Intraperitoneal injection of antisense peptide nucleic acids targeted to the mu receptor decreases response to morphine and receptor protein levels in rat brain
Bm. Mcmahon et al., Intraperitoneal injection of antisense peptide nucleic acids targeted to the mu receptor decreases response to morphine and receptor protein levels in rat brain, BRAIN RES, 904(2), 2001, pp. 345-349
To determine the effectiveness of peptide nucleic acids (PNAs) in vivo, we
designed and synthesized PNAs antisense to the mu receptor, the molecular t
arget of morphine for inducing antinociception. Responsiveness of rats to m
orphine and the levels of mu receptor expression after treatment was measur
ed. We delivered intraperitoneal injections of antisense PNAs targeted to t
he mu receptor (AS-MOR), mismatch PNAs (AS-MOR MM), antisense PNAs targeted
to the neurotensin receptor subtype 1 (AS-NTR1). or saline and then challe
nged the rats with 5 mg/kg morphine (intraperitonally) or neurotensin direc
tly into the periaqueductal gray region of the brain. To avoid tolerance, s
eparate groups of animals were tested at 24, 48, and 72 h post-PNA treatmen
t. Only animals treated with the AS-MOR showed a reduction in their antinoc
iceptive response to morphine. The lack of effect of morphine on the AS-MOR
rats was profound at 24 and 48 h, but animals tested at 72 h were similar
to control groups. At 24 h the AS-MOR rats had a significant 55% decrease i
n the levels of mu receptor in their periaqueductal gray region, while AS-M
OR MM rats showed no significant change. Lastly, the AS-MOR rats continued
to show a normal antinociceptive response to neurotensin. This study, there
fore, provides additional support for the use of PNAs to target proteins wi
thin brain by systemically administered PNAs. (C) 2001 Elsevier Science B.V
. All rights reserved.