Regional Anesthesia and Pain

Saito, Osamu; Aoe, Tomohiko; Kozikowski, Alan P.; Jayaprakash, Sarva; Neale, Joseph H.; Yamamoto, Tatsuo

doi:10.1007/bf03022832

Cited by 22 publications

(10 citation statements)

References 27 publications

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“…Preclinical and clinical research has shown that blocking NMDA receptors produces a significant analgesic effect on bone cancer pain 20, 21, 26, 32 , suggesting that NMDA receptors are required for the induction of bone cancer-evoked pain hypersensitivites. To test whether spinal NMDA receptors are involved in PCC-induced activation of dorsal horn mTOR and its downstream pathway, the rats were infused i.th.…”

Section: Resultsmentioning

confidence: 99%

“…Given that NMDA receptors play a critical role in spinal central sensitization 18, 33 and that blocking NMDA receptors produces a significant analgesic effect on bone cancer pain 20, 21, 26, 32 , we propose that spinal cord NMDA receptor-mediated activation of mTOR and its downstream effectors is required for development and maintenance of bone cancer-induced pain hypersensitivities. We used a rat model of bone cancer pain produced by prostate cancer cell (PCC) injection of the tibia to determine first whether pre- and post-treatment with i.th.…”

Section: Introductionmentioning

confidence: 98%

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Spinal Cord NMDA Receptor-Mediated Activation of Mammalian Target of Rapamycin Is Required for the Development and Maintenance of Bone Cancer-Induced Pain Hypersensitivities in Rats

Shih

Kao

Wang

et al. 2012

The Journal of Pain

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Mammalian target of rapamycin (mTOR) controls mRNA translation and is critical for neuronal plasticity. However, how it participates in central sensitization underlying chronic pain is unclear. Here, we show that NMDA receptors are required for the functional role of spinal cord mTOR in bone cancer pain induced by injecting prostate cancer cells (PCCs) into the tibia. Intrathecal rapamycin, a specific mTOR inhibitor, dose-dependently attenuated the development and maintenance of PCC-induced mechanical allodynia and thermal hyperalgesia. Rapamycin alone did not affect locomotor activity and acute responses to thermal or mechanical stimuli. Phosphorylation of mTOR and p70S6K (a downstream effector) was increased time-dependently in L4-5 dorsal horn and transiently in L4-5 dorsal root ganglions on the ipsilateral side after PCC injection, although total expression of mTOR or p70S6K was not changed in these regions. The increases in dorsal horn were abolished by intrathecal infusion of DL-AP5, an NMDA receptor antagonist. Moreover, NMDA receptor subunit NR1 colocalized with mTOR and p70S6K in dorsal horn neurons. These findings suggest that PCC-induced dorsal horn activation of the mTOR pathway participates in NMDA receptor-triggered dorsal central sensitization under cancer pain conditions. Perspective The present study shows that inhibition of spinal mTOR blocks cancer-related pain without affecting acute pain and locomotor function. Given that mTOR inhibitors are FDA-approved drugs, mTOR in spinal cord may represent a potential new target for preventing and/or treating cancer-related pain.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Spinal Cord NMDA Receptor-Mediated Activation of Mammalian Target of Rapamycin Is Required for the Development and Maintenance of Bone Cancer-Induced Pain Hypersensitivities in Rats

Shih

Kao

Wang

et al. 2012

The Journal of Pain

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“…4,17–21 Microinjection of a GCPII inhibitor into either the PAG or RVM, important nuclei in the descending pain pathway, produced an analgesic effect in the rat formalin model of inflammatory pain. 22 Similarly, the locus coeruleus (LC) is a key nucleus of the descending pain inhibitory system.…”

Section: Introductionmentioning

confidence: 99%

A role for the locus coeruleus in the analgesic efficacy of N-acetylaspartylglutamate peptidase (GCPII) inhibitors ZJ43 and 2-PMPA

et al. 2017

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N-acetylaspartylglutamate (NAAG) is the third most prevalent and widely distributed neurotransmitter in the mammalian nervous system. NAAG activates a group II metabotropic glutamate receptor (mGluR3) and is inactivated by an extracellular enzyme, glutamate carboxypeptidase II (GCPII) in vivo. Inhibitors of this enzyme are analgesic in animal models of inflammatory, neuropathic and bone cancer pain. NAAG and GCPII are present in the locus coeruleus, a center for the descending noradrenergic inhibitory pain system. In the formalin footpad model, systemic treatment with GCPII inhibitors reduces both phases of the inflammatory pain response and increases release of spinal noradrenaline. This analgesic efficacy is blocked by systemic injection of a group II mGluR antagonist, by intrathecal (spinal) injection of an alpha 2 adrenergic receptor antagonist and by microinjection of an α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor antagonist directly into the contralateral locus coeruleus. Footpad inflammation increases release of glutamate in the contralateral locus coeruleus and systemic treatment with a GCPII inhibitor blocks this increase. Direct injection of GCPII inhibitors into the contralateral or ipsilateral locus coeruleus reduces both phases of the inflammatory pain response in a dose-dependent manner and the contralateral effect also is blocked by intrathecal injection of an alpha 2 adrenergic receptor antagonist. These data support the hypothesis that the analgesic efficacy of systemically administered GCPII inhibitors is mediated, at least in part, by the contralateral locus coeruleus via group II mGluR, AMPA and alpha 2 adrenergic receptors.

