Descending facilitatory pathways from the rostroventromedial medulla mediate naloxone-precipitated withdrawal in morphine-dependent rats

Abstract

Opioids produce analgesic effects, and extended use can produce physical dependence in both humans and animals. Dependence to opiates can be demonstrated by either termination of drug administration or through precipitation of the withdrawal syndrome by opiate antagonists. Key features of the opiate withdrawal syndrome include hyperalgesia, anxiety, and autonomic signs such as diarrhea. The rostral ventromedial medulla (RVM) plays an important role in the modulation of pain and for this reason, may influence withdrawal-induced hyperalgesia. The mechanisms that drive opiate withdrawal-induced hyperalgesia have not been elucidated. Here, rats made dependent upon morphine received naloxone to precipitate withdrawal. RVM microinjection of lidocaine, kynurenic acid (excitatory amino acid antagonist) or YM022 (CCK2 receptor antagonist) blocked withdrawal-induced hyperalgesia. Additionally, these treatments reduced both somatic and autonomic signs of naloxone-induced withdrawal. Spinal application of ondansetron, a 5HT3 receptor antagonist thought to ultimately be engaged by descending pain facilitatory drive, also blocked hyperalgesia and somatic and autonomic features of the withdrawal syndrome. These results indicate that the RVM plays a critical role in mediating components of opioid withdrawal that may contribute to opioid dependence.

Perspective: Manipulations targeting these descending pathways from the RVM may diminish the consequences of prolonged opioid administration-induced dependence and be useful adjunct strategies in reducing the risk of opioid addiction.

Figure 1

A) Microinjection of lidocaine (4% in 0.5µl bilaterally) attenuated the naloxone-precipitated withdrawal behaviors in morphine dependent rats. Off-site microinjection of lidocaine did not alter naloxone-precipitated withdrawal behaviors. B). Lidocaine also prevented the reduction in hot plate latency observed 30 minutes after naloxone injection. Off-site microinjection of lidocaine failed to block morphine-induced thermal hypersensitivity or naloxone induced enhanced thermal hypersensitivity. C). Lidocaine reduced the number of animals demonstrating naloxone precipitated diarrhea. Off-site microinjection of lidocaine failed to block naloxone induced diarrhea. D) RVM lidocaine, but not off-site injections, also attenuated the weight loss observed after naloxone injection. (E) Diagram showing site of injection within the RVM (0) and off-site injections (X). Data in all graphs are expressed as mean ± SEM, n=6–12 per group, * p<0.05 compared to RVM saline/systemic naloxone; # p<0.05 compared to RVM saline/systemic saline (control group).

Figure 2

A) Microinjection of kynurenic acid (1 nmol in 0.5µl bilaterally) attenuated the withdrawal behaviors observed after systemic injection of naloxone in morphine-dependent rats. B). Kynurenic acid also prevented the reduction in hot plate latency observed 30 minutes after naloxone injection C). RVM kynurenic acid reduced the number of animals demonstrating diarrhea and D) also attenuated the weight loss observed after naloxone injection. (E) Diagram showing site of injection within the RVM (0) and off-site injections (X). Data are expressed as mean ± SEM, n=6–10 per group, * p<0.05 compared to RVM saline/systemic naloxone; # p<0.05 compared to RVM saline/systemic saline (control group).

Figure 3

A) Microinjection of YM022 (0.25 ng in 0.5µl bilaterally) attenuated the withdrawal behaviors observed after systemic injection of naloxone in morphine dependent rats. B). YM022 also prevented the reduction in hot plate latency observed 30 minutes after naloxone injection C). YM022 reduced the number of animals demonstrating diarrhea and D) also attenuated the weight loss observed after naloxone injection. (E) Diagram showing site of injection within the RVM (0) and off-site injections (X). Data are expressed as mean ± SEM, n=6–10 per group, * p<0.05 compared to RVM saline/systemic naloxone; # p<0.05 compared to RVM saline/systemic saline (control group).

Figure 4

A) Spinal application of ondansetron (30µg in 5µl) attenuated the withdrawal behaviors observed after systemic injection of naloxone in morphine dependent rats B). Ondansetron also prevented the reduction in hot plate latency observed 30 minutes after naloxone injection C). Ondansetron reduced the number of animals demonstrating diarrhea and D) also attenuated the weight loss observed after naloxone injection. Data are expressed as mean ± SEM, n=6–10 per group, * p<0.05 compared to RVM saline/systemic naloxone; # p<0.05 compared to RVM saline/systemic saline (control group).