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and recovery (weeks 9-11)
[95]
. The preclinical stage of FCA arthritis (first week) is
characterized by discrete radiological lesions of the forepaws and a slight increase in
the threshold for struggle triggered by foot pressure, presumably due to an impend-
ing, initially painless, stiffness. The acute stage of arthritis (weeks 2-4) is defined by
signs of hyperalgesia, lack of mobility, and a pause in body weight gain; during the
acute period, hindpaw and forepaw joint diameters increase
[95]
. In the later, acute,
stages of disease (day 12), adjuvant arthritis rats are often relatively immobile due to
severity of paw swelling. At day 18th, an increase in scratching behavior and signs of
hyperalgesia are clearly established as compared with the adjuvant's vehicle-injected
group. FCA arthritis is induced most easily in inbred Lewis rats; it is also produced, to
a milder extent, in Wistar and Sprague-Dawley rats
[93,96-100]
.
Use of the adjuvant arthritis model offers an opportunity to study pathological
changes in a variety of tissues other than the joints
[53]
. Among these, CNS changes
are most relevant
[50-52]
. The major objective of our work during the last years has
been to examine several circadian correlates of both the preclinical and acute phases
of arthritis in rats.
6.4.1 Adjuvant Arthritis Disrupts Normal
Chronobiological Organization
We have examined a number of immune and neuroendocrine circadian rhythms in
FCA-injected rats by looking for changes in the preclinical phase of arthritis (2-3
days after FCA injection), as well as in the acute phase of the disease (18 days after
FCA injection) (
Tables 6.1-6.3
).
Generally, changes in circadian rhythms in lymph node immune function tended
to be more profound at the preclinical phase of the disease. For example, B-cell- and
T-cell-mediated mitogenic activity of LPS and concanavalin (Con A), respectively,
were modified in amplitude or acrophase during the preclinical phase
[101]
but exhib-
ited few or no changes during the acute phase of experimental arthritis
[102]
(
Table
6.1
). Similarly, 24-hour variations of B and T cells, as well as of CD4 (T helper) and
CD8 (T cytolytic) cells, became significantly changed during the preclinical phase
[101,103]
but showed an absence of changes during the acute phase
[102]
. In the case
of lymph node cell proliferation and local autonomic nerve activity, the increase in
amplitude and mesor of rhythms found in the preclinical phase of arthritis was higher
than that observed as the disease progressed
[104]
. Therefore, the results suggest that
some sort of homeostatic compensation for initial changes in circadian rhythmicity of
immune changes occurs with the development of arthritis (
Table 6.1
).
Regarding changes in neuroendocrine rhythmicity during rat arthritis, early data
from FCA-injected rats had indicated that the 24-hour organization of the biologic
responses was altered. For example, morning-evening differences in circulating
ACTH and corticosterone disappeared by days 7-21, and between days 6 and 8 after
FCA injection a loss of the adrenocortical omithine decarboxylase (ODC) circadian
rhythm of activity was found
[105]
. In our own studies conducted during the preclini-
cal phase of arthritis, we found a significant effect of immune-mediated inflammatory
response on diurnal rhythmicity of circulating ACTH, GH, prolactin, and thyrotropin
