It has recently been observed that nerve growth factor induces the rap
id onset of thermal hyperalgesia, and the more delayed onset of mechan
ical hyperalgesia when administered to mature rats. Though several mec
hanisms have been proposed to explain this phenomenon, it is still not
well understood. Previous studies have shown that nerve growth factor
can directly excite nociceptive sensory ganglion neurons in culture v
ia activation of kappa excitatory opioid receptors. The possible invol
vement of these excitatory opioid receptors in mediating the hyperalge
sia was investigated. Nerve growth factor-induced thermal hyperalgesia
in rodents was prevented by co-administration of the non-selective op
iate antagonist naloxone, as well as by the kappa-selective antagonist
nor-binaltorphimine. Addition of the long-acting opioid antagonist, n
altrexone, partially prevented mechanical hyperalgesia. Administration
of low dose dynorphin to mice (a selective kappa-receptor agonist) mi
micked the hyperalgesic effects of nerve growth factor. Opiate antagon
ists and anti-nerve growth factor antibody both interfered with Freund
's adjuvant-induced inflammatory hyperalgesia. Altogether, these obser
vations suggest that activation of excitatory opioid receptors plays a
role in mediating nerve growth factor-induced hyperalgesia and that,
in turn, nerve growth factor contributes to the hyperalgesia associate
d with inflammatory states. Since opioid receptor antagonists are well
tolerated clinically, they may be useful for patients receiving nerve
growth factor as part of ongoing trials of the factor in peripheral n
europathy.