Term
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Definition
unpleasant sensory and emotional experience associated with actual or potential tissue damage.
2 components of pain: a sensory component (which tells us that it's painful) and an affective component (emotional aspect) |
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Term
| types of pain: nociceptive pain |
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Definition
nociceptive pain is an early warning physiological system which serves to detect and minimize contact with potentially damaging stimuli, such as intense heat, sharp or cold, thus serving as a protective function.
nociceptive pain in concerned with the sensing of noxious stimuli
thus, only high threshold noxious stimuli can activate this kind of pain |
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Term
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Definition
pain is a specialized function of the sensory nervous system which is carried out by the spinothalamic tract
the spinothalamic tract is the tract responsible for nociceptive pain |
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Term
| organization of the spinothalamic tract |
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Definition
[image]
1st order neuron is the blue neuron (or nociceptor) as it is the first neuron
another term to describe a 1st order neuron is primary neuron
the 2nd order neuron is the green neuron as it is 2nd in the relay of neuronal information
with most neuronal tracts (including the spinothalamic tract) the 2nd order neuron crosses to the other side of the spinal cord and ascends to terminate in the brain
the 3rd order neuron is in red and projects from the thalamus to the somatosensory cortex |
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Term
| afferent and efferent neurons |
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Definition
afferent:
going towards the CNS
used quite often with sensory nerves as sensory information is taken to the CNS to where it is then processed
efferent:
going away from the CNS
this term is used with motor systems
movement begins int he CNS to where information from the CNS is relayed to motor neurons located int he periphery |
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Term
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Definition
Nociception, the neural processes of encoding and processing noxious stimuli
in contrast pain is composed of sensory and affective components.
the sensory component is nociception or detecting the noxious stimulus while the affective component is the emotional component of pain |
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Term
| 4 steps in pain processing |
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Definition
transduction
transmission
modulation
perception |
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Term
| definition of transduction |
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Definition
| stimuli are translated into electrical and chemical activity |
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Term
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Definition
a nociceptor is a sensory neuron that only detects noxious stimuli
a nociceptor DOES NOT detect non-noxious stimuli such as light touch |
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Term
| components of a nociceptor |
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Definition
[image]
components of the nociceptor include a peripheral terminal that transduces external stimuli and initiates action potentials, the cell body that controls the identity of the neuron (and is also involved in neurotransmitter and protein synthesis), and the central terminal which conveys the message to the central nervous system
the peripheral terminal, axon and dorsal root ganglion (or the cell body) are located in the peripheral nervous system
in contrast, the central terminal is located in the spinal cord which is part of the CNS
in terms of the definition of the dorsal root ganglion, ganglion refers to a collection of cell bodies
nociceptors are sensory neurons. all sensory neurons respond to their adequate stimulus which is the form of energy a sensory neuron is most sensitive to. for nociceptors, the adequate stimulus is noxious stimulation (whether it be noxious mechanical, noxious thermal or noxious chemical stimulation)
not all nociceptors respond to each or all of these and may be activated at different levels of noxious input |
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Term
| classification of neurons based on their axons |
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Definition
A-BETA FIBERS:
only encode non-noxious stimuli such as light touch, vibration and propioception
no nociceptor has A-beta fibers
TYPE 1 A-DELTA FIBERS:
myelinated, medium diameter -> faster conduction than C fibers
high threshold mechanireceptors (they respond to noxious mechanical stmulation)
respond to chemical stimulation
Type 1 also respond to noxious heat (although they respond at a much higher heat threshold than Type 2 A-delta fibers)
mediates fast sharp pain
TYPE 2 A-DELTA FIBERS:
much lower threshold for noxious heat than type 1 A-delta fibers
respond to lower noxious temperatures than type 1
in comparison to type 1 they have much higher mechanical thresholds
also respond to chemical stimuli
thought to mediate first pain to heat
C FIBERS:
small and unmyelinated -> slower conduction
most are polymodal meaning they respond to noxious chemical, thermal, and mechanical stimuli
some are "silent nociceptors" - C fibers that are not normally active however, following inflammation these silent nociceptors become active and can respond to a varitey of stimulus modalities (noxious heat, chemical, or mechanical)
all nociceptors have either A-delta or C fibers, but not all A-delta and C fibers carry nociceptive information |
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Term
| transduction of noxious stimuli: types of noxious stimuli recognized |
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Definition
for noxious chemical stimulation transduction occurs through several different types of receptors:
ASIC - acid sensing ion channels
P2X2 and P2X3 receptors - ATP recpetors
B1 and B2 receptors - bradykinin receptors
for noxious thermal stimuli:
TRPV1 and TRPV2 channels are used
for noxious mechanical stimuli:
not kown |
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Term
| transduction of noxious stimuli: receptor potentials |
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Definition
receptor potentials can be produced by ionotropic or metabotropic mechanisms
metabotropic mechanisms:
