brain). (B322.2.w2)

Analgesic drug action:

  • Local anaesthetics may be used to block nerve transmission from the site of the noxious stimulus, for example during suturing of wounds. (J288.59.w1)
  • Opioid and alpha-2 adrenergic agonists have their effects by actions at specific receptors in the nervous system. (J288.59.w1)
  • NSAIDs may act in part in the central nervous system. (J298.75.w1)
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Central (Brain) Connections

Afferent fibres entering the brain carrying nociceptive inputs synapse at various levels; the thalamus is considered to be the most important. (B322.2.w2, B327.40.w40, J4.219.w4)

  • Fibres in the spinothalamic tracts mainly form synapses in the ventral and medial thalamus, to cells which have projections to the somatosensory cortex. (B327.40.w40)
    • Only about 10-15% of fibres of the paleospinothalamic tract (mainly C-fibres) pass through the brain stem to terminate in the thalamus. The remainder terminate widely within the brain stem, in either the reticular nuclei of the medulla, pons and mesencephalon, the tectal area of the mesencephalon deep to the superior and inferior colliculi or the periaquaductal grey matter around the aquaduct of Sylvius. Multiple short-fibre neurons then relay pain signals from the brain stem areas into the intralaminar and ventrolateral nuclei of the thalamus, portions of the hypothalamus, and other regions of the basal brain adjacent to these. (B332.48.w48)
  • The rostromedial medulla is critical in integration and processing of ascending nociceptive information; it contains excitatory and inhibitory cells which either facilitate or inhibit nociceptive reflexes and nociceptive behaviours. (J4.219.w4)
  • There are species variations in the distribution and numbers of neurons within the thalamic nuclei specifically activated by ascending nociceptive activity. (B325.w3, J4.191.w4)

From the thalamus, following processing, nociceptive inputs are relayed to widespread areas of the cerebral cortex including somatosensory areas, association areas and parts of the limbic system. (B325.w3, B327.40.w40, J4.219.w4)

  • The limbic system includes various cortical and subcortical areas of the brain and is concerned with many aspects of the motivational-affective dimensions of pain. Emotional reactions and affective experiences generated in the limbic system are expressed in behaviours such as crying out and attack or defence, as well as coordinated autonomic activity and endocrine responses. Many of these responses are achieved via the hypothalamus, with which the limbic system is closely linked. (B325.w3)
  • One part of the limbic system is the periaquaductal grey matter; neurons projecting from this region control many of the antinociceptive and autonomic responses that follow noxious stimulation. (J4.219.w4)

The level at which a noxious stimulus becomes perceived as pain is speculated to be possibly the thalamus or only the cortex. (B322.2.w2)

  • Sectioning the brain above the mesencephalon, thus preventing pain signals reaching the cerebrum, or completely removing the somatic sensory areas of the cerebral cortex, do not prevent animals perceiving pain and evincing evidence of suffering if any part of the body is subject to trauma. Therefore it appears likely that conscious perception of pain can result from pain impulses entering the reticular formation of the brain stem, the thalamus and other lower centres. (B332.48.w48)

The most rostral area involved in pain control is the prefrontal cortex or medial frontal cortex. (B322.2.w2)

  • The cortex is thought to play an important role in interpreting pain quality. (B332.48.w48)

Some ascending nociceptive fibres terminate in the reticular formation. This is the area of the brain which is thought to govern consciousness and level of sleep. (B322.2.w2, B332.48.w48) 

  • Increased reticular activity due to increased noxious input can overcome the effects of general anaesthetics. (B322.2.w2)

Analgesic drug action:

  • Opioid and alpha-2 adrenergic agonists have their effects by actions at specific receptors in the nervous system. (J288.59.w1)
  • General anaesthetics prevent perception of pain by establishing an unconscious state in the individual. (J288.59.w1)
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Descending control - Inhibition and Facilitation

Perception of pain resulting from signals reaching the higher centres of the brain is not only dependent on ascending information. Ascending signals are modified by the action of descending control pathways, which provide both descending inhibition and descending facilitation of nociception. (J4.219.w4, J135.96.w2)
  • Factors which may modulate pain perception include emotional state, expectation, volition, blood pressure, stress and counterirritation, as well as drugs. (J4.191.w5)

