NT69L, a novel analgesic, shows synergy with morphine.
BACKGROUND
Neurotensin (NT) is a neuropeptide with antinociceptive effects that are mediated through NT receptors, of which there are three known subtypes (NTS1, NTS2, and NTS3). Morphine is a mu-opioid receptor agonist commonly used for pain treatment but is associated with side effects that can be serious. We hypothesize that selective NT receptor agonists may represent a novel class of analgesics and their use in conjunction with morphine will have synergistic properties which may reduce the dose of morphine administered and its side effects.


METHODS
The antinociceptive activity of an NT agonist (NT69L) and morphine was studied in rats using the hot plate test to determine if there is synergism between the two drugs in reducing pain. The NTS2 receptor antagonist, levocabastine, was used to determine the receptor subtype involved in the analgesic effect of NT69L and morphine.


RESULTS
The administration of both NT69L and morphine resulted in a dose-dependent analgesic effect. The isobolographic analysis demonstrated that the combination of sub-analgesic doses of NT69L and morphine was synergistic in the hot plate test. Pretreatment with the NTS2 receptor antagonist, levocabastine attenuated the antinociceptive effect of NT69L and the combined effect of NT69L and morphine in the hot plate test.


CONCLUSIONS
The results support the hypothesis that the synergistic combination of NT69L and morphine would improve the pharmacological treatment of pain while minimizing specific adverse effects of each of the drugs at a higher dose. NTS2 is important for the antinociceptive effect of NT69L and morphine.
Boules
M
M
Neuropsychopharmacology Laboratory, Mayo Foundation for Medical Education and Research, Jacksonville, Florida, USA. boules.mona@mayo.edu
Shaw
A
A
Liang
Y
Y
Barbut
D
D
Richelson
E
E
D000700:Analgesics / Q000008:administration & dosage / Q000494:pharmacology*; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006358:Hot Temperature; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009496:Neurotensin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010146:Pain / Q000188:drug therapy; D010147:Pain Measurement; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology*; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
D000700:Analgesics; D000701:Analgesics, Opioid; C099727:Ntsr2 protein, rat; D010446:Peptide Fragments; D010880:Piperidines; D018028:Receptors, Neurotensin; C407426:neurotensin 69L; D009496:Neurotensin; D009020:Morphine; C047340:levocabastine