Low-dose
naloxone-precipitated withdrawal
hyperalgesia is a reliable
indicator of physical dependence after chronic
morphine treatment. A remarkably similar long-lasting (>3-4 h)
hyperalgesia is evoked by injection of a low dose of
naloxone (10 microg/kg, s.c.) in naïve mice after acute pretreatment with the
glycolipid,
GM1 ganglioside (1 mg/kg) (measured by warm-water-immersion tail-flick assays). GM1 treatment markedly increases the efficacy of excitatory Gs-coupled
opioid receptor signaling in nociceptive neurons. Co-treatment with an ultra-low-dose (0.1 ng/kg, s.c.) of the broad-spectrum
opioid receptor antagonist,
naltrexone or the selective
kappa opioid receptor antagonist,
nor-binaltorphimine, blocks
naloxone-evoked
hyperalgesia in GM1-pretreated naïve mice and unmasks prominent, long-lasting (>4 h) inhibitory
opioid receptor-mediated
analgesia. This unmasked
analgesia can be rapidly blocked by injection after 1-2 h of a high dose of
naltrexone (10 mg/kg) or
nor-binaltorphimine (0.1 mg/kg). Because no exogenous
opioid is administered to GM1-treated mice, we suggest that
naloxone may evoke
hyperalgesia by inducing release of endogenous bimodally acting
opioid agonists from neurons in nociceptive networks by antagonizing putative presynaptic inhibitory
opioid autoreceptors that "gate" the release of endogenous
opioids. In the absence of exogenous
opioids, the specific pharmacological manipulations utilized in our tail-flick assays on GM1-treated mice provide a novel bioassay to detect the release of endogenous bimodally acting (excitatory/inhibitory)
opioid agonists. Because mu excitatory
opioid receptor signaling is blocked by ultra-low doses of
naloxone, the higher doses of
naloxone that evoke
hyperalgesia in GM1-treated mice cannot be mediated by activation of
mu opioid receptors. Co-treatment with ultra-low-dose
naltrexone or
nor-binaltorphimine may selectively block signaling by endogenous GM1-sensitized excitatory
kappa opioid receptors, unmasking inhibitory
kappa opioid receptor signaling, and converting endogenous
opioid receptor-mediated
hyperalgesia to
analgesia. Co-treatment with
kelatorphan stabilizes putative endogenous
opioid peptide agonists released by
naloxone in GM1-treated mice, so that
analgesia is evoked rather than
hyperalgesia. Acute treatment of chronic
morphine-dependent mice with ultra-low-dose
naltrexone (0.1 ng/kg) results in remarkably similar rapid blocking of
naloxone (10 microg/kg)-precipitated withdrawal
hyperalgesia and unmasking of prominent
opioid analgesia. These studies may clarify complex mechanisms underlying
opioid physical dependence and
opioid addiction.