bradykinin receptor (B2) - coupled to Gq; activation of B2 receptor results in activation of PLC -> IP3 (increased intracellular Ca)
ionotropic mechanism:
TRPV1 - coupled to Na channels; binding of the TRPV1 agonist capsaicin to the TRPV1 receptor results in the influx of Na into the cell |
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Term
| how is the intensity of a stimulus perceived? |
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Definition
intensity of stimulus determines amplitude and duration of receptor potential
more intense noxious stimuli will produce larger receptor potentials as well as longer receptor potentials (and result in a higher frequency of action potentials)
weaker noxious stimuli will produce shorter receptor potentials of shorter duration (and as a result less action potentials) |
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Term
| mechanism of spatial and temporal summation of receptor potentials |
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Definition
spatial summation:
if transducer channels are opened in close approximation to one another, their currents can add together, pushing the membrane potential closer to threshold than if one was activated alone
postsynaptic membranes 1 and 2 are closer to one another than postynaptic membranes 1 and 3
if glutamate is released onto postsynaptic membranes 1 and 2 it will result in an increase in membrane potential since they are closer together (summation)
if glutamate is released onto postsynaptic membranes 1 and 3 the increase in membrane potential also summates but is less than 1 and 2 since 1 and 3 are further apart
temporal summation:
depends on the frequency of the transducer channels being opened
if there are many stimuli activating the nociceptor, the frequency of the stimuli activating it can also summate in terms of raising the membrane potential to threshold more rapidly |
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Term
| mechanism of generator potential |
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Definition
generator potentials are receptor potentials that cause direct changes in action potential frequency (and associated with opening of voltage gated Na channels)
subtypes of Na Channels:
Nav1.7, 1.8, and 1.9
mutations of these receptors result in loss or gain in function
a mutation in Nav1.7 that results in loss of function can lead to congenital insensitivity to pain
gain in function mutation of Nav1.7 is paroxysmal extreme pain disorder - Na channels does not completely inactivate leading to a persistent current -> repetitive firing of action potentials in nociceptors -> paroxysmal pain |
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Term
| speed of transmission in different nerve fibers |
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Definition
[image]
A-beta fibers are large diameter and myelinated: speed of transmission is the fastest
A-delta fibers are medium diameter and myelinated - conduct slower than A-beta
C fibers are small and non-myelinated - slowest of the group in terms of transmission speed |
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Term
| 2 different stages of pain transmission |
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Definition
sudden pain is produced by A-delta fibers
aching, longer lasting pain is produced by C fibers
(type 1 A-delta fibers are high threshold mechanoreceptors and are believed to mediate the first pain to mechanical stimuli. type 2 A-delta fibers are thought to mediate first pain to heat) |
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Term
| voltage gated Ca channels are important in what NT release? |
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Definition
after the action potential travels down the axon, there is activation of voltage gated Ca channels
this results in neurotransmitter relase
for nociceptors the release is of the excitatory NT glutamate or neuropeptide neurotransmitters calcitonin gene related peptide (CGRP) and substance P. |
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Term
| afferent and efferent functions of nociceptors |
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Definition
nociceptors are pseudouniporal neurons and have the same neurotransmitters are the peripheral and central terminals
in response to injury, nociceptors have afferent (going towards the CNS) and efferent (moving away from the CNS) functions |
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Term
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Definition
the spinal cord can be divided into grey matter and white matter
[image]
white matter:
stained dark
contains axons
grey matter:
lighers
contains cell bodies
organized into posterior (dorsal) and anterior (ventral) horns
dorsal horns contains sensory neurons
ventral horns contain motor neurons |
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Term
| neurons that project to higher centers (i.e. to the thalamus) |
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Definition
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Term
neurons that produce a dynamic response over a broad stimulus range (ranging from innocuous to noxious)
the major type of dorsal horn neurons encoding stimulus intensity
excited by thermal, mechanical, and chemical stimuli mediated via both C and A-delta fibers as well as non-noxious stimuli by A-beta fibers |
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Definition
| wide dynamic range (WDR) neurons |
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Term
neurons that can process information within local circuits
can modulate either the input or output of other neurons
can be excitatory or inhibitory |
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Definition
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Term
| which laminae do C fibers provide input to? |
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Definition
| C fibers project to laminae I, II, and V |
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Term
| which laminae do A-delta fibers provide input to? |
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Definition
| A-delta fibers project to laminae I and V |
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Term
| which laminae do A-beta fibers provide input to? |
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Definition
| A-beta fibers provide input to laminae III, IV, and V |
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Term
| which laminae is reffered to as being nociceptive specific? |
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Definition
| laminae I - only nociceptive neurons (A-delta and C) provide input to this layer |
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Term
| which laminae are referred to as being non-noxious? |
