Potentiation of brain stimulation reward by morphine: Effects of neurokinin-1 receptor antagonism

Department of Neurology and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, 170 Manning Dr., CB 7025, Chapel Hill, NC 27599-7025, USA.
Psychopharmacology (Impact Factor: 3.88). 09/2011; 220(1):215-24. DOI: 10.1007/s00213-011-2469-z
Source: PubMed


The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists.
This study was conducted to measure the effects of opioid and NK1R blockade on the potentiation of brain stimulation reward (BSR) by morphine using the intracranial self-stimulation method.
Adult male C57BL/6J mice (n = 15) were implanted with unipolar stimulating electrodes in the lateral hypothalamus and trained to respond for varying frequencies of rewarding electrical stimulation. The BSR threshold (θ(0)) and maximum response rate (MAX) were determined before and after intraperitoneal administration of saline, morphine (1.0-17.0 mg/kg), or the NK1R antagonists L-733,060 (1.0-17.0 mg/kg) and L-703,606 (1.0-17.0 mg/kg). In morphine antagonism experiments, naltrexone (0.1-1.0 mg/kg) or 10.0 mg/kg L-733,060 or L-703,606 was administered 15 min before morphine (1.0-10.0 mg/kg) or saline.
Morphine dose-dependently decreased θ(0) (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ(0); 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ(0) or MAX, attenuated the effects of 3.0 and 10.0 mg/kg morphine, and 1.0 and 0.3 mg/kg naltrexone blocked the effects of 10.0 mg/kg morphine. Naltrexone given before saline did not affect θ(0) or MAX.
The decrease in θ(0) by morphine reflects its rewarding effects, which were attenuated by NK1R and opioid receptor blockade. These results demonstrate the importance of substance P signaling during limbic reward system activation by opioids.

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    • "Adult (>P60) male mice (h/mOPRM1-118AA: n = 49; 118GG: n = 48) were implanted with stimulating electrodes in the medial forebrain bundle at the level of the lateral hypothalamus (coordinates: AP -1.3, ML -1.0, DV -5.0 mm) and were conditioned to perform intracranial self-stimulation as previously described (Robinson et al, 2012). During each testing session, mice responded during three consecutive series of 15 descending frequencies. "
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    • "Intracranial self-stimulation (ICSS) is an operant behavioral method in which mice respond for rewarding electrical stimulation of the medial forebrain bundle at the level of the lateral hypothalamus . All ICSS methods were done as previously described (Robinson et al., 2012), using the curve-shift method of ICSS (Carlezon and Chartoff, 2007). The maximum response rate (MAX) and the lowest frequency that sustained responding brain stimulation reward (BSR threshold, u 0 ) were compared before and after drug administration. "
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