Kappa opioid receptors participate in nerve growth factor-induced hyperalgesia

It has recently been observed that nerve growth factor induces the rapid onset of thermal hyperalgesia, and the more delayed onset of mechanical hyperalgesia when administered to mature rats. Though several mechanisms 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 via activation of κ excitatory opioid receptors. The possible involvement of these excitatory opioid receptors in mediating the hyperalgesia was investigated. Nerve growth factor-induced thermal hyperalgesia in rodents was prevented by co-administration of the non-selective opiate antagonist naloxone, as well as by the κ-selective antagonist nor-binaltorphimine. Addition of the long-acting opioid antagonist, naltrexone, partially prevented mechanical hyperalgesia. Administration of low dose dynorphin to mice (a selective κ-receptor agonist) mimicked the hyperalgesic effects of nerve growth factor. Opiate antagonists and anti-nerve growth factor antibody both interfered with Freund's adjuvant-induced inflammatory hyperalgesia. Altogether, these observations 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 associated 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 neuropathy.