Withdrawal syndrome after the cessation of μ-
opioid receptor agonists remains an obstacle in the clinical treatment of
pain. There is limited information available on the mechanisms that underlie the expression of the withdrawal signs of
opioids, and especially regarding the involvement of μ-
opioid receptor subtypes and the location of the responsible
opioid receptors. Therefore, the present study was designed to determine the mechanism of the expression of withdrawal signs in μ-
opioid receptor agonist-dependent mice.
Morphine-,
oxycodone- and
fentanyl-dependent mice showed a marked loss of
body-weight and other signs of withdrawal after a
naloxone challenge. Interestingly, the phenotype of the withdrawal signs for
morphine and
oxycodone was different from that of
fentanyl. Furthermore, pretreatment with
naloxonazine (so-called μ1-
opioid receptor antagonist), did not significantly alter the withdrawal signs precipitated by
naloxone in these μ-
opioid receptor agonist-dependent mice, whereas the peripherally limited
opioid receptor antagonist naloxone methiodide significantly increased the loss of
body-weight accompanied by
diarrhea, indicating that a peripheral
naloxonazine-insensitive site for
opioid receptors, as an adaptation mechanism, plays an important role in the expression of at least the loss of
body-weight. On the other hand, i.c.v. treatment with
naloxone methiodide potently induced jumping behavior and trembling in
morphine-dependent mice. These results indicate that the prolonged activation of supraspinal μ-
opioid receptors plays a role in most of the physical dependence induced by μ-
opioid receptor agonists in mice. Thus, the
withdrawal symptoms observed after the cessation of μ-
opioid receptor agonists are distinctly regulated though supraspinal and peripheral
naloxonazine-insensitive sites of μ-
opioid receptors.