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Definition
laminae III and IV
only A-beta fibers project to these laminae |
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Term
| 2nd order neuron of laminae I |
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Definition
| projection neuron that terminates in the lateral thalams |
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Term
| second order neuron of laminae III and IV |
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Definition
| projection neurons that projects to the brain using a separate pathway known as the dorsal column medial lemniscus pathway which mediates light touch |
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Term
| 2nd order neuron of laminae V |
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Definition
| a wide dynamic range neuron (also a projection neuron) |
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Term
| key transmitters released from central terminal of the primary afferent |
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Definition
glutamate
substace P
CGRP
binding of these transmitters results in excitatory post synaptic potentials (EPSP) |
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Term
| actions of the AMPA receptor |
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Definition
the AMPA receptor is the receptor primarily responsible for fast excitatory transmission as they exhibit fast opening kinetics
when glutamate binds to AMPA receptors there is a rapid increase in intracellular Na in the postsynaptic membrane
the cell is depolarized and triggers an action potential
NMDA receptors require sufficient depolarization to remove the Mg block in order to conduct ions
metabotropic mechanisms take much longer to produce their actions compared to ion channels |
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Term
| actions of peptide NTs on their receptors (CGRP and substance P) |
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Definition
CGRP can act on the CGRP receptor (coupled to Gs)
substance P can act on the NK1 receptor (coupled to Gq)
once peptide NTs are released there is no uptake mechanism for these substances
they can produce their effects much longer |
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Term
| mechanism of the descending inhibition pathway |
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Definition
PAG-RVM PATHWAY:
areas of the brain important in terms of emotion (such as the amygdala), have direct input into the PAG and can activate the descending system
the major role of the descending inhibitory pathway is to selectively inhibit noxious stimuli received at the dorsal horn
in the periaqueductal grey (PAG)-rostral ventral medulla (RVM) pathway, input from the amygdala comes in and activates the PAG
from the PAG, it sends a neuron to the RVM
within the RVM there is a particular nucleus known as nucleus raphe magnus (NRM) which contains serotonin
neurons from the NRM then send serotonergic neurons into the dorsal horn where they terminate
serotonin is able to act on 5HT receptors to provide inhibitory feedback on the dorsal horn
DLPT:
for the dorsal lateral pontine tegmentum (DLPT) pathway, it also recieves input from the PAG (but via a separate tract than for the RVM
the PAG sends a neuron to the locus coereleus (LC) where it terminates
the LC is a major source of NE in the brain
from the LC another neuron projects to the spinal cord and releases NE
NE then acts on alpha2 receptors in the spinal cord to provide inhibitory feedback on the dorsal horn
the alpha2 agonist clonidine has analgesic effects believed to be mediated through this pathway
ENKEPHALINS
NE and 5HT not only act on their receptors to provide inhibitory feedback into the dorsal horn, but they can also activate enkephalins containing interneurons
enkephalin is an endogenous opioid that acts on delta opioid receptor
opioid receptors are located in the dorsal horn on the central terminal of the primary afferent and on 2nd order neurons
release of enkephalin can inhibit incoming nociceptive information as well as inhibit the 2nd order neuron from sending nociceptive information
NE AND 5HT
NE acts on the alpha2 receptor while 5HT acts on a 5HT receptor to either inhibit release of nociceptive transmitters by acting on the central terminal of the priamary afferent or by inhibiting the 2nd order neuron projection neuron from relaying the nociceptive signal by acting on their receptor |
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Term
| development of subjective, sensory, and emotional experience of pain |
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Definition
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Term
| mechanism of nociceptive perception |
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Definition
from lamniae I and V, the 2nd order neurons from the spinal cord terminate in the lateral thalamic nuclei
from there the 3rd order neuron projects from the lateral thalamus to the somatosensory cortex which provides information as to the location of the injury as well as the sharp, well localized pain; this circuit is known as the neospinothalamic tract
2nd order neurons can also project and terminate in the medial thalamic nuclei
from there 3rd order neuron projects from the medial thalamus to the basal ganglia as well as other areas of the cortex; this circuit is known as the paleospinothalamic tract and is believed to mediate the affective of "emotional" aspect of pain and is responsible for poorly localized persisting pain |
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Term
| types of pain: inflammatory pain |
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Definition
inflammatory pain is produced due to tissue damage caused by injury or infection
this pain is productive (usually, but not always)
assists in the healing of injured body parts as it discourages physical contact and movement through pain hypersensitivity |
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Term
thresholds are lowered so that stimuli that would normally not produce pain now begin to produce pain
i.e. pat on the back after getting a sunburn |
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Definition
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Term
| responsiveness is increased, so that noxious stimuli produce an exaggerated and prolonged pain |
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Definition
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Term
pain hypersensitivity may persist long after an injury has healed or occur in the absence of any injury. in this case, pain provides us with no benefits and is a manifestation of pathological change in the nervous system.
