Possible
Role of NGF in the Etiology of Fibromyalgia
Alice
A. Larson, Ph.D.
Fibromyalgia syndrome
(FMS) is characterized by a 3-fold increase in the concentration of substance
P (SP) in the cerebrospinal fluid (CSF). This increase may result from
enhanced release during pain, contributing to the hyperalgesia that is
characteristic of FMS. The expression of SP in primary afferent neurons
is influenced by nerve growth factor (NGF), a neurotrophic factor that
induces hyperalgesia. NGF has been previously found to be elevated in
the synovial fluid and circulation of patients with arthritis. Because
FMS is not associated with inflammation, we tested the hypothesis that
an elevated concentration of NGF in the spinal cord plays a role in the
etiology of FMS. We measured CSF concentrations of NGF using a two-site
enzyme immunoassay and found an increased concentration of NGF in the
CSF of patients diagnosed with FMS. These data suggest that hyperalgesia
may be precipitated by elevated NGF activity.
Where
NGF induces hyperalgesia by increasing SP activity along nociceptive afferent
pathways is unknown as SP is only one of the many proteins whose synthesis
is regulated by NGF. Also increased are metallopeptidases that metabolize
SP. In light of an enhanced synthesis of both SP and its metabolizing
enzyme in response to NGF, N-terminal metabolites of SP would be expected
to accumulate in the CSF of patients with FMS. Although SP is thought
to mediate pain, N-terminal metabolites of SP induce a long-term antinociception
when injected into the spinal cord of mice. To determine the impact of
elevated concentrations of both SP N-terminal fragments and NGF on pain
transmission, we evaluated their effects alone, as well as when injected
together on pain responses in mice.
Pain
was assessed using the abdominal stretch (writhing) assay for chemical
pain and the tail flick assay for thermal pain. The average tail flick
latency of mice was significantly decreased for 1 to 2 days after injection
of NGF, indicating hyperalgesia, while abdominal stretch responses were
not affected. In contract, SP(1-7) was antinociceptive in the abdominal
stretch assay, but has no effect on thermal responses. When SP(1-7) was
administered together with a fixed dose of NGF, SP(1-7) inhibited the
hyperalgesic effect of NGF in a dose-related fashion. The D-isomer of
SP(1-7) had no such effect but reversed that of SP(1-7) on NGF-induced
hyperalgesia. Administration of NGF to mice together with a fixed dose
of SP(1-7) also prevented the antinociceptive effect of SP(1-7) on writhing
behaviors.
Together these data suggest an important
interaction between NGF and SP N-terminal activity in pain transmission.
N-terminal metabolites of SP appear to feed back, antagonizing the action
of NGF whereas increasing concentrations of NGF, such as those in patients
with FMS, prevent the antinociceptive effective of SP metabolites. This
mutual antagonism may be important in the regulation of pain in FMS.
Presented at the National Fibromyalgia
Research Association's New Dimensions in Fibromyalgia Symposium,
September 14-15, 1997, in Portland, Oregon.
