Pain Systems I: Nociceptors And Nociceptive Pathways
Pain is defined as an unpleasant sensory or
emotional experience associated
with actual or potential tissue damage. Much of what is known about pain
mechanisms has derived from animal-based research where the affective component
is unclear. For this reason neuroscientists prefer to use the term nociception,
which defines the processing of information about damaging stimuli up to the
point where perception occurs. This is an important distinction because tissue
damage is not inevitably linked to pain and vice versa.
Nociceptors
Nociceptors are found in the skin, visceral organs,
skeletal and cardiac muscle and in association with blood vessels. They conduct
information about noxious events to the dorsal horn of the spinal cord where
the primary afferents synapse.
There are basically two types of
nociceptor, distinguished by the diameter of the afferent fibre and the
stimulus required to activate it.
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The high-threshold
mechanoreceptor (HTM) is activated by intense mechanical stimulation and innervated by thinly myeli- nated
Aδ fibres conducting at 5–30 m/s.
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Polymodal
nociceptors (PMN)
respond to intense mechanical stimulation, temperatures in excess of about 42
°C and irritant chemicals. These receptors are innervated by unmyelinated C
fibres conducting at 0.5–2 m/s.
Sharply localized pain is thought
to be conducted in the faster conducting fibres whereas poorly localized pain
is conducted in the C fibres.
Although nociceptors are
histologically simple free nerve endings, the process of transduction at
the receptor ending is complex and is associated with some of the chemical mediators
of inflammation and tissue damage. Thus, adenosine triphosphate (ATP),
bradykinin, histamine and prostaglandins all either activate or sensitize the
receptor ending. Indeed, some of the transmitters in the nociceptive pathway
are themselves released peripherally (e.g. substance P) to produce
further sensitization of the receptor ending. Nociceptor receptor sensitization
helps explain the perception of heightened pain (primary hyperalgesia)
in areas of tissue damage and is essentially a peripheral phenomenon usually of
relatively short duration.
Chronic and referred pain
Pain that lasts many months is
known as chronic pain. It is often disabling and resistant to treatment. It may
arise following damage to either the peripheral or central nervous system or
chronic inflammatory states (e.g. osteoarthritis). Changes in peripheral
nociceptor sensitivity does not explain secondary hyperalgesia,
in which light touch outside the immediate area of cutaneous damage can lead to
pain.
A more serious problem associated
with peripheral or central nerve damage is allodynia. In this
condition light stroking of the skin can give rise to severe pain. Disturbed
patterns of sensory input to the dorsal horn (e.g. following compression or
sectioning of a peripheral nerve trunk) can lead to long-term changes in the
processing of noxious information in the dorsal horn. At these sites, the
arrival of axonally conducted substance P in the superficial layers of the
dorsal horn leads to both an increase in receptive field sizes and the
sensitivity of some dorsal horn neurones. These functional changes are mediated
in part by the synaptic release of glutamate acting on postsynaptic N-methyl-D-aspartate
(NMDA) receptors and may contribute to some chronic pain states.
In addition, allodynia and
secondary hyperalgesia are linked to increased activity in microglia and
astrocytes, and the release of a number of agents (interleukin-1 and -6, tumour
necrosis factor [TNF], nitric oxide [NO], ATP and prostaglandins).
Damage to peripheral nerve trunks
can lead to complex regional pain syndrome (CPRS).
One form is associated with disturbances to the sympathetic nervous system
(SNS) (CRPS-1, of which reflex sympathetic dystrophy is an example). Severing a
peripheral nerve trunk leads to the formation of a neuroma which acts as a
genera- tor of ectopic action potentials (ectopic foci) sending barrages of
action potentials to the spinal cord. This activity is thought to explain the
development of phantom limb pain with the neuroma being sensitive to both
mechanical stimulation and SNS activity (i.e. noradrenaline).
Visceral nociceptors project into
the spinal cord via the small-diameter myelinated and unmyelinated fibres of
the autonomic nervous system
(ANS), and synapse at the spinal level of their embryological origin. The development of pain in an internal organ can
therefore produce the perception of a painful stimulus in the skin rather than
the organ itself, at least in the early stages of inflammation – a phenomenon
known as referred pain. For example, inflammation of the appendix initially
leads to pain being perceived at the umbilicus.
Nociceptive pathways
The majority of nociceptors and thermos
receptors project into the spinal cord
via the dorsal root, although some pass through the ventral horn. On reaching
the spinal cord these sensory nerves synapse in a complex fashion in the dorsal
horn.
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The
postsynaptic cell conveying nociceptive information projects up the spinal cord
as the spinothalamic, spinoreticulothalamic and spinomesencephalic
tracts (latter not shown on figure), with the axons crossing at the spinal
level by passing around the central canal of the cord. This crossing of fibres
often occurs a few levels above where the nociceptive fibres enter the cord,
and thus damage in the region of the central canal as seen in syringomyelia
results in a loss of pain and temperature sensibility (see Chapter 54).
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The
postsynaptic cell and presynaptic nociceptive nerve terminal receive synapses
from other peripherally projecting somatosensory systems, descending
projections from the brainstem and interneurones intrinsic to the dorsal horn.
Many of these interneurones contain endogenous opioid substances known
as enkephalins and endorphins which activate opioid receptors of which there
are three main subtypes (μ, κ, δ). There is therefore enormous potential for
modifying the transfer of nociceptive information at the level of the dorsal
horn (see Chapter 33).
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The ascending
nociceptive pathways synapse in a number of different central nervous
system (CNS) sites. Information concerning noxious events ascends in either the
spinothalamic tract (providing accurate localization) or the
spinoreticulothalamic system (transmit- ting information concerning the
affective components of pain). However, some of the nuclei in the brainstem to
which these path- ways project (e.g. the raphé nucleus and locus coeruleus) in
turn send axons back down the spinal cord to the dorsal horn, and can be
exploited in the control of chronic pain syndromes (see Chapter 33).
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The
thalamic termination of the spinothalamic pathway is in the ventroposterior and
intralaminar nuclei (IL) (including the posterior group), which in turn project
to multiple cortical areas but especially the primary and secondary
somatosensory area (SmI and SmII) and the anterior cingulate cortex. Lesions to
any of these sites alter the perception of pain but do not produce a true and
complete loss of pain or analgesia, and indeed may even produce a chronic pain
syndrome. Such syndromes are not uncommonly seen with small thalamic
cerebrovascular accidents.
The thermoreceptors, and to a
lesser extent the nociceptors, also project to the hypothalamus, which has an
important role in thermoregulation and the autonomic response to a painful
stimulus (see Chapters 3 and 11).
