Potentiation of brain stimulation reward by morphine: effects of neurokinin-1 receptor antagonism
- 277 Downloads
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 (θ0) 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 θ0 (maximum effect = 62% of baseline) and altered MAX when compared to saline. L-703,606 and L-733,060 altered θ0; 10.0 mg/kg L-733,060 and L-703,606, which did not affect θ0 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 θ0 or MAX.
The decrease in θ0 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.
KeywordsMorphine Opioid Neurokinin Substance P Dopamine Reward Reinforcement
This research was supported by R01-AA 018335 (CJM) and the NIAAA intramural research budget (MH).
Conflicts of interest
- Franklin KBJ, Paxinos G (2008) The Mouase Brain in Stereotaxic Coordinates, 3rd ed. Elsevier/Academic Press, Amsterdam; New YorkGoogle Scholar
- Goodman LS, Brunton LL, Chabner B, Knollmann BC (2011) Goodman & Gilman's the pharmacological basis of therapeutics, 12th edn. McGraw-Hill, New YorkGoogle Scholar
- Substance Abuse and Mental Health Services Administration (2010) Results from the 2009 National Survey on Drug Use and Health: Volume I. Summary of national findings. In: Department of Health and Human Services (ed) (http://www.oas.samhsa.gov/NSDUH/2k9NSDUH/2k9Results.htm). Office of Applied Studies, Rockville, MD
- Rupniak NM, Carlson EJ, Webb JK, Harrison T, Porsolt RD, Roux S, de Felipe C, Hunt SP, Oates B, Wheeldon A (2001) Comparison of the phenotype of NK1R−/− mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs. Behav Pharmacol 12:497–508PubMedCrossRefGoogle Scholar
- Seabrook GR, Shepheard SL, Williamson DJ, Tyrer P, Rigby M, Cascieri MA, Harrison T, Hargreaves RJ, Hill RG (1996) L-733,060, a novel tachykinin NK1 receptor antagonist; effects in [Ca2+]i mobilisation, cardiovascular and dural extravasation assays. Eur J Pharmacol 317:129–35PubMedCrossRefGoogle Scholar
- Warner M, Chen LH, Makuc DM (2009) Increase in fatal poisonings involving opioid analgesics in the United States, 1999–2006. NCHS Data Brief: 1–8.Google Scholar