Previous studies have demonstrated a role for adenosine in mediating o
piate effects. Adenosine receptors and their functions have been shown
to be regulated by chronic opiate treatment. This study examines the
role of adenosine receptors in the expression opiate withdrawal behavi
ors. The effects of single doses of parenterally administered adenosin
e receptor subtype-selective agonists and antagonists on opiate withdr
awal signs in morphine-dependent mice were measured. Mice received sub
cutaneous morphine pellet treatment for 72 h and then underwent naloxo
ne-precipitated withdrawal after pretreatment with adenosinergic agent
s. Adenosine agonists attenuated different opiate withdrawal signs. Th
e A(1) agonist R-N-6(phenylisopropyl)adenosine (0, 0.01, 0.02 mg/kg, I
P) significantly reduced wet dog shakes and withdrawal diarrhea, while
the A(2a)-selective agonist 2-p-(2-carboxethyl) phenylethylamino-5'-N
-ethylcarboxamidoadenosine or CGS 21680 (0, 0.01, 0.05 mg/kg, IF) sign
ificantly inhibited teeth chattering and forepaw treads. Adenosine rec
eptor antagonists enhanced different opiate withdrawal signs. The aden
osine A(1) antagonist 1,3-dipropyl-8-cyclopentylxanthine (0, 1, 10 mg/
kg, IP) significantly increased weight loss and the A(2) antagonist, 3
,7-dimethyl-1-propargylxanthine (0, 1 and 10 mg/kg, IP) enhanced wet d
og shakes and withdrawal diarrhea. Treatment effects of adenosinergic
agents were not due to nonspecific motor effects, as demonstrated by a
ctivity monitoring studies. These results support a role for adenosine
receptors in the expression of opiate withdrawal and suggest the pote
ntial utility of adenosine agonists in its treatment.