The effects of the descending control system are exerted at various levels including the midbrain, medulla and spinal cord, to reduce or modulate ascending noxious information and thereby reduce the sensation of pain at the levels of perception. (B322.2.w2)

  • Nociceptive neurons in the dorsal horn of the spinal cord are subject to tonically active descending inhibitory modulation. (B323.4.w4, J4.191.w5)
  • It is thought that the descending inhibition system is designed to allow an individual to partially or completely ignore noxious stimuli, for example to allow the individual to run away from immediate danger, and, if an animal has survived an immediate danger, to allow it to undertake other activities important for survival, such as finding food, rather than responding further to pain. (B322.2.w2)
  • Stress-induced analgesia may be adaptive (i.e. increase survival) by reducing pain from injury and thereby allowing the animal to enact appropriate attack or escape behaviours. It may also be useful in injured animals using immobility or feigning death as strategies for eventual escape from a predator, by reducing pain sensation and associated motor responses, and this may also prevent further damage while the animal recovers from injury. (J4.191.w5)

Pathways and control centres

Two key areas of the brain which are integrating centres for descending inhibition are the periaquaductal grey area (PAG) in the midbrain and the ventromedial medulla. (B322.2.w2)

  • Various sites in the brainstem, such as the rostral ventromedial medulla (RVM) are known to be associated with both descending inhibition and descending facilitation, but different descending spinal nerve pathways from these brainstem sites are involved in inhibition and facilitation. (J135.96.w2)
  • Descending systems originating in the brainstem and able to modify generation of activity, including nociceptive activity, in ascending pathways, arise from the periaquaductal grey (PAG), raphe nuclei, lateral reticular formation and hypothalamus. (B325.w3)
  • The rostromedial medulla is critical in modulation of descending output from the brain. (J4.219.w4)

The periaquaductal grey area (PAG) in the midbrain is known to be an important integration centre for descending inhibition. (B322.2.w2) The PAG receives inputs from various brain areas including the cortex, thalamus and hypothalamus. (B327.40.w40)

  • Electrical stimulation of particular regions of the brain, including the periaquaductal grey area (PAG) and the raphe magnus nucleus can produce analgesia, reversible when the stimulation ceases. (B322.2.w2, J4.191.w5, J22.164.w1) To a lesser extent, analgesia can be produced by electrical stimulation of higher centres sending signals to these regions, particularly the periventricular nuclei of the hypothalamus. (B332.48.w48, J22.164.w1)
  • The main neuronal pathway which is activated by stimulation of the PAG runs to the nucleus raphe magnus (NRM) and then to fibres descending in the dorsolateral funniculus of the spinal cord, which form synaptic connections on interneurons of the dorsal horn. The main transmitter at these synapses is 5-hydroxytryptamine (5-HT); the interneurons then act to inhibit the discharge of spinothalamic neurons. The NRM also receives an input, via the adjacent nucleus reticularis paragigantocellularis, from spinothalamic neurons: the descending inhibitory system may form part of a regulatory feedback loop with transmission through the dorsal horn controlled depending on the amount of activity reaching the thalamus. (B327.40.w40)

Neurotransmitters

  • A variety of neurotransmitters are involved in the synapses of the descending inhibition pathways, including glutamate, noradrenaline, 5-hydroxytryptamine (5-HT, serotonin), gamma-aminobutyric acid (GABA) and endogenous opioid peptides. (B322.2.w2)
    • Various chemical transmitters are involved including serotonin and enkephalins. Enkephalins are secreted in the raphe magnus nucleus from fibres originating in the periaquaductal grey and the periventricular nuclei. Serotonin is secreted by fibres originating in the from the raphe magnus nucleus and terminating in the dorsal horns of the spinal cord; enkephalins are then secreted by local spinal cord neurons. (B332.48.w48)
      • Enkephalin is believed to cause both presynaptic inhibition, probably by blocking calcium channels in nerve terminal membranes, and postsynaptic inhibition, of Aδ and C nociceptive fibres where they synapse in the dorsal horn of the spinal cord. (B332.48.w48)
  • It is probable that the descending inhibitory pathway is an important site of action for opioid analgesics: both the PAG and the substantia gelatinosa are rich in neurons containing enkephalin, and opioid antagonists can prevent analgesia induced by electrical stimulation of the descending control system (B327.40.w40)

