PROSTAGLANDINS AND SENSITIZATIONS OF SENSORY NEURONS

Project: Research project

Description

Pro-inflammatory agents such as the prostaglandins (PG) are known to
sensitize sensory neurons to noxious stimulation, resulting in a
condition of heightened sensitivity known as hyperalgesia. At present,
we know very little about the cellular mechanisms whereby PGs modulate
the sensitivity and excitability of sensory neurons and the role PGs play
in regulating the intensity or duration of the neurogenic inflammatory
response. The studies outlined in this proposal are designed to
elucidate those physiological mechanisms and PG-induced alterations in
sensory transduction cascades that produce sensitization in sensory
neurons of the dorsal root ganglion. The proposed studies utilize isolated sensory neurons of the rat dorsal
root ganglion grown in cell culture. This model preparation permits
investigation of the cellular mechanisms giving rise to PG-induced
sensitization in the absence of potential modulating factors released by
other cell types. Thus, the direct actions of pro-inflammatory agents
to regulate neuronal excitability can be determined. The actions of PGs
and excitatory chemical agents, such as bradykinin and capsaicin, are
recorded electrophysiologically through utilization of whole-cell and
perforated-vesicle patch-clamp recording techniques. Bradykinin and
capsaicin are used to probe the levels of neuronal sensitization and thus
elucidate whether PC modulation occurs at the level of second messenger
mediated cascades or directly at the neuronal membrane. Initial studies
will establish a fundamental understanding of the electrophysiological
properties of the neuronal responses to bradykinin and capsaicin. This
cellular response forms the basic probe to examine the state of neuronal
sensitization. Subsequent studies, will further characterize the
essential parameters required to produce PG-induced sensitization, such
as PG concentration, type of PG, and the time course of PG action.
Finally, we will establish the role of PG activation of second messenger-
mediated transduction cascades in the physiological mechanisms regulating
excitability or sensitivity of the response in sensory neurons. These studies should provide a basic understanding of the cellular
mechanisms regulating sensory neuron excitability and the roles these
processes play in the initiation and maintenance of neurogenic
inflammation. This should also contribute to our understanding of
chronic or long-term modifications of neuronal activity such as in long-
term potentiation and facilitation. Ultimately, if we can isolate the
ionic conductance)s) and establish the regulatory mechanisms producing
this enhanced excitability, it will be possible to design drugs that
selectively block this conductance or the altered pathway and thus, curb
the pain and heightened sensitivity associated with chronic inflammatory
conditions, such as rheumatoid arthritis.
StatusFinished
Effective start/end date8/1/947/31/99

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $126,590.00
  • National Institutes of Health: $139,690.00

Fingerprint

Sensory Receptor Cells
Prostaglandins
Bradykinin
Capsaicin
Spinal Ganglia
Second Messenger Systems
Long-Term Potentiation
Drug Design
Hyperalgesia
Patch-Clamp Techniques
Rheumatoid Arthritis
Cell Culture Techniques
Maintenance
Neurogenic Inflammation
Pain
Membranes
Ganglia

ASJC

  • Medicine(all)
  • Neuroscience(all)