TY - JOUR
T1 - Antisense oligodeoxynucleotide to the CCKB receptor produces naltrindole- and [Leu5]enkephalin antiserum-sensitive enhancement of morphine antinociception
AU - Vanderah, Todd W.
AU - Lai, Josephine
AU - Yamamura, Henry I.
AU - Porreca, Frank
PY - 1994/12
Y1 - 1994/12
N2 - Cholecystokinin (CCK) has been shown to attenuate, while CCK antagonists enhance, the antinociceptive activity of morphine, suggesting that this peptide may act as an endogenous modulator of the opioid system. Here, we have investigated the effects of administration of a synthetic oligodeoxynucleotide (oligo) complementary to the 5' coding region of the cloned mouse CCK„ receptor (antisense), or a mismatch oligo, on the antinociceptive effects of morphine. Intracerebroventricular (i.c.v.) treatment of mice with CCK„ antisense, but not mismatch, oligo for 3 days resulted in an enhancement of the antinociceptive potency of i.c.v. morphine, as indicated by an approximately 6-fold leftward shift of the dose-effect curve. The antinociceptive effects of morphine in control and CCK„ antisense-treated animals were investigated in the presence or absence of naltrindole, an opioid 8 receptor antagonist, as well as in the presence or absence of antisera directed against either [Leu5]- or [Mets]enkephalin. The enhanced potency of morphine in mice pretreated with CCK„ antisense oligo was blocked by a-selective dose of naltrindole and antisera to [Leu5]enkephalin, but not [Met5]enkephalin; naltrindole, or antisera towards [Leu5]enkephalin or [Met5]enkephalin did not produce antinociceptive effects when given alone and did not alter the antinociceptive actions of morphine in control mice. These data suggest that CCK may act via CCK„ receptors to tonically inhibit the release of [Leu5]enkephalin, or a [Leu5]enkephalin-like peptide. The enhancement of morphine antinociception seen in the presence of blockade of the CCK„ receptor may be the result of the well-known enhancement of morphine antinociception by opioid 8 agonists.
AB - Cholecystokinin (CCK) has been shown to attenuate, while CCK antagonists enhance, the antinociceptive activity of morphine, suggesting that this peptide may act as an endogenous modulator of the opioid system. Here, we have investigated the effects of administration of a synthetic oligodeoxynucleotide (oligo) complementary to the 5' coding region of the cloned mouse CCK„ receptor (antisense), or a mismatch oligo, on the antinociceptive effects of morphine. Intracerebroventricular (i.c.v.) treatment of mice with CCK„ antisense, but not mismatch, oligo for 3 days resulted in an enhancement of the antinociceptive potency of i.c.v. morphine, as indicated by an approximately 6-fold leftward shift of the dose-effect curve. The antinociceptive effects of morphine in control and CCK„ antisense-treated animals were investigated in the presence or absence of naltrindole, an opioid 8 receptor antagonist, as well as in the presence or absence of antisera directed against either [Leu5]- or [Mets]enkephalin. The enhanced potency of morphine in mice pretreated with CCK„ antisense oligo was blocked by a-selective dose of naltrindole and antisera to [Leu5]enkephalin, but not [Met5]enkephalin; naltrindole, or antisera towards [Leu5]enkephalin or [Met5]enkephalin did not produce antinociceptive effects when given alone and did not alter the antinociceptive actions of morphine in control mice. These data suggest that CCK may act via CCK„ receptors to tonically inhibit the release of [Leu5]enkephalin, or a [Leu5]enkephalin-like peptide. The enhancement of morphine antinociception seen in the presence of blockade of the CCK„ receptor may be the result of the well-known enhancement of morphine antinociception by opioid 8 agonists.
KW - Antinociception
KW - Antisense oligodeoxynucleotides
KW - CCK receptor
KW - Enkephalins
KW - Mouse
UR - http://www.scopus.com/inward/record.url?scp=0028670364&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0028670364&partnerID=8YFLogxK
U2 - 10.1097/00001756-199412000-00049
DO - 10.1097/00001756-199412000-00049
M3 - Article
C2 - 7696612
AN - SCOPUS:0028670364
SN - 0959-4965
VL - 5
SP - 2601
EP - 2605
JO - NeuroReport
JF - NeuroReport
IS - 18
ER -