The aim of this study was to investigate the neuroanatomical regions implicated in the expression of the physical signs of
morphine withdrawal by using local intracerebral
injections of
methylnaloxonium in dependent rats. Guide cannulas were implanted and aimed at the lateral ventricle, nucleus accumbens, central amygdala, anterior hypothalamus, medial thalamus, periaqueductal gray matter, locus coeruleus and nucleus raphe magnus. After surgery, rats were made physically dependent by s.c. implantation of two 75-mg
morphine pellets.
Methylnaloxonium, a quaternary derivative of
naloxone (31-1000 ng), was administered 72 hr after pellet implantation.
Methylnaloxonium administered i.c.v. induced a withdrawal syndrome similar to systemic
naloxone, although several signs such as
diarrhea, salivation, lacrimation and
rhinorrhea did not appear, suggesting possible peripheral mediation. The most sensitive site for
methylnaloxonium-precipitated withdrawal was the locus coeruleus. Signs such as jumping, rearing and locomotor activity were particularly frequent after
methylnaloxonium injections into the locus coeruleus. Rearing and locomotor activity were also strongly increased after
methylnaloxonium administration into the periaqueductal gray matter. Wet dog shakes were mainly observed after
methylnaloxonium administration into the anterior preoptic hypothalamus and nucleus raphe magnus.
Injections of
methylnaloxonium into the amygdala produced a weak withdrawal syndrome, and the nucleus accumbens and medial thalamus were the least sensitive structures. These results suggest that the locus coeruleus, and secondarily the periaqueductal gray matter, play an important role in the precipitation of the physical signs of
opiate withdrawal, mainly in the expression of its motor component. The expression of other signs of withdrawal appear to be multisite determined.