Ultra-low doses (ULD) of the opioid receptor antagonists, naloxone and naltrexone, augment the analgesic actions of morphine, block the induction of tolerance, and reverse established tolerance by an unknown mechanism. Preclinical studies demonstrate that chronic morphine administration induces spinal gliosis and that inhibition of gliosis prevents the development of analgesic tolerance to opioids. Thus, this thesis investigated the inhibition of spinal gliosis as a mechanism by which ULD antagonists attenuate analgesic tolerance and opioid-induced hyperalgesia.
Immune cell activation is implicated in the etiology of morphine tolerance and intrathecal catheterization, a technique commonly used to study the spinal effects of drugs, causes profound gliosis. Thus, the first study investigated the effects of catheter-induced gliosis on acute and chronic morphine analgesic tolerance. Catheterization-induced gliosis did not alter antinociceptive responses to acute intrathecal morphine; however, tolerance to chronic morphine was exacerbated in catheterized rats compared to sham and surgery-naïve controls.
The potentiation of analgesic tolerance to chronic morphine by spinal gliosis provided evidence that glia modulate opioid analgesia; therefore, inhibition of opioid-induced activation of glia was explored as a potential mechanism by which ULD antagonists prevent tolerance. The second series of experiments reported morphine-induced activation of spinal microglia and astrocytes was blocked by co-administering ULD naltrexone with morphine. These findings prompted us to elucidate the specific molecular target through which ULD antagonists attenuate opioid analgesia.
Activation of glial Toll-like receptor 4 (TLR4) induces gliosis and may contribute to analgesic tolerance and/or morphine-induced hyperalgesia (MIH). Antagonism of TLR4 by the opioid receptor-inactive (+) stereoisomer of naloxone was identified as a potential mechanism by which ULD antagonists modulate opioid analgesia. Tolerance and MIH developed in mice expressing non-functional TLR4 and in wildtype controls. Analgesic tolerance was stereoselectively blocked by ULD (-)naloxone, whereas MIH was blocked by both naloxone enantiomers.
Collectively, these studies demonstrate analgesic tolerance and MIH occur through distinct mechanisms. ULD naloxone attenuates analgesic tolerance likely via an opioid receptor-mediated mechanism that is TLR4-independent. ULD antagonists do not attenuate tolerance via inhibition of spinal gliosis as hypothesized. In contrast, ULD antagonists prevent MIH by inhibiting opioid-induced gliosis in an opioid receptor- and TLR4-independent manner.
Immune cell activation is implicated in the etiology of morphine tolerance and intrathecal catheterization, a technique commonly used to study the spinal effects of drugs, causes profound gliosis. Thus, the first study investigated the effects of catheter-induced gliosis on acute and chronic morphine analgesic tolerance. Catheterization-induced gliosis did not alter antinociceptive responses to acute intrathecal morphine; however, tolerance to chronic morphine was exacerbated in catheterized rats compared to sham and surgery-naïve controls.
The potentiation of analgesic tolerance to chronic morphine by spinal gliosis provided evidence that glia modulate opioid analgesia; therefore, inhibition of opioid-induced activation of glia was explored as a potential mechanism by which ULD antagonists prevent tolerance. The second series of experiments reported morphine-induced activation of spinal microglia and astrocytes was blocked by co-administering ULD naltrexone with morphine. These findings prompted us to elucidate the specific molecular target through which ULD antagonists attenuate opioid analgesia.
Activation of glial Toll-like receptor 4 (TLR4) induces gliosis and may contribute to analgesic tolerance and/or morphine-induced hyperalgesia (MIH). Antagonism of TLR4 by the opioid receptor-inactive (+) stereoisomer of naloxone was identified as a potential mechanism by which ULD antagonists modulate opioid analgesia. Tolerance and MIH developed in mice expressing non-functional TLR4 and in wildtype controls. Analgesic tolerance was stereoselectively blocked by ULD (-)naloxone, whereas MIH was blocked by both naloxone enantiomers.
Collectively, these studies demonstrate analgesic tolerance and MIH occur through distinct mechanisms. ULD naloxone attenuates analgesic tolerance likely via an opioid receptor-mediated mechanism that is TLR4-independent. ULD antagonists do not attenuate tolerance via inhibition of spinal gliosis as hypothesized. In contrast, ULD antagonists prevent MIH by inhibiting opioid-induced gliosis in an opioid receptor- and TLR4-independent manner. / Thesis (Ph.D, Pharmacology & Toxicology) -- Queen's University, 2013-04-25 15:06:50.731
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/7942 |
| Date | 25 April 2013 |
| Creators | Mattioli, THERESA ALEXANDRA |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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