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Journal of Neuroscience, Vol 15, 165-172, Copyright © 1995 by Society for Neuroscience
Perineurial defect and peripheral opioid analgesia in inflammation
I Antonijevic, SA Mousa, M Schafer and C Stein
Department of Neurobiology, AFRC Barbraham Institute, Cambridge, United Kingdom.
Opioid receptors have been demonstrated on sensory nerves in both inflamed
and normal subcutaneous tissue but locally applied opioid agonists produce
analgesia in inflamed tissue only. Inflammation confers a disruption of the
perineurial barrier that can also be induced deliberately by hyperosmolar
solutions. The present study examines at which stage of Freund's
adjuvant-induced inflammation peripheral opioid analgesic effects become
manifest and whether a perineurial defect contributes to the appearance of
such effects. To this end we have monitored the temporal evolution of
inflammatory signs (swelling, temperature, hyperalgesia) and of peripheral
antinociceptive effects (by the paw pressure test) of mu-, delta-, and
kappa-selective opioids. Using horseradish peroxidase histochemistry, the
perineurial barrier was assessed in normal and inflamed tissue and
following its artificial disruption by hyperosmolar saline and mannitol in
vivo. Finally, we sought to elicit analgesia in normal tissue by the
concomitant application of mannitol and receptor-selective opioids or by an
extremely lipophilic opioid agonist (fentanyl). We found that peripheral
opioid antinociception and perineurial leakage occur simultaneously at a
very early stage (within 12 hr) of the inflammatory reaction and that both
can be mimicked by the administration of hyperosmolar solutions in normal
tissue. Fentanyl produced peripheral antinociception in noninflamed tissue
that was potentiated by mannitol or inflammation. Our findings demonstrate
that the perineurium is a crucial determinant for peripheral opioid
analgesia and that the efficacy of locally applied hydrophilic or
lipophilic neuromodulatory compounds can be improved dramatically by the
concomitant modulation of perineurial permeability.(ABSTRACT TRUNCATED AT
250 WORDS)
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