CHARACTERIZATION OF ANTINOCICEPTION TO OPIOID RECEPTOR-SELECTIVE AGONISTS AFTER ANTISENSE OLIGODEOXYNUCLEOTIDE-MEDIATED KNOCK-DOWN OF OPIOID RECEPTORS IN-VIVO
Ej. Bilsky et al., CHARACTERIZATION OF ANTINOCICEPTION TO OPIOID RECEPTOR-SELECTIVE AGONISTS AFTER ANTISENSE OLIGODEOXYNUCLEOTIDE-MEDIATED KNOCK-DOWN OF OPIOID RECEPTORS IN-VIVO, The Journal of pharmacology and experimental therapeutics, 277(1), 1996, pp. 491-501
Pharmacological studies in vivo and in vitro have suggested the existe
nce of subtypes of the delta opioid receptor termed delta(1) and delta
(2) (delta(1) and delta(2)). The hypothesis of subtypes of delta recep
tors was further explored by assessing the effects of administration o
f antisense or mismatch oligodeoxynucleotides (ODN) in vivo to the clo
ned DOR, or to a conserved region of the cloned opioid receptors, on t
he antinociceptive responses elicited by selective mu, kappa and delta
opioid receptor agonists in mice. Additionally, the density of opioid
delta receptors in brain after delta opioid receptor (DOR) ODN treatm
ent was investigated. Repeated twice daily intracerebroventricular (i.
c.v.) administration of DOR antisense, but not mismatch, ODN, produced
a dose- and time-related blockade of i.c.v. [D-Ala(2), Glu(4)]deltorp
hin (delta(2) agonist), but not [D-Pen(2), D-Pen(5)]enkephalin (delta(
1) agonist), antinociception. The antinociceptive responses to selecti
ve CL and kappa opioid agonists were unaffected by DOR antisense or mi
smatch ODN treatments. The antinociceptive effect of an A(90) dose of
[D-Ala(2), Glu(4)]deltorphin was significantly reduced by the third da
y of DOR antisense ODN administration and persisted over a treatment p
eriod of 6 days with recovery by the third posttreatment day. Saturati
on studies in mouse whole brain preparations with the selective delta-
radioligand [H-3]naltrindole showed that DOR antisense, but not mismat
ch, ODN treatment produced a significant time-related reduction in B-m
ax values of approximately 30 to 40% by day 6, without changing the K-
d value. The reduction in DOR density was reversible and returned to c
ontrol levels within 3 days after cessation of antisense ODN treatment
. The i.c.v. administration of an antisense, but not mismatch, ODN dir
ected to a conserved region of the cloned opioid receptors, termed com
mon opioid receptor antisense ODN, inhibited the antinociceptive effec
ts of i.c.v. mu, kappa and delta agonists, including [D-Pen(2), D-Pen(
5)]enkephalin. These data further support the hypothesis of subtypes o
f opioid delta receptors.