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Patrick W Mantyh - One of the best experts on this subject based on the ideXlab platform.
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dissociation between the relief of skeletal pain behaviors and skin hypersensitivity in a model of Bone Cancer pain
Pain, 2016Co-Authors: Jean Marc G Guedon, Lisa A Majuta, Michelle N Fealk, Geraldine Longo, Michelle L Thomspon, Patrick W MantyhAbstract:Recent studies have suggested that in humans and animals with significant skeletal pain, changes in the mechanical hypersensitivity of the skin can be detected. However, whether measuring changes in skin hypersensitivity can be a reliable surrogate for measuring skeletal pain itself remains unclear. To explore this question, we generated skeletal pain by injecting and confining GFP-transfected NCTC 2472 osteosarcoma cells unilaterally to the femur of C3H male mice. Beginning at day 7 post-tumor injection, animals were administered vehicle, an antibody to the P2X3 receptor (anti-P2X3) or anti-NGF antibody. Pain and analgesic efficacy were then measured on days 21, 28, and 35 post-tumor injection using a battery of skeletal pain-related behaviors and von Frey assessment of mechanical hypersensitivity on the plantar surface of the hind paw. Animals with Bone Cancer pain treated with anti-P2X3 showed a reduction in skin hypersensitivity but no attenuation of skeletal pain behaviors, whereas animals with Bone Cancer pain treated with anti-NGF showed a reduction in both skin hypersensitivity and skeletal pain behaviors. These results suggest that although Bone Cancer can induce significant skeletal pain-related behaviors and hypersensitivity of the skin, relief of hypersensitivity of the skin is not always accompanied by attenuation of skeletal pain. Understanding the relationship between skeletal and skin pain may provide insight into how pain is processed and integrated and help define the preclinical measures of skeletal pain that are predictive end points for clinical trials.
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ngf blockade at early times during Bone Cancer development attenuates Bone destruction and increases limb use
Cancer Research, 2014Co-Authors: Gwen Mccaffrey, Michelle L Thompson, Lisa A Majuta, Michelle N Fealk, Stephane R Chartier, Geraldine Longo, Patrick W MantyhAbstract:Studies in animals and humans show that blockade of nerve growth factor (NGF) attenuates both malignant and non-malignant skeletal pain. While reduction of pain is important, a largely unanswered question is what other benefits NGF blockade might confer in Bone Cancer patients. Using a mouse graft model of Bone sarcoma, we demonstrate that early treatment with an NGF antibody reduced tumor-induced Bone destruction, delayed time to Bone fracture, and increased the use of the tumor-bearing limb. Consistent with animal studies in osteoarthritis and head and neck Cancer, early blockade of NGF reduced weight loss in mice with Bone sarcoma. In terms of the extent and time course of pain relief, NGF blockade also reduced pain 40-70% depending on the metric assessed. Importantly, this analgesic effect was maintained even in animals with late stage disease. Our results suggest that NGF blockade immediately upon detection of tumor metastasis to Bone may help preserve the integrity and use, delay the time to tumor-induced Bone fracture, and maintain body weight.
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administration of a tropomyosin receptor kinase inhibitor attenuates sarcoma induced nerve sprouting neuroma formation and Bone Cancer pain
Molecular Pain, 2010Co-Authors: Joseph R Ghilardi, William G Mantyh, Aaron P Bloom, Katie T Freeman, Michael A. Kuskowski, Juan Miguel Jimenezandrade, Patrick W MantyhAbstract:Pain often accompanies Cancer and most current therapies for treating Cancer pain have significant unwanted side effects. Targeting nerve growth factor (NGF) or its cognate receptor tropomyosin receptor kinase A (TrkA) has become an attractive target for attenuating chronic pain. In the present report, we use a mouse model of Bone Cancer pain and examine whether oral administration of a selective small molecule Trk inhibitor (ARRY-470, which blocks TrkA, TrkB and TrkC kinase activity at low nm concentrations) has a significant effect on Cancer-induced pain behaviors, tumor-induced remodeling of sensory nerve fibers, tumor growth and tumor-induced Bone remodeling. Early/sustained (initiated day 6 post Cancer cell injection), but not late/acute (initiated day 18 post Cancer cell injection) administration of ARRY-470 markedly attenuated Bone Cancer pain and significantly blocked the ectopic sprouting of sensory nerve fibers and the formation of neuroma-like structures in the tumor bearing Bone, but did not have a significant effect on tumor growth or Bone remodeling. These data suggest that, like therapies that target the Cancer itself, the earlier that the blockade of TrkA occurs, the more effective the control of Cancer pain and the tumor-induced remodeling of sensory nerve fibers. Developing targeted therapies that relieve Cancer pain without the side effects of current analgesics has the potential to significantly improve the quality of life and functional status of Cancer patients.