Further information

  • Descending facilitation may be involved in the development of secondary (central) hyperalgesia. (J135.96.w2) [See below: Central Sensitization]
  • Following peripheral nerve injury there is an increased expression of cholecystokinin (CCK), an endogenous opioid antagonist, and a corresponding increase in the CCK -B receptor. These responses may inhibit the protection induced by endogenous peptide release and contribute to the decreased potency of opioids in neuropathic pain. (J4.219.w4)
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Peripheral Sensitization

  • Most sensory receptors adapt to stimuli, i.e. they respond less to a continuing stimulus. In contrast nociceptors may become more sensitive if painful stimuli continue. The increase in sensitivity of the pain receptors as pain continues is called hyperalgesia. The process by which activation of a nociceptor by a stimulus (such as noxious heat) causes a decrease in the threshold required for a stimulus to result in transmission of action potentials is called autosensitisation. (B332.48.w48, J22.288.w1)
  • When tissues are damaged and inflamed, a number of chemicals are released from cells. While some of these directly activate nociceptors, an important effect of many of these chemicals, which have been described as an "inflammatory soup", is to lower the activation threshold of nociceptors: that is, to make nociceptors more sensitive to noxious stimuli, whether chemical, mechanical, or thermal. This is known as heterosensitization. (J290.21.w1, B327.40.w40, B332.48.w48, J9.413.w1, J4.219.w4, J22.288.w1)
    • There appear to be at least two phases to this peripheral sensitization, an early phase, then spread over several hours a late phase. (J290.21.w1)
    • Chemicals which are involved in peripheral sensitization include extracellular protons (H+ ions), K+, ATP, arachidonic acid, cyclooxygenase-2 (COX-2), nitric oxide synthetase, thrombin, trypsin, serotonin, bradykinin, adrenaline (epinephrine) prostaglandins such as PGE2, cytokines such as interleukin 1, nucleotides, nerve growth factor (NGF), 5-HT and substance P. These interact with receptors or ion channels on sensory nerve endings. Some of the chemicals directly activate the nerve endings, while others work synergistically to lower the activation threshold. (B332.48.w48, J4.219.w4, J9.413.w1, J22.288.w1, J298.75.w1)
      • Prostaglandins and substance P are chemicals which enhance sensitivity of pain endings although they do not themselves excite the pain receptors. (B332.48.w48)
    • Release of peptides and neurotransmitters, such as substance P, calcitonin-gene-related peptide and ATP, from nociceptor peripheral terminals which are activated by noxious stimuli, can promote release of factors from neighbouring non-neuronal cells and vascular tissue, a process known as neurogenic inflammation which itself facilitates production of "inflammatory soup". (J9.413.w1)
  • Local sensitization due to release of chemical mediators occurs only in the immediate area of inflammation. (P61.62.w3)
  • The area in which the nociceptors become more sensitive is known as the area of primary hyperalgesia. (J4.219.w4)
  • As well as lowering the threshold for response of nociceptors to stimuli, chemicals released by tissue damage and inflammation also contribute to activation of the so-called silent or sleeping nociceptors. For example inflammation causes activation of silent nociceptors in joints, resulting in hypersensitivity to mechanical stimuli, so that normal joint movement is painful. (J4.219.w4)
Analgesic drug action:
  • NSAIDs (and steroids) act to control pain by reducing inflammation and swelling (J288.59.w1, J298.75.w1)
  • Because many different chemicals can cause peripheral sensitisation, inhibiting a single chemical is not likely to completely inhibit peripheral sensitization. (J22.288.w1, J298.75.w1)
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Central sensitisation

