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.
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