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Nervous System
respond to all three types of stimuli (mechanical, thermal,
and chemical). Mechanical stimuli can arise from intense
pressure applied to skin or from the violent contraction
or extreme stretch of a muscle. Extremes of both heat and
cold can stimulate nociceptors. Chemical stimuli arise
from a number of sources, including chemical mediators
released from injured and inflamed tissues. These chemi-
cal mediators produce their effects by directly stimulating
nociceptors or sensitizing them to the effects of nocicep-
tive stimuli; perpetuating the inflammatory responses
that lead to the release of chemical agents that act as
nociceptive stimuli; or inciting neurogenic reflexes that
increase the response to nociceptive stimuli. For example,
bradykinin, histamine, serotonin, and potassium activate
and also sensitize nociceptors, resulting in the lowering
of the activation threshold. This in turn results in a trans-
mission of afferent signals to the dorsal horn and causes
neurogenic inflammation.
8
Other chemical mediators act
alone or in concert to sensitize nociceptors through other
chemical agents such as prostaglandins. Aspirin and
other nonsteroidal anti-inflammatory drugs (NSAIDs)
are effective in controlling pain because they block the
enzyme needed for prostaglandin synthesis.
Peripheral Pain Fibers.
Two types of afferent fibers
transmit pain signals from the free nerve endings into
the CNS: myelinated A
δ
fibers and unmyelinated C
fibers.
1,2
The larger A
δ
fibers have considerably greater
conduction velocities, transmitting impulses at a rate of
10 to 30 m/second. The C fibers are the smallest of all
peripheral nerve fibers; they transmit impulses at the
rate of 0.5 to 2.5 m/second. Pain conducted by A
δ
fibers
traditionally is called
fast pain
or first pain and typi-
cally is elicited by mechanical or thermal stimuli. C-fiber
pain often is described as
slow-wave pain
or second pain
because it is slower in onset and longer in duration, con-
tinuing to elicit pain for up to 80 hours.
9
It typically is
incited by chemical stimuli or by persistent mechanical
or thermal stimuli. The slow postexcitatory impulses
generated in C fibers are now believed to be responsible
for central sensitization to chronic pain.
Nociceptive stimulation that activates C fibers can
cause a response known as
neurogenic inflammation
that produces vasodilation and an increased release of
chemical mediators to which nociceptors respond. This
inflammatory process results in vasodilation and the
leakage of proteins and fluids into the extracellular space
around the terminal end of the nociceptor. As a result,
there is increased activity of immune cells, which further
contributes to the inflammatory process.
8
This mecha-
nism is thought to be mediated by a dorsal root neuron
reflex that produces retrograde transport and release
of chemical mediators, which in turn causes increasing
inflammation of peripheral tissues. This reflex can set
up a vicious cycle, which has implications for persistent
pain and hyperalgesia (excessive sensitivity to pain), a
condition in which the second-order neurons are overly
sensitive to low levels of noxious stimulation.
The transmission of impulses between the periph-
eral nociceptive neurons and dorsal horn neurons in the
spinal cord is mediated by neurotransmitters released
from nerve endings of the nociceptive neurons.
10
Some of
these neurotransmitters are amino acids (e.g., glutamate),
others are amino acid derivatives (e.g., norepinephrine),
and still others are low–molecular-weight peptides com-
posed of two or more amino acids. The amino acid glu-
tamate is a major excitatory neurotransmitter released
from the central nerve endings of the nociceptive neu-
rons. Substance P, a neuropeptide, also is released in
the dorsal horn by C fibers in response to nociceptive
stimulation. Substance P elicits slow excitatory poten-
tials in dorsal horn neurons. Unlike glutamate, which
confines its action to the immediate area of the synaptic
terminal, some neuropeptides released in the dorsal horn
can diffuse some distance because they are inactivated
by reuptake mechanisms. This may help to explain the
excitability and unlocalized nature of many persistently
painful conditions. Neuropeptides such as substance P
also appear to prolong and enhance the action of glu-
tamate. If these neurotransmitters are released in large
quantities or over extended periods, they can lead to
secondary hyperalgesia.
Spinal Cord Circuitry and Ascending
Pathways
On entering the spinal cord through the dorsal roots,
the pain fibers bifurcate and ascend or descend one or
two segments before synapsing with association neurons
in the dorsal horn. From the dorsal horn, the axons of
association projection neurons cross through the ante-
rior commissure to the opposite side and then ascend
upward in the previously described neospinothalamic
and anterolateral pathways (Fig. 35-8).
The faster-conducting fibers in the neospinotha-
lamic tract are associated mainly with the transmission
of sharp–fast pain information to the thalamus. In the
thalamus, synapses are made and the pathway continues
to the contralateral parietal somatosensory area to pro-
vide the precise location of the pain. Typically, the pain
is experienced as bright, sharp, or stabbing in nature.
The paleospinothalamic tract is a slower-conducting,
multisynaptic tract concerned with the diffuse, dull,
aching, and unpleasant sensations that commonly are
associated with chronic and visceral pain. Fibers of this
system also travel up the contralateral (i.e., opposite)
anterolateral pathway to terminate in several thalamic
regions, including the intralateral nuclei, which project
to the limbic system. These projections are associated
with the emotional or affective–motivational aspects of
pain. Spinoreticular fibers from this pathway project
bilaterally to the reticular formation of the brain stem.
This component of the paleospinothalamic system facili-
tates avoidance reflexes at all levels. It also contributes
to elevated levels of alertness and increased heart rate
and blood pressure that can occur with pain.
Brain Centers and Pain Perception
Information from tissue injury is carried from the spinal
cord to brain centers in the thalamus where the basic sen-
sation of hurtfulness, or pain, occurs (see Fig. 35-8). In the
neospinothalamic system, interconnections between the
