The development of tolerance to opioid analgesics reduces their long-term usefulness. Previous studies have proposed the involvement of an increased activity of “antiopid systems”, like N/OFQ/NOP receptor, for this opioid side effect. The present study aim to test if NOP receptor blockade, in the ventrolateral periaqueductal gray (vlPAG), a key site in the descending pain-control system, affected the tolerance to the opioid antinociceptive action. Repeated injection of morphine (10mg/kg s.c.) or [D-Ala2-NMe-Phe4-Gly-ol5]-enkephalin (DAMGO) (1µg/1µl intra vlPAG), a selective MOP opioid agonist, induced analgesia that lasted up to 3 days when rats became tolerant, as quantified by the tail flick and the hot plate tests. Administration of (±)–J 113397(4 µg/1µl intra vlPAG), a non-peptidic NOP receptor antagonist, on day 4, restored the analgesic effect of opioids. When the daily administration of morphine or DAMGO was preceded by the NOP antagonist, the two opioids maintained their analgesic profile until 5 days of observation; however the suspension of the NOP antagonist in opioid-treated rats induced the reappearance of tolerance. In conclusion, these results suggest that the antagonism of the NOP receptor in the vlPAG could provide a potential strategy for improving the efficacy of opioid therapy for pain conditions.

NOP RECEPTOR ANTAGONISM IN THE VENTROLATERAL PERIAQUEDUCTAL GRAY ATTENUATES THE DEVELOPMENT OF OPIOID TOLERANCE.

PARENTI, Carmela;
2012

Abstract

The development of tolerance to opioid analgesics reduces their long-term usefulness. Previous studies have proposed the involvement of an increased activity of “antiopid systems”, like N/OFQ/NOP receptor, for this opioid side effect. The present study aim to test if NOP receptor blockade, in the ventrolateral periaqueductal gray (vlPAG), a key site in the descending pain-control system, affected the tolerance to the opioid antinociceptive action. Repeated injection of morphine (10mg/kg s.c.) or [D-Ala2-NMe-Phe4-Gly-ol5]-enkephalin (DAMGO) (1µg/1µl intra vlPAG), a selective MOP opioid agonist, induced analgesia that lasted up to 3 days when rats became tolerant, as quantified by the tail flick and the hot plate tests. Administration of (±)–J 113397(4 µg/1µl intra vlPAG), a non-peptidic NOP receptor antagonist, on day 4, restored the analgesic effect of opioids. When the daily administration of morphine or DAMGO was preceded by the NOP antagonist, the two opioids maintained their analgesic profile until 5 days of observation; however the suspension of the NOP antagonist in opioid-treated rats induced the reappearance of tolerance. In conclusion, these results suggest that the antagonism of the NOP receptor in the vlPAG could provide a potential strategy for improving the efficacy of opioid therapy for pain conditions.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/20.500.11769/111934
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