SPINAL-CORD MECHANISMS OF OPIOID TOLERANCE AND DEPENDENCE - FOS-LIKE IMMUNOREACTIVITY EXPRESSION INCREASES IN SUBPOPULATIONS OF SPINAL-CORDNEURONS DURING WITHDRAWAL
Ds. Rohde et al., SPINAL-CORD MECHANISMS OF OPIOID TOLERANCE AND DEPENDENCE - FOS-LIKE IMMUNOREACTIVITY EXPRESSION INCREASES IN SUBPOPULATIONS OF SPINAL-CORDNEURONS DURING WITHDRAWAL, Neuroscience, 72(1), 1996, pp. 233-242
Tolerance to the analgesic effects of morphine results in part from th
e development of a compensatory response in neurons that express the o
pioid receptor or of neural circuits in which those neurons participat
e. According to this Formulation, withdrawal from morphine results in
an overshoot of several neuronal properties because of the unopposed a
ction of the compensatory response system. To identify the population
of spinal cord neurons that underlies this state, we monitored express
ion of Fos-like immunoreactivity, after naltrexone-precipitated abstin
ence in normal and morphine-tolerant rats. After daily (five days) imp
lantation of morphine or placebo pellets, the rats received an injecti
on of saline or naltrexone and behavior was monitored for 1 h. The rat
s were then killed, their spinal cords removed and 50-mu m transverse
sections of the lumbar cord were immunostained with a rabbit polyclona
l antiserum directed against Fos. Naltrexone injection in the placebo
group did not increase spinal cord Fos expression. Naltrexone-precipit
ated abstinence resulted in an increase in Fos expression at all level
s of the spinal cord; the greatest increase and densest staining was i
n laminae I through VI. Importantly, when withdrawal was precipitated
in anesthetized rats, we recorded a significant reduction in Fos expre
ssion, particularly in laminae III through VI, but there was persisten
t expression in the superficial dorsal horn, particularly in lamina I.
These results suggest that spinal cord nociresponsive neurons are sen
sitized during the development of tolerance. This sensitization is unm
asked by the administration of naltrexone and is manifested by fos ind
uction in laminae I/II in awake or anesthetized withdrawing animals. T
he underlying mechanisms of tolerance development may be similar to th
ose that underlie injury-induced central sensitization and hyperalgesi
a.