It has been recognised since the 1980's that post-injury pain hypersensitivity involves a central component as well as peripheral hypersensitivity. (J9.306.w1, J298.75.w1)
  • Central sensitization involves changes at the levels of the spinal cord and brain occurring after a period of noxious stimulation. (B322.2.w2, J9.306.w1, J22.288.w1)
  • The results of central sensitization include secondary hyperalgesia (hyperalgesia in areas beyond the injured tissue) (B322.2.w2, J4.219.w4, J135.96.w2) and allodynia. (J4.219.w4, J22.288.w1)
    • Central sensitization involves changes occurring within the neuronal networks processing nociceptive information, increasing neuron excitability, particularly in the spinal cord. This change appears to result from the afferent barrage from peripheral nociceptors at the time of the painful insult. (J9.306.w1, J22.288.w1, J290.21.w1) It may start within minutes but involves a change in gene expression and lasts for a period of time which exceeds the input from peripheral nociceptors. (J290.21.w1)
    • Central sensitization allows pain to be produced by activity in non-nociceptive primary sensory fibres (Aβ fibres), by increasing excitability of spinal neurons and altering sensory processing in the spinal cord. (J4.219.w4, J9.413.w1)
    • Part of central sensitization is due to depression of the normal inhibitory mechanisms action on spinal neurons. (J22.288.w1)
    • "Wind-up" is the characteristic in which the synaptic responses of dorsal horn neurons to nociceptive inputs steadily increase in amplitude with each stimulus, if stimuli are delivered at physiological frequencies. (B327.40.w40)
  • The longer that pain is in existence the greater the degree of central sensitisation that develops and, in consequence, the harder it is to manage that pain. (B322.5.w5)
    • Long-lasting central sensitisation may be responsible for conditions such as phantom limb pain. (J290.21.w1)

Transmitters:

  • NMDA (N-methyl-D-aspartate) receptors are known to be involved in central sensitization. (J22.288.w1)
  • The main transmitter involved in central sensitization in the spinal cord is probably glutamate acting at a spinal N-methyl-D-aspartate (NMDA) receptor. (B322.2.w2, J135.96.w2)
  • Ketamine, being an NMDA antagonist, has the potential to reverse central hypersensitivity and may reduce acute pain. (B322.5.w5, J298.75.w1)

Longer-term changes:

  • Changes can take place within neurons, involving movements of ions across cell membranes and various neurotransmitters. A variety of chemicals such as nerve growth factor, oestrogen, some cytokines, can cause neurons to grow sprouts which form new synapses. Such chemicals are probably released during injury and during abnormal neuronal activity giving rise to pain. (B322.2.w2)
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Other physiological responses to pain

  • Ascending nociceptive activity affects autonomic control systems including respiratory, cardiovascular and gastrointestinal control centres in the caudal brainstem. Effects which may be seen include changes in respiratory rate, heart rate, peripheral vasoconstriction, sweating and gastric mobility. Changes in muscle tone, spinal reflex sensitivity, generation of coordinated locomotory activity and responses such as blinking and head turning are associated with actions on major somatic motor systems (e.g. the tecto-spinal, reticulo-spinal and vestibulo-spinal systems). (B322.2.w2, B325.w3, J4.191.w4)
    • These changes are not reliable indicators of pain as they may be induced or modified by stress-related endocrine changes, drugs and external physical effects. (B322.2.w2)
  • Profound endocrine changes such as release of hormones from the pituitary, thyroid, parathyroid and adrenal glands can occur in response to pain or injury. (B322.2.w2)
  • Pain can suppress immune function and enhance development of tumours. For example it has been shown experimentally in rats that pain associated with surgery enhances metastatic colonisation of tumour cells and that this effect can be attenuated by provision of analgesia using systemic morphine or by using a spinal block. (P61.62.w3, J297.54.w1, J302.94.w1)
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Chronic pain