what produces pain hypersensitivity? |
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Definition
2 mechanisms:
peripheral and central sensitization |
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Term
| mechanism of peripheral sensitization |
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Definition
peripheral sensitization occurs when inflammatory mediators are released from injured and inflammatory cells sensitize the nociceptor, reducing the threshold for activation and increasing responsiveness
as a result, low intensity stimuli that would be considered innocuous can how activate the nociceptive pathway (allodynia)
also, painful stimuli result in an exaggerated pain response (hyperalgesia)
when injury occurs, this results in the generation of substances such as prostaglandins, ATP and bradykinin which activate 2nd messenger pathways that result in activation of kinases
kinases can cause neurons to become hyperexcitable (fires more often than what if normally would) or can reduce the threshold of the nociceptor for activation
additionally, C polymodal nociceptors can become active with inflammation to where there is now additional painful input coming into the CNS
the receptors involved in thermal hyperalgesia is TRPV1
once inflammation occurs, kinases become active and phosphorylate TRPV1, lowering the temperature threshold for activation of TRPV1
a 2nd theory is that endogenous PIP2 inhibits TRPV1. if PLC is activated (by bradykinin) TRPV1 is no longer repressed by PIP2 (as it is being converted to IP3 and DAG through the action of PLC) and TRPV1 becomes sensitized
changes in transcription and translation:
ultimately leads to increased receptor/channel expression
changes in protein expression takes days in contrast, activation of 2nd messengers can take minutes |
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Term
| mechanism of central sensitization |
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Definition
central sensitization is an increase in the excitability of neurons within the CNS
increased excitability is caused by a burst of activity of nociceptors, which alters the synaptic strength of connections between the nociceptor and the neurons of the spinal cord
chentral sensitization can change, distort, or amplify pain, increasing its degree, duration, and spatial extent in a manner that no longer directly reflects the specific qualities of peripheral noxious stimuli
central sensitization also has 2 phases similar to that of peripheral sensitization: 1) an immediate but relatively transient phase (activation of 2nd messenger cascades that utilize kinases) 2) a slower onset but longer lasting phase that involves new gene expression
the early phase reflects changes in synaptic connections within the spinal cord after a signal has been received from nociceptors
the central terminals of the nociceptor release neurotransmitters such as glutamate
glutamate binds to AMPA receptors and eventually brings membrane potential up to threshold to where NMDA receptors lose their Mg block and begin to participate in glutamate binding.
NMDA receptors are highly permeable to Ca; increase in Ca activates incracellular signaling pathways that lead to the phosphorylation of membrane receptors and channels particularly the NMDA and AMPA receptors for glutamate
these post-translational changes lower the threshold and opening characteristics of these channels, thereby increasing the excitability of the neurons |
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Term
| mechanism of mechanical allodynia |
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Definition
non-noxious mechanical stimuli begin to elicit pain
low threshold sensory fibers (A-beta) activated by very light touch of the skin begin to activate neurons in the spinal cord that normally only respond to noxious stimuli
as a result, an input that would normally evoke an innocuous sensation now produces pain
although the pain fells as if it originates in the periphery, it is actually a manifestation of central sensitization |
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Term
| mechanism of pathological pain |
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Definition
pathological pain is not protective, but maladaptive
results from abnormal functioning of the nervous system
pathological pain can occur after damage to the nervous system (neuropathic pain) but also in conditions in which there is no such damage or inflammation (dysfunctional pain - IBS, fibromyalgia) |
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Term
| peripheral lesions can lead to changes in the expression of Ca channels |
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Definition
Ca channels are key to neuronal function, particularly in regulating neurotrasmitter release from nerve terminals, including those that transmit pain at the level of the spinal cord
after peripheral nerve injury, Ca channel accessory subunits increase their expression in the dorsal horn and dorsal root ganglia
this subunit is involved in trafficking Ca channels |
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