TY - JOUR
T1 - Intraperitoneal injection of antisense peptide nucleic acids targeted to the mu receptor decreases response to morphine and receptor protein levels in rat brain
AU - McMahon, Beth M.
AU - Stewart, Jennifer A.
AU - Jackson, Joshua
AU - Fauq, Abdul
AU - McCormick, Daniel J.
AU - Richelson, Elliott
N1 - Funding Information:
This work was supported by the Mayo Foundation and grants from NIMH (MH 61000 and MH60305) as well as the R.H. Smith Neurodegenerative Fellowship (BMM).
PY - 2001/6/22
Y1 - 2001/6/22
N2 - To determine the effectiveness of peptide nucleic acids (PNAs) in vivo, we designed and synthesized PNAs antisense to the mu receptor, the molecular target of morphine for inducing antinociception. Responsiveness of rats to morphine and the levels of mu receptor expression after treatment was measured. We delivered intraperitoneal injections of antisense PNAs targeted to the mu receptor (AS-MOR), mismatch PNAs (AS-MOR MM), antisense PNAs targeted to the neurotensin receptor subtype 1 (AS-NTR1), or saline and then challenged the rats with 5 mg/kg morphine (intraperitonally) or neurotensin directly into the periaqueductal gray region of the brain. To avoid tolerance, separate groups of animals were tested at 24, 48, and 72 h post-PNA treatment. Only animals treated with the AS-MOR showed a reduction in their antinociceptive 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 in the levels of mu receptor in their periaqueductal gray region, while AS-MOR MM rats showed no significant change. Lastly, the AS-MOR rats continued to show a normal antinociceptive response to neurotensin. This study, therefore, provides additional support for the use of PNAs to target proteins within brain by systemically administered PNAs.
AB - To determine the effectiveness of peptide nucleic acids (PNAs) in vivo, we designed and synthesized PNAs antisense to the mu receptor, the molecular target of morphine for inducing antinociception. Responsiveness of rats to morphine and the levels of mu receptor expression after treatment was measured. We delivered intraperitoneal injections of antisense PNAs targeted to the mu receptor (AS-MOR), mismatch PNAs (AS-MOR MM), antisense PNAs targeted to the neurotensin receptor subtype 1 (AS-NTR1), or saline and then challenged the rats with 5 mg/kg morphine (intraperitonally) or neurotensin directly into the periaqueductal gray region of the brain. To avoid tolerance, separate groups of animals were tested at 24, 48, and 72 h post-PNA treatment. Only animals treated with the AS-MOR showed a reduction in their antinociceptive 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 in the levels of mu receptor in their periaqueductal gray region, while AS-MOR MM rats showed no significant change. Lastly, the AS-MOR rats continued to show a normal antinociceptive response to neurotensin. This study, therefore, provides additional support for the use of PNAs to target proteins within brain by systemically administered PNAs.
KW - Antinociception
KW - Antisense
KW - Morphine
KW - Mu receptor
KW - Peptide nucleic acid
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U2 - 10.1016/S0006-8993(01)02511-2
DO - 10.1016/S0006-8993(01)02511-2
M3 - Article
C2 - 11406133
AN - SCOPUS:0035933505
SN - 0006-8993
VL - 904
SP - 345
EP - 349
JO - Brain Research
JF - Brain Research
IS - 2
ER -