Opioid-induced Hyperalgesia: Underlying Mechanisms and Clinical Relevance

Persistent Link:
http://hdl.handle.net/10150/195034
Title:
Opioid-induced Hyperalgesia: Underlying Mechanisms and Clinical Relevance
Author:
Vardanyan, Anna
Issue Date:
2007
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Metastatic bone cancer causes severe pain that is primarily treated with opioids. A recently developed model of bone cancer pain was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced spontaneous and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or in vivo but increased sarcoma-induced bone destruction and incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity suggesting enhancement of sarcoma-induced osteolysis. Thus, morphine treatment may "add-on" additional mechanisms of pain beyond those induced by sarcoma. Despite the potential clinical significance, the exact mechanisms of opioid-induced hypersensitivity remain unknown. The vanilloid 1 receptor (TRPV1) is a molecular integrator of noxious stimuli. Sustained morphine elicited thermal and tactile hypersensitivity in WT, but not TRPV1 KO mice. Sustained morphine enhanced capsaicin-induced flinching and plasma extravasation in rats, indicating increased activity of these receptors in the periphery. Immunohistochemical studies indicate increase in TRPV1 expression in DRG and sciatic nerve, but not spinal cord, suggesting increased trafficking of TRPV1 channel to the periphery. Possible mechanisms of this enhanced expression and function of TRPV1 channels is activation of p38 MAPK. Sustained intrathecal infusion of p38 MAPK inhibitor prevents morphine-induced hypersensitivity and enhanced capsaicin-induced flinching, indicating the role of p38MAPK in the development of morphine-induced pain, possibly through sensitization of TRPV1 receptors. Acute administration of p38 MAPK inhibitor reversed morphine-induced pain suggesting the importance of p38 MAPK in the maintenance of morphine-induced hypersensitivity, likely through activation of TRPV1 channel. Sustained morphine also up-regulates NGF content in skin, which is then transported to DRG neurons where phosporilation of p38MAPK takes place. Single injection of anti-NGF peptibody blocked the development of morphine-induced hypersensitivity, enhanced capsaicin-induced flinching and plasma extravasation. Co-treatment with these compounds blocks the development of morphine-induced hyperalgesia and may optimize treatment of chronic pain states, like bone cancer pain.
Type:
text; Electronic Dissertation
Keywords:
bone; cancer; morphine; pain
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Medical Pharmacology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Porreca, Frank

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleOpioid-induced Hyperalgesia: Underlying Mechanisms and Clinical Relevanceen_US
dc.creatorVardanyan, Annaen_US
dc.contributor.authorVardanyan, Annaen_US
dc.date.issued2007en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractMetastatic bone cancer causes severe pain that is primarily treated with opioids. A recently developed model of bone cancer pain was used to evaluate the effects of sustained morphine treatment. In cancer-treated mice, morphine enhanced spontaneous and evoked pain; these effects were dose-dependent and naloxone-sensitive. SP and CGRP positive DRG cells did not differ between sarcoma or control mice, but were increased following morphine in both groups. Morphine increased ATF-3 expression only in DRG cells of sarcoma mice. Morphine did not alter tumor growth in vitro or in vivo but increased sarcoma-induced bone destruction and incidence of spontaneous fracture in a dose- and naloxone-sensitive manner. Morphine increased osteoclast activity suggesting enhancement of sarcoma-induced osteolysis. Thus, morphine treatment may "add-on" additional mechanisms of pain beyond those induced by sarcoma. Despite the potential clinical significance, the exact mechanisms of opioid-induced hypersensitivity remain unknown. The vanilloid 1 receptor (TRPV1) is a molecular integrator of noxious stimuli. Sustained morphine elicited thermal and tactile hypersensitivity in WT, but not TRPV1 KO mice. Sustained morphine enhanced capsaicin-induced flinching and plasma extravasation in rats, indicating increased activity of these receptors in the periphery. Immunohistochemical studies indicate increase in TRPV1 expression in DRG and sciatic nerve, but not spinal cord, suggesting increased trafficking of TRPV1 channel to the periphery. Possible mechanisms of this enhanced expression and function of TRPV1 channels is activation of p38 MAPK. Sustained intrathecal infusion of p38 MAPK inhibitor prevents morphine-induced hypersensitivity and enhanced capsaicin-induced flinching, indicating the role of p38MAPK in the development of morphine-induced pain, possibly through sensitization of TRPV1 receptors. Acute administration of p38 MAPK inhibitor reversed morphine-induced pain suggesting the importance of p38 MAPK in the maintenance of morphine-induced hypersensitivity, likely through activation of TRPV1 channel. Sustained morphine also up-regulates NGF content in skin, which is then transported to DRG neurons where phosporilation of p38MAPK takes place. Single injection of anti-NGF peptibody blocked the development of morphine-induced hypersensitivity, enhanced capsaicin-induced flinching and plasma extravasation. Co-treatment with these compounds blocks the development of morphine-induced hyperalgesia and may optimize treatment of chronic pain states, like bone cancer pain.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectboneen_US
dc.subjectcanceren_US
dc.subjectmorphineen_US
dc.subjectpainen_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineMedical Pharmacologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorPorreca, Franken_US
dc.contributor.committeememberKing, Tamaraen_US
dc.contributor.committeememberLai, Josephineen_US
dc.contributor.committeememberVanderah, Todden_US
dc.contributor.committeememberFrench, Edwarden_US
dc.identifier.proquest2475en_US
dc.identifier.oclc659748394en_US
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