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a cannabinoid 2 receptor agonist attenuates Bone Cancer induced pain and Bone loss
Life Sciences, 2010Co-Authors: Alysia N Lozanoondoua, Patrick W Mantyh, Courtney Wright, Anna Vardanyan, Tamara King, Tally M Largentmilnes, Mark A Nelson, Juan Miguel Jimenezandrade, Todd W VanderahAbstract:Abstract Aims Cannabinoid CB 2 agonists have been shown to alleviate behavioral signs of inflammatory and neuropathic pain in animal models. AM1241, a CB 2 agonist, does not demonstrate central nervous system side effects seen with CB 1 agonists such as hypothermia and catalepsy. Metastatic Bone Cancer causes severe pain in patients and is treated with analgesics such as opiates. Recent reports suggest that sustained opiates can produce paradoxical hyperalgesic actions and enhance Bone destruction in a murine model of Bone Cancer. In contrast, CB 2 selective agonists have been shown to reduce Bone loss associated with a model of osteoporosis. Here we tested whether a CB 2 agonist administered over a 7 day period inhibits Bone Cancer-induced pain as well as attenuates Cancer-induced Bone degradation. Main methods A murine Bone Cancer model was used in which osteolytic sarcoma cells were injected into the intramedullary space of the distal end of the femur. Behavioral and radiographic image analysis was performed at days 7, 10 and 14 after injection of tumor cells into the femur. Key findings Osteolytic sarcoma within the femur produced spontaneous and touch evoked behavioral signs of pain within the tumor-bearing limb. The systemic administration of AM1241 acutely or for 7 days significantly attenuated spontaneous and evoked pain in the inoculated limb. Sustained AM1241 significantly reduced Bone loss and decreased the incidence of Cancer-induced Bone fractures. Significance These findings suggest a novel therapy for Cancer-induced Bone pain, Bone loss and Bone fracture while lacking many unwanted side effects seen with current treatments for Bone Cancer pain.
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tumor induced injury of primary afferent sensory nerve fibers in Bone Cancer pain
Experimental Neurology, 2005Co-Authors: Christopher M. Peters, Joseph R Ghilardi, Nancy M Luger, Matthew J Schwei, David B Mach, Molly A. Sevcik, Theodore H. Lindsay, Kazufumi Kubota, Cathy P Keyser, Patrick W MantyhAbstract:Bone is the most common site of chronic pain in patients with metastatic Cancer. What remains unclear are the mechanisms that generate this pain and why Bone Cancer pain can be so severe and refractory to treatment with opioids. Here we show that following injection and confinement of NCTC 2472 osteolytic tumor cells within the mouse femur, tumor cells sensitize and injure the unmyelinated and myelinated sensory fibers that innervate the marrow and mineralized Bone. This tumor-induced injury of sensory nerve fibers is accompanied by an increase in ongoing and movement-evoked pain behaviors, an upregulation of activating transcription factor 3 (ATF3) and galanin by sensory neurons that innervate the tumor-bearing femur, upregulation of glial fibrillary acidic protein (GFAP) and hypertrophy of satellite cells surrounding sensory neuron cell bodies within the ipsilateral dorsal root ganglia (DRG), and macrophage infiltration of the DRG ipsilateral to the tumor-bearing femur. Similar neurochemical changes have been described following peripheral nerve injury and in other non-Cancerous neuropathic pain states. Chronic treatment with gabapentin did not influence tumor growth, tumor-induced Bone destruction or the tumor-induced neurochemical reorganization that occurs in sensory neurons or the spinal cord, but it did attenuate both ongoing and movement-evoked Bone Cancer-related pain behaviors. These results suggest that even when the tumor is confined within the Bone, a component of Bone Cancer pain is due to tumor-induced injury to primary afferent nerve fibers that innervate the tumor-bearing Bone. Tumor-derived, inflammatory, and neuropathic mechanisms may therefore be simultaneously driving this chronic pain state.
