CONTRIBUTION OF SACRAL SPINAL-CORD NEURONS TO THE AUTONOMIC AND SOMATIC CONSEQUENCES OF WITHDRAWAL FROM MORPHINE IN THE RAT

In this study, we monitored Fos-like immunoreactivity in the sacral sp inal cord to identify neurons that are likely to contribute to the aut onomic manifestations of opioid antagonist-precipitated withdrawal in morphine-tolerant rats. Injection of systemic antagonist increased the Fos-like immunoreactivity throughout the first sacral segment, partic ularly in laminae I/II, X, and in the sacral parasympathetic nucleus ( SPN). Selective peripheral withdrawal, with a hydrophilic antagonist t hat does not cross the blood-brain barrier (BBB), induced diarrhea, bu t no other withdrawal signs were evident. Compared to rats that withdr ew systemically, peripheral withdrawal evoked significantly less Fos-l ike immunoreactivity in laminae V/VI, X and the SPN. By contrast, sele ctive spinal withdrawal, by intrathecal injection of an opioid antagon ist that does not cross the BBB, provoked hyperactivity of the hindlim bs and tail, but no diarrhea. These animals demonstrated significantly increased Fos-like immunoreactivity in laminae I/II, V/VI, the SPN, a nd the ventral horn compared to rats that withdrew systemically. Anima ls treated neonatally with capsaicin, to eliminate C-fiber input, demo nstrated withdrawal behavior similar to intact withdrawing rats, excep t that the capsaicin-pretreated rats had significantly greater weight loss. However, this group had less Fos-like immunoreactivity in lamina e V/VI, X and the SPN compared to the intact withdrawing rats. These d ata suggest that withdrawal from morphine evokes hyperactivity of sacr al neurons, particularly those involved in regions that process nocice ptive and autonomic information. Peripheral withdrawal is sufficient t o induce diarrhea, but it does not fully explain the associated weight loss. Unmyelinated primary afferents may contribute a tonic periphera l inhibition of circuits that regulate gut motility and intestinal flu id transport. Taken together, these data suggest that chronic exposure to opioids induces a latent sensitization in sacral cord neurons that can be manifested as neuronal hyperactivity during withdrawal; this m echanism may underlie withdrawal-induced hyperalgesia and gut hypermot ility.