Civil Engineering Reference
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periphery. The release of prostaglandin E2, which occurs in response to the upregulation of the enzyme
causes a shift in the peripheral terminal of the nociceptor lowering its threshold and increasing its
excitability.
Likewise, there are also a host of other inflammatory-related mediators, which also have direct and
indirect effects on pain and nociception. Serotonin (5HT) is elevated in inflammation. It is released
from platelets downstream from mast cell degranulation, as occurs during inflammatory responses. Ser-
totonin can cause pain by locally activating primary afferents and can further enhance sensitivity of
sensory responses to bradykinin. Also, leukotriene B4 is a neutrophil attractant that can directly sensitize
afferents. Certainly, each of these mediators has a complicated mechanism of action far more compli-
cated than has been reviewed here.
Substance P is a potent pro-nociceptive neurotransmitter, which is transported to the periphery after
afferent activation. It has inflammatory effects by causing vasodilation and release of prostaglandin E2
and cytokines. These protein releases further impact the local responses of inflammation as well as
nociception. Substance P can cause a release of calcium from intracellular stores and in turn lead to
NO production and neuronal excitability and long-term sensitization.
34,36
Substance P is also shown
to have a role in pain in the CNS. Also contributing to sensitization, CGRP, a neuropeptide often
colocalized with substance P in the spinal cord, regulates nociceptive responses by further promoting
the release of substance P as well as glutamate from primary afferents and retarding the metabolism
of substance P.
1,35
Antibodies to substance P and CGRP have been demonstrated to attenuate pain symp-
toms in inflammatory models of carageenan-induced hyperalgesia and painful nerve injury.
34,46
These
results strongly implicate both neuropeptides in the transmission of pain. Additionally, application of
antagonists to the substance P receptor, NK-1, has induced antinociception in the CNS after chronic
nerve constriction,
35
as well as globally in rodent models of inflammatory arthritis.
28
However,
despite research indicating the potent role of substance P and CGRP in many types of pain, little is
known about the relative contributions of these neuropeptides to the onset or maintenance of pain
symptoms, either in persistent or resolving pain.
Excitatory amino acids, such as glutamate, have potent roles in pain, both locally at the site of injury
and in the CNS. Indeed, glutamate is produced by both non-neuronal and neuronal cells in the peri-
phery. Both of these sources act on primary afferents by activating them when bound to any of the
NMDA, kainite, AMPA or metabotropic glutamate receptors.
55
Certainly, this positive feedback mech-
anism of nociceptor excitation leads to peripheral sensitization and correspondingly to altered afferent
signaling into the spinal cord. Glutamate receptors are expressed in dorsal root ganglion cells,
46
suggesting its direct involvement in afferent signaling to the cord. As the NMDA glutamate receptor
has a key role in regulating synaptic efficacy, there is also a direct role of this receptor in the plasticity
changes, which occur in the spinal cord associated with central sensitization changes of persistent pain.
Cytokines can directly or indirectly regulate cascades that can lead to the transmission and modulation
of pain. The broad collection of cytokines includes both pro-inflammatory and anti inflammatory pro-
teins, both of which are upregulated in painful injuries.
10,11,25,56,57
In particular, in models of neural
injury either distal (peripheral injury) or proximal (nerve root injury) to the DRG, spinal IL-1b, IL-6,
IL-10 and TNF mRNA are all significantly elevated.
61
However, not all of these factors are pro-
inflammatory. In fact, IL-10 has been shown to suppress NO production in cultured astrocytes and
also suppress proliferation in macrophages,
66
providing an anti-inflammatory mechanism. Additionally,
the presence of cytokines often stimulates a positive feedback loop as demonstrated in the case of IL-1,
which can stimulate its own production.
56
Cytokines mediate cellular processes through the production
or suppression of NO. NO has an immunoregluatory role in the CNS. Its production leads directly to the
hyperalgesic NMDA pathway as discussed earlier. Cytokines regulate NO by interfering with the
production of NOS (nitric oxide synthase). Of the two main forms of NOS, inducible and constitutive,
astrocytes can produce both types, whereas microglia are only responsible for inducible NOS.
66
TNF-a
and IL-1bcontrol the stimulation of the production of iNOS in both astrocytes and glia therefore indu-
cing the production of NO from those cell types. Alternatively, TGF-bsuppresses NO production in both
astrocytes and microglia, whereas IL-10 only affects NO production in astrocytes.
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