Ds. Rohde et al., CONTRIBUTION OF SACRAL SPINAL-CORD NEURONS TO THE AUTONOMIC AND SOMATIC CONSEQUENCES OF WITHDRAWAL FROM MORPHINE IN THE RAT, Brain research, 745(1-2), 1997, pp. 83-95
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.