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

Abstract

Rationale: The abuse potential of opioids may be due to their reinforcing and rewarding effects, which may be attenuated by neurokinin-1 receptor (NK1R) antagonists.

Objective: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Fig. 1

Placement of intracranial self-stimulation monopolar electrodes in C57BL/6J mice. Electrodes were aimed at the right medial forebrain bundle at the level of the lateral hypothalamus (panel A). Black circles represent the most ventral position of the electrode tip as detected by visual inspection of Nissl-stained brain sections using light microscopy (panel B).

Fig. 2

Responding for different frequencies of brain stimulation reward for an individual C57BL/6J mouse. Each response curve depict the effects of the following drug treatment combinations on responding: saline/saline (open circles), saline/10.0 mg/kg morphine sulfate (gray circles),1.0 mg/kg naltrexone/10.0 mg/kg morphine sulfate (black square), 10.0 mg/kg L-733,060/10.0 mg/kg morphine sulfate (black triangle), or 10.0 mg/kg L-703,606/10.0 mg/kg morphine sulfate (black diamond).

Fig. 3

Dose-response relationship for morphine on BSR threshold and maximum operant response rate in C57BL/6J mice. BSR threshold (θ₀, panel A) and maximum response rate (MAX, panel B) are presented as mean (±1 SEM, vertical lines) percent of pre-injection baseline after treatment with saline vehicle (white circle, n = 13) or morphine sulfate (grey circles; 1.0, 3.0, 10.0, and 17.0 mg/kg; n = 13). Asterisks indicate significance (p < 0.05) vs. saline vehicle.

Fig. 4

Effect of naltrexone pre-treatment on morphine-induced changes in BSR threshold and maximum response rate in C57BL/6J mice. BSR threshold (θ₀, panel A) and maximum response rate (MAX, panel B) are presented as mean (±1 SEM, vertical lines) percent of pre-injection baseline after treatment with naltrexone followed by saline vehicle (white squares, n = 13) or morphine sulfate (10.0 mg/kg, grey squares, n = 13). Asterisks indicate significance (p < 0.05) vs. naltrexone alone.

Fig. 5

Dose-response relationship for the neurokinin-1 receptor (NK1R) antagonists L-733,060 and L-703,606 on BSR threshold and maximum response rate in C57BL/6J mice. BSR threshold (θ₀, panel A) and maximum response rate (MAX, panel B) are presented as mean (±1 SEM, vertical lines) percent of pre-injection baseline after treatment with saline (white circles, n = 13), L-733,060 (black triangles, n = 13), or L-703,606 (black diamonds, n = 10). Asterisks indicate significance (p < 0.05) of L-733,060 dose vs. saline vehicle.

Fig. 6

Effect of L-733,060, L-703,606, or saline vehicle pre-treatment on morphine-induced changes in BSR threshold and maximum response rate in C57BL/6J mice. BSR threshold (θ₀, panel A) and maximum response rate (MAX, panel B) are presented as mean (±1 SEM, vertical lines) percent of pre-injection baseline after treatment with L-733,060 (10.0 mg/kg, black triangles, n = 13), L-703,606 (10.0 mg/kg, black diamonds, n = 10), or saline vehicle (grey circles, n = 13) followed by morphine sulfate. Asterisks indicate significance (p < 0.05) of morphine dose vs. vehicle.