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Anesth Analg. 2002 Oct;95(4):979-84, table of contents.

Hyperalgesia during opioid abstinence: mediation by glutamate and substance p.

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  • 1Veterans Affairs Palo Alto Health Care System and Stanford University Department of Anesthesiology, Palo Alto, California 94304, USA.


Opioid-abstinence hyperalgesia (OAH) is a phenomenon characterized by thermal and mechanical hyperalgesia that occurs between intermittent doses of opioids or after the chronic administration of these drugs when administration is abruptly stopped. In these studies we attempted to determine whether the activation of spinal cord dorsal horn neurons was greater in mice with OAH than in control mice in response to the intrathecal administration of the primary neurotransmitters glutamate and substance P. After mice were treated with an established protocol consisting of the implantation of morphine pellets followed by removal after 6 days, the mice were hyperalgesic as assessed with the hotplate and Hargreaves thermal paw withdrawal assays. Mechanical allodynia was also demonstrated. The intrathecal injection of either glutamate (5-25 micro g) or substance P (0.02-0.1 nmol) caused greater pain behaviors in mice with OAH than in control mice. Likewise, it was observed that the dorsal horn regions of OAH mice had more Fos-positive nuclei after either glutamate or substance P administration than did control mice. We conclude that mice with OAH exhibit increased pain behaviors and have increased numbers of Fos-positive nuclei in response to intrathecal glutamate and substance P administration when compared with control mice. Thus, spinal sensitization to primary neurotransmitters may be responsible in part for the manifestation of OAH.


Opioids are a mainstay of treatment for many types of chronic pain. These studies provide evidence that the hyperalgesia induced by chronic opioid administration may be in part to spinal neuroplastic changes.

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