Stress 181quickly transmit sharp pain signals. In contrast, C-“bers are
not myelinated. Thus, their signals are sent more slowly than
the A-delta “bers, and transmit dull and aching pain signals.
When either the A-delta or C-“bers are activated and synapse
at the spinal cord, substance P is released, which in turn stim-
ulates the ascending nerve to send the pain signal to the brain
(Figure 8.2). Thus, substance P appears to be crucial to the
transmission of pain signals from the peripheral nervous
system to the CNS. After the signal ascends, it may take at least
two different pathways. The acute pain pathway synapses in
the somatosensory cortex directly via the thalamus. Another,
less direct pathway is to “rst pass through synaptic connec-
tions in the brain stem, thalamus, hypothalamus, and other
limbic structures before synapsing at the thalamus. The latter
pathway, which is associated with more chronic forms of
pain, is noteworthy because it travels through the so-called
emotion-centered (limbic) parts of the brain. Thus, indirect
processing via the limbic structures provides a physiological
substrate to the affective components of pain.
Pain signals are also regulated by descending pathways.
The brain has evolved to release several neurotransmitters to
inhibit pain perception. Among these transmitters are en-
dogenous opioids and serotonin. Endogenous opioids such as
beta-endorphins are characterized by pain-relieving proper-
ties. Endogenous opioids are also intrinsically related to the
HPA axis, as CRH stimulates their release. Like endogenous
opioids, serotonin, a neurotransmitter also involved in
mood regulation, serves to close the pain gate (Basbaum &
Fields, 1984).
The example just described illustrates how tissue injury
such as in RA and OA causes pain perception. However, what
about conditions like FM in which there is no discernable tis-
sue damage yet considerable perceived pain? Melzack and
Wall (1965) proposed an explanation for that scenario as
well. They observed the •wind-upŽ phenomenon in which
repetitive stimulation of nociceptive “bers resulted in greater
stimulation of the dorsal horn neurons (Melzack & Wall,
1965; cited in Bennett, 1999). Over time, these dorsal horn
neurons require less and less actual stimulation to become ac-
tivated. Eventually, nonnociceptive sensory stimuli can acti-
vate the nociceptive neurons of the dorsal horn, creating pain
impulses (Kramis, Roberts, & Gillette, 1996). One of the
neuropeptides that mediates this process is substance P
(Clauw & Chrousos, 1997). The production of pain sensation
from nonnociceptive stimuli is referred to as allodynia,and
the process that produces allodynia is called central sensiti-
zation(Bennett, 1999). Bennett refers to central sensitiza-
tion process as •an increased excitability of spinal and
supraspinal neural circuits.Ž Thus, with the central sensitiza-
tion process, not only does nonnociceptive stimuli produce
pain sensations, but the total area of the body initially con-
sidered painful widens. Central sensitization may explain
why regional pain syndromes often become widespread. An-
other quality of central sensitization relevant to arthritis and
musculoskeletal conditions is that central sensitization is
more likely to occur in muscle “bers than in skin “bers
(Wall & Woolf, 1984). Thus, individuals with musculoskele-
tal pain are at an increased risk for the sequelae of central
sensitization.
The stress response is intrinsically linked to nociception.
What is particularly noteworthy about the descending path-
way in the context of this chapter is that the transmitters
involved are stimulated by acute stress. Stress-induced anal-
gesia occurs when the release of these transmitters, particu-
larly the endogenous opioids, inhibits pain perception (Fields
& Basbaum, 1994; Lewis, Terman, Sharit, Nelson, &
Liebeskind, 1984). Acute stress also stimulates the release of
other substances, such as serotonin, NE, and CRH (Clauw &
Chrousos, 1997). Likewise, release of beta endorphin during
acute stress may suppress immune responses and therefore
pain (Akil et al., 1984). Under acutely stressful experiences,
these substances serve to close the pain gate.
Other nociceptive substances besides substance P can
serve to open the pain gate. For instance, bradykinin is a sub-
stance that produces pain by stimulating production of hista-
mine and prostaglandins and exciting nociceptive neurons
(Marieb, 1993). Furthermore, disease processes associated
with in”ammation can open the pain gate. For instance, Il-6,
which is released during in”ammation, is also intrinsically
involved in nocioception (Arruda, Colburn, Rickman,
Rutkowski, & DeLeo, 1998).
There are several reasons why the CNS has been hypothe-
sized to play a role in RA disease activity. First, the wide-
spread symmetric pattern of joint in”ammation and the
proximal joint involvement suggests that a CNS abnormality
may underlie RA disease activity. There is evidence to sup-
port this observation. First, patients with RA who have suf-
fered paralysis no longer experience RA disease activity on
the paralyzed side (Glick, 1967). There is also evidence that
substance P may play a role in RA disease activity. For in-
stance, substance P stimulates lymphocyte proliferation and
other in”ammatory responses (Felten, Felten, Bellinger, &
Lorton, 1992). Also, results of one study suggest a positive
correlation between substance P “ ber innervation and arthri-
tis in”ammation (Levine, Coberre, Helms, & Basbaum,
1988). These observations indicate that the CNS is involved
in RA ”are-ups.
CNS involvement may also in”uence OA. For instance,
the common transition from localized to the widespread pain
that occurs in many individuals with OA may re”ect a central