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“…Ketamine produces the partial inhibition of mechanical allodynia of skin cancer at an intraperitoneal dose of 30 mg/kg 13) and the complete inhibition of pain-related behaviors of mice with bone cancer. 19) Thus, the analgesic efficacy of ketamine may also depend on the types of cancer and pain.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Evaluation of Morphine and Non-opioid Analgesic Adjuvants in a Mouse Model of Skin Cancer Pain

Andoh

Sugiyama

Fujita

et al. 2008

Biological & Pharmaceutical Bulletin

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Pain at the end stage of cancer is a serious problem for patients. Since severe pain enhances the growth and metastasis of tumors, 2,3) pain relief is important for not only the quality of life of patients but also cancer therapy. The three-step analgesic ladder advocated by the World Health Organization is effective in cancer pain treatment.4) Strong opioid analgesics such as morphine are used to relieve severe pain of patients with advanced cancer. However, neuropathic cancer pain has been claimed to be resistant to opioid analgesics and the efficacy of opioid analgesics and analgesic adjuvants are controversial.5-7) The proportion of patients with pure neuropathic cancer pain is relatively low and many patients experience cancer pain that is driven by a mix of both nociception and neuropathy. 7)We have developed a mouse model of skin cancer pain, 3) which has mixed nociceptive-neuropathic pain. 8,9) Parenteral administration of morphine inhibits thermal hyperalgesia at relatively high doses; but the effects almost disappeared after the sixth administration.3) In the present experiments, we examined analgesic potency and tolerance of oral administration of morphine. Regarding analgesic adjuvant such as ketamine, mexiletine and baclofen which are used in patients with refractory pain including neuropathic pain, [10][11][12] allodynia of mice with skin cancer is partially inhibited by ketamine, but not mexiletine and baclofen.13) Thus, we also examined the effects of analgesic adjuvants on the thermal hyperalgesia in the skin cancer pain model. MATERIALS AND METHODSAnimals Male C57BL/6 mice (6 weeks of age at the melanoma inoculation; Japan SLC, Ltd., Shizuoka, Japan) were used. They were housed six per cage under controlled temperature (22Ϯ1°C) and humidity (55Ϯ10%). The room was lighted from 7:00 a.m. to 7:00 p.m. and during the behavioral test. Food and water were available ad libitum. The study was approved by the Committee for Animal Experiments at University of Toyama.Drugs Morphine hydrochloride (Sankyo, Tokyo, Japan) and ketamine (Sigma, St. Louis, MO, U.S.A.) were dissolved in tap water. Mexiletine hydrochloride and baclofen, purchased from Sigma, were dissolved in physiological saline. Tumor Inoculation B16-BL6 cells, a highly invasive variant of B16 melanoma derived from the C57BL/6 mouse, 14) were kindly provided by Dr. I. J. Fidler, MD Anderson Cancer Center, Houston, TX, U.S.A. B16-BL6 cells were cultured in Eagle's minimum essential medium containing 10% fetal bovine serum. The melanoma cells (2ϫ10 5 cells/20 ml) suspended in the medium was subcutaneously injected into the plantar region of the unilateral hind paw. To assess the growth of melanoma in situ, the volume of glabrous region of the hind paw was plethysmographically determined.Behavioral Test For the test of thermal hyperalgesia, radiant heat was applied to the plantar region of the hind paw and the latency of its withdrawal response was determined, using a tail-flick apparatus (Ugo Basile, Milan, Italy). The intensity of radiant heat wa...

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Regional Anesthesia and Pain

Cited by 22 publications

References 27 publications

Spinal Cord NMDA Receptor-Mediated Activation of Mammalian Target of Rapamycin Is Required for the Development and Maintenance of Bone Cancer-Induced Pain Hypersensitivities in Rats

Spinal Cord NMDA Receptor-Mediated Activation of Mammalian Target of Rapamycin Is Required for the Development and Maintenance of Bone Cancer-Induced Pain Hypersensitivities in Rats

A role for the locus coeruleus in the analgesic efficacy of N-acetylaspartylglutamate peptidase (GCPII) inhibitors ZJ43 and 2-PMPA

Pharmacological Evaluation of Morphine and Non-opioid Analgesic Adjuvants in a Mouse Model of Skin Cancer Pain

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