Chronic pain persists beyond the expected time after which an injury would have healed; often it is not possible to identify a specific injury giving rise to chronic pain. (B325.w3)
  • In some chronic pain states, pain is associated with an old insult, for example following nerve injury, as in phantom limb pain; it may also occur without any recognised predisposing event. (B326.5.w5, B327.40.w40)
  • Chronic pain may be due to an ongoing pathology in the periphery, or may by independent of the original trigger which initiated the pain. (J298.75.w1)
  • There may or may not be a well defined time at which chronic pain started. (B325.w3)
  • The cause of chronic pain is not always obvious or identifiable. (B325.w3)
  • Chronic pain may be spontaneous; this is seen particularly in denervation syndromes.(J298.75.w1)
  • Chronic pain may be provoked by a peripheral stimulus, but typically is excessive in duration or amplitude and may occur in response to stimuli which would not normally be associated with pain. (J298.75.w1)
  • Knowledge of neural mechanisms involved with chronic pain are still limited. (J4.191.w3)
  • "Signs of chronic pain [in humans] include changes in behaviour and functional ability, signs of depression, helplessness, loss of libido, weight loss and disturbed sleep patterns. " (B325.w3)
  • In chronic pain and chronic stress, levels of circulating stress hormones are reduced. (B322.2.w2)
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Visceral pain

Visceral pain, i.e. pain from the internal (visceral) organs, differs from somatic pain in several respects. (J298.75.w2)

Stimuli causing visceral pain

  • Damage to, even gross destruction of, some visceral organs, such as the lung, liver parenchyma and parenchymal parts of the kidney, appears not to result in pain. (B332.48.w48, J298.75.w2)
    • The liver capsule is very sensitive to stretch and to direct trauma, although the liver parenchyma is insensitive. (B332.48.w48)
  • Stimuli such as crushing, tearing, cutting and burning of many visceral organs appears not to cause pain (or any other sensation). (J298.75.w2)
  • Distention of hollow, muscular-walled organs such as those of the gastro-intestinal tract (oesophagus to rectum), the urinary tract (from kidney pelvis to bladder) and the gall bladder, results in pain. Pain can also be elicited by spasm or active contraction of smooth muscle of such organs, for example around an obstruction, by ischaemia (e.g. in ischaemic heart disease) and, importantly, by inflammation. Some chemicals, such as bradykinin, produce pain when applied to visceral tissues. (B332.48.w48, J9.413.w1, J298.75.w2)
    • Spatial summation may be important: in general, a stimulus which causes diffuse stimulation of large numbers of pain endings throughout a large area of a visceral organ (e.g. distention of a large area) is likely to cause severe pain, while very localised damage, stimulating few pain endings, is unlikely to cause pain. For example damaging chemicals leaked from the gastro-intestinal tract into the peritoneal cavity, and affecting a wide area of the visceral peritoneum, stimulates visceral nociceptors over a wide area and can cause severe pain.  (B332.48.w48, J298.75.w2)

Localization and referral of visceral pain

  • Visceral pain is generally poorly localised (J9.413.w1, J284.75.w1) and it may be referred to parts of the body distant from the source of pain. (J284.75.w1)
    • Visceral pain is generally perceived as being deep and dull. (J9.413.w1) 
      • Visceral pain may be perceived as deep in the body, usually midline, and extensive rather than focal; in humans it is known that this may be accompanied by feelings of nausea and general ill-being. (J298.75.w2)
    • Commonly, visceral pain is referred, that is, it is felt at a site distant from the site of the originating stimulus, generally an area of skin and/or muscle which is innervated by the same spinal nerves that innervate the affected visceral organ. (B332.48.w48, J298.75.w2)
      • While primary hyperalgesia occurs at the site of the original stimulus, the referred site of pain may show secondary hyperalgesia. (J298.75.w2)
    When a disease process affecting a visceral organ spreads to affect the parietal peritoneum, pleura or pericardium, structures which are extensively innervated from peripheral spinal nerves, sharp pain results. This pain is generally located directly over the affected viscera. (B332.48.w48)
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Authors & Referees

Authors Dr Debra Bourne MA VetMB PhD MRCVS (V.w5)
Referee A.B.Forbes BVM&S.,CBiol.,MIBiol.,DipEVPC.,MRCVS (V.w66)

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