Pain wind-up
Encyclopedia
Pain
wind-up is central pain sensitization caused by repeated painful stimulation of peripheral nerves at sufficient intensity to stimulate group C nerve fiber
s, leading to progressively increasing electrical response in the corresponding spinal posterior horn neurons. This slow, cumulative effect is partly due to the slow response of NMDA receptor
s, but may also be linked to sustained release of substance P
, a neuropeptide
, in the posterior horns. The process leads to increased pain in response to painful stimuli (hyperalgesia
), pain in response to normally non-painful stimuli (allodynia
), and spontaneous pain.
After repeated stimulation, wide dynamic range neurons
become increasingly excitable. This hyper-excitability can be caused by an increased neuronal response to a noxious stimulus (hyperalgesia), a larger neuronal receptive field
, or spread of the hyper-excitability to other segments. This condition is maintained by C fibers. C fibers cause central sensitization of the dorsal horn in the spinal cord in response to their hyperactivity. The mechanism underlying this phenomenon involves the release of glutamate
by these pathologically sensitized C fibers. The glutamate interacts with the postsynaptic
NMDA receptor
s, which aids the sensitization of the dorsal horn. Presynaptic
neuronal voltage-gated N-calcium channels are largely responsible for the release of this glutamate as well as the neuropeptide
, substance P
. The expression of presynaptic
neuronal voltage-gated N-calcium channels increases after a nerve lesion or repeated stimulation. Ziconotide is a specific antagonist of these N-type voltage gated Calcium channels. NMDA receptor
activation (by glutamate) enhances postsynaptic Nitric Oxide Synthase
. Nitric Oxide is thought to migrate back to the presynaptic membrane to enhance the expression of the voltage-gated N-calcium channels resulting in a pain wind-up phenomenon. Ketamine
(NMDA receptor antagonist) and Nitric Oxide Synthase
inhibitors can block pain wind-up. This abnormal central sensitization cycle results in increased pain (hyperalgesia) and pain responses from previously non-noxious stimuli evoke a pain response (allodynia
).
Central sensitization of the dorsal horn neurons that is evoked from C fiber activity is responsible for temporal
summation of “second pain” (TSSP). This event is called ‘windup’ and relies on a frequency
greater or equal to 0.33Hz
of the stimulus. Windup is associated with chronic pain
and central sensitization. This minimum frequency was determined experimentally by comparing healthy patient fMRI’s
when subjected to varying frequencies of heat pulses. The fMRI maps show common areas activated by the TSSP responses which include contralateral thalamus
, primary somatosensory cortex, bilateral secondary somatosensory cortex
, anterior and posterior insula
, mid-anterior cingulate cortex
, and supplementary motor areas
. TSSP events are also associated with other regions of the brain associated with somatosensory processing, pain perception and modulation, cognition
, and pre-motor activity.
During surgery, if not treated with the appropriate anesthetics, substantial pain wind-up can occur, causing the patient to wake up in a hyperalgesic state. This can be prevented with the use of opiates, ketamine, local anesthetics, or Ziconotide. Pain wind-up is not prevented by most inhalation anesthetics.
They will also address the underlying causes which caused the constant pain transmission; e.g. stiffness in the joints, chronic spasm in the surrounding muscle, postural stiffness and early fatigue.
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
wind-up is central pain sensitization caused by repeated painful stimulation of peripheral nerves at sufficient intensity to stimulate group C nerve fiber
Group C nerve fiber
-Location:C fibers are found in the peripheral nerves of the somatic sensory system. They are afferent fibers, conveying input signals from the periphery to the central nervous system.-Structure:...
s, leading to progressively increasing electrical response in the corresponding spinal posterior horn neurons. This slow, cumulative effect is partly due to the slow response of NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s, but may also be linked to sustained release of substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
, a neuropeptide
Neuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
, in the posterior horns. The process leads to increased pain in response to painful stimuli (hyperalgesia
Hyperalgesia
Hyperalgesia is an increased sensitivity to pain, which may be caused by damage to nociceptors or peripheral nerves. Temporary increased sensitivity to pain also occurs as part of sickness behavior, the evolved response to infection.-Types:...
), pain in response to normally non-painful stimuli (allodynia
Allodynia
Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...
), and spontaneous pain.
After repeated stimulation, wide dynamic range neurons
Wide dynamic range neuron
The wide dynamic range or "convergent" neuron is the most populous type of those neurons whose cell bodies are located in the dorsal horn of the spinal cord. WDR neurons are responsive to all sensory modalities and a broad range of intensity of stimulation from peripheral nerves...
become increasingly excitable. This hyper-excitability can be caused by an increased neuronal response to a noxious stimulus (hyperalgesia), a larger neuronal receptive field
Receptive field
The receptive field of a sensory neuron is a region of space in which the presence of a stimulus will alter the firing of that neuron. Receptive fields have been identified for neurons of the auditory system, the somatosensory system, and the visual system....
, or spread of the hyper-excitability to other segments. This condition is maintained by C fibers. C fibers cause central sensitization of the dorsal horn in the spinal cord in response to their hyperactivity. The mechanism underlying this phenomenon involves the release of glutamate
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
by these pathologically sensitized C fibers. The glutamate interacts with the postsynaptic
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
s, which aids the sensitization of the dorsal horn. Presynaptic
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
neuronal voltage-gated N-calcium channels are largely responsible for the release of this glutamate as well as the neuropeptide
Neuropeptide
Neuropeptides are small protein-like molecules used by neurons to communicate with each other. They are neuronal signaling molecules, influence the activity of the brain in specific ways and are thus involved in particular brain functions, like analgesia, reward, food intake, learning and...
