Jj. Buccafusco et al., SPINAL NMDA RECEPTOR - NITRIC-OXIDE MEDIATION OF THE EXPRESSION OF MORPHINE-WITHDRAWAL SYMPTOMS IN THE RAT, Brain research, 679(2), 1995, pp. 189-199
Previous studies in this laboratory have demonstrated that cholinergic
receptors within the spinal cord play an important role in the expres
sion of naloxone-precipitated withdrawal symptoms in the morphine-depe
ndent rat. Related cardiovascular studies in non-dependent animals hav
e demonstrated that this spinal cholinergic system is linked to a glut
amatergic, NMDA presser pathway which also involves the participation
of a nitric oxide (NO) generating system. The purpose of this study wa
s to determine whether spinal NMDA receptors and/or NO are involved in
the expression of morphine withdrawal symptoms. Rats bearing previous
ly implanted intrathecal (IT) catheters were dependent on morphine fol
lowing chronic i.a. infusion of increasing doses over 5 days. Naloxone
(0.5 mg/kg) was administered via the i.a. line to precipitate withdra
wal; and both cardiovascular and behavioral symptoms were recorded ove
r 60 min. Pretreatment 20 min before naloxone with IT injection of eit
her of the NMDA receptor antagonists, MK-801 or AP-7 (100-200 nmol), p
roduced a significant reduction in the expression of both the cardiova
scular and behavioral symptoms of up to about 60%. IT pretreatment wit
h the NO synthase inhibitor L-NAME - a methyl ester derivative of L-ar
ginine, also produced a dose-dependent, L-arginine reversible inhibiti
on of the cardiovascular (mainly the presser) component of withdrawal,
but had no significant effect on the expression of behavioral signs.
In contrast, IT pretreatment with L-NOARG and L-NMMA, non-ester analog
s of L-arginine, significantly inhibited the expression of the behavio
ral signs of withdrawal but did not alter the presser component. A com
bined pretreatment with L-NAME and L-NOARG resulted in suppression of
both presser and behavioral components of withdrawal. The anti-withdra
wal actions of either class of NO synthase inhibitor could not be attr
ibuted to blockade of local muscarinic receptors. These findings are c
onsistent with a role for both spinal NMDA receptors and a NO generati
ng system in the expression of both the behavioral and autonomic compo
nents of naloxone-precipitated withdrawal. They also suggest that diff
erent structural analogs of L-arginine have different profiles of acti
vity in this regard - opening the possibility that different isozymes
of NO synthase located within the same spinal region mediate different
physiological or behavioral functions.