, substance P
Substance P
In the field of neuroscience, substance P is a neuropeptide: an undecapeptide that functions as a neurotransmitter and as a neuromodulator. It belongs to the tachykinin neuropeptide family. Substance P and its closely related neuropeptide neurokinin A are produced from a polyprotein precursor...
. The expression of presynaptic
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
neuronal voltage-gated N-calcium channels increases after a nerve lesion or repeated stimulation. Ziconotide is a specific antagonist of these N-type voltage gated Calcium channels. NMDA receptor
NMDA receptor
The NMDA receptor , a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function....
activation (by glutamate) enhances postsynaptic Nitric Oxide Synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
. Nitric Oxide is thought to migrate back to the presynaptic membrane to enhance the expression of the voltage-gated N-calcium channels resulting in a pain wind-up phenomenon. Ketamine
Ketamine
Ketamine is a drug used in human and veterinary medicine. Its hydrochloride salt is sold as Ketanest, Ketaset, and Ketalar. Pharmacologically, ketamine is classified as an NMDA receptor antagonist...
(NMDA receptor antagonist) and Nitric Oxide Synthase
Nitric oxide synthase
Nitric oxide synthases are a family of enzymes that catalyze the production of nitric oxide from L-arginine. NO is an important cellular signaling molecule, having a vital role in many biological processes...
inhibitors can block pain wind-up. This abnormal central sensitization cycle results in increased pain (hyperalgesia) and pain responses from previously non-noxious stimuli evoke a pain response (allodynia
Allodynia
Allodynia is a pain due to a stimulus which does not normally provoke pain. Temperature or physical stimuli can provoke allodynia, and it often occurs after injury to a site...
).
Central sensitization of the dorsal horn neurons that is evoked from C fiber activity is responsible for temporal
Time
Time is a part of the measuring system used to sequence events, to compare the durations of events and the intervals between them, and to quantify rates of change such as the motions of objects....
summation of “second pain” (TSSP). This event is called ‘windup’ and relies on a frequency
Frequency
Frequency is the number of occurrences of a repeating event per unit time. It is also referred to as temporal frequency.The period is the duration of one cycle in a repeating event, so the period is the reciprocal of the frequency...
greater or equal to 0.33Hz
Hertz
The hertz is the SI unit of frequency defined as the number of cycles per second of a periodic phenomenon. One of its most common uses is the description of the sine wave, particularly those used in radio and audio applications....
of the stimulus. Windup is associated with chronic pain
Chronic pain
Chronic pain has several different meanings in medicine. Traditionally, the distinction between acute and chronic pain has relied upon an arbitrary interval of time from onset; the two most commonly used markers being 3 months and 6 months since the initiation of pain, though some theorists and...
and central sensitization. This minimum frequency was determined experimentally by comparing healthy patient fMRI’s
Functional magnetic resonance imaging
Functional magnetic resonance imaging or functional MRI is a type of specialized MRI scan used to measure the hemodynamic response related to neural activity in the brain or spinal cord of humans or other animals. It is one of the most recently developed forms of neuroimaging...
when subjected to varying frequencies of heat pulses. The fMRI maps show common areas activated by the TSSP responses which include contralateral thalamus
Thalamus
The thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
, primary somatosensory cortex, bilateral secondary somatosensory cortex
Secondary somatosensory cortex
The human secondary somatosensory cortex is a region of cerebral cortex lying mostly on the parietal operculum.Region S2 was first described by Adrian in 1940, who found that feeling in cats' feet was not only represented in the previously described primary somatosensory cortex but also in a...
, anterior and posterior insula
Insular cortex
In each hemisphere of the mammalian brain the insular cortex is a portion of the cerebral cortex folded deep within the lateral sulcus between the temporal lobe and the frontal lobe. The cortical area overlying it towards the lateral surface of the brain is the operculum...
, mid-anterior cingulate cortex
Cingulate cortex
The cingulate cortex is a part of the brain situated in the medial aspect of the cortex. It includes the cortex of the cingulate gyrus, which lies immediately above the corpus callosum, and the continuation of this in the cingulate sulcus...
, and supplementary motor areas
Supplementary motor area
The supplementary motor area is a part of the sensorimotor cerebral cortex . It was included, on purely cytoarchitectonic arguments, in area 6 of Brodmann and the Vogts...
. TSSP events are also associated with other regions of the brain associated with somatosensory processing, pain perception and modulation, cognition
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
, and pre-motor activity.
During surgery, if not treated with the appropriate anesthetics, substantial pain wind-up can occur, causing the patient to wake up in a hyperalgesic state. This can be prevented with the use of opiates, ketamine, local anesthetics, or Ziconotide. Pain wind-up is not prevented by most inhalation anesthetics.
Medical Management
Certain drugs can reduce the excitatory nature of the nerves, for example anti-epileptics or anti-depressants.Physiotherapy Management
Physiotherapy focuses on restoring normal impulse transmissions in these nerves by gentle soft massage involving stroking, and teaches the patient to do so themselves.They will also address the underlying causes which caused the constant pain transmission; e.g. stiffness in the joints, chronic spasm in the surrounding muscle, postural stiffness and early fatigue.