Teresa Pelissier - One of the best experts on this subject based on the ideXlab platform.
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the antinociceptive effect of resveratrol in Bone Cancer pain is inhibited by the silent information regulator 1 inhibitor selisistat
Journal of Pharmacy and Pharmacology, 2019Co-Authors: Sebastian Lux, Nicolas Lobos, Carolyne Lespayrebolledo, Edison Salashuenuleo, Marcelo J Kogan, Christian Flores, Mauricio Pinto, Alejandro Hernandez, Teresa PelissierAbstract:OBJECTIVES To study the antinociceptive effect of single and repeated doses of resveratrol in a Bone Cancer pain model, and whether this effect is prevented by the Silent Information Regulator 1 (SIRT1) inhibitor selisistat. METHODS The femoral intercondylar Bone of BALB/c mice was injected with 1 000 000 BJ3Z Cancer cells. Bone resorption and tumour mass growth (measured by in vivo X-ray and fluorescence imaging), as well as mechanical nociceptive thresholds (von Frey device) and dynamic functionality (rotarod machine), were evaluated during the following 4 weeks. Acute resveratrol (100 mg/kg i.p.) and/or selisistat (10 mg/kg s.c.) were administered on day 14. Chronic resveratrol (100 mg/kg i.p., daily) and/or selisistat (0.5 μg/h s.c., Alzet pump) were administered between days 14 and 20. KEY FINDINGS Tumour growth gradually incremented until day 31, while mechanical hyperalgesia started on day 3 after Cancer cell injection. Acute resveratrol increased the mechanical threshold of pain (peaking at 1.5 h), while the dynamic functionality decreased. Chronic resveratrol produced a sustained antinociceptive effect on mechanical hyperalgesia and improved the loss of dynamic functionality induced by the Bone Cancer tumour. Selisistat prevented all the effects of resveratrol. CONCLUSIONS Acute and chronic resveratrol induces antinociceptive effect in the model of metastatic osseous oncological pain, an effect that would be mediated by SIRT1 molecular signalling.
Jisheng Han - One of the best experts on this subject based on the ideXlab platform.
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interleukin 6 mediated functional upregulation of trpv1 receptors in dorsal root ganglion neurons through the activation of jak pi3k signaling pathway roles in the development of Bone Cancer pain in a rat model
Pain, 2015Co-Authors: Dong Fang, Jie Cai, Jisheng Han, Lingyu Kong, Xiaodan Liu, Guogang XingAbstract:Primary and metastatic Cancers that affect Bone are frequently associated with severe and intractable pain. The mechanisms underlying the pathogenesis of Bone Cancer pain still remain largely unknown. Previously, we have reported that sensitization of primary sensory dorsal root ganglion (DRG) neurons contributes to the pathogenesis of Bone Cancer pain in rats. In addition, numerous preclinical and clinical studies have revealed the pathological roles of interleukin-6 (IL-6) in inflammatory and neuropathic hyperalgesia. In this study, we investigated the role and the underlying mechanisms of IL-6 in the development of Bone Cancer pain using in vitro and in vivo approaches. We first demonstrated that elevated IL-6 in DRG neurons plays a vital role in the development of nociceptor sensitization and Bone Cancer-induced pain in a rat model through IL-6/soluble IL-6 receptor (sIL-6R) trans-signaling. Moreover, we revealed that functional upregulation of transient receptor potential vanilloid channel type 1 (TRPV1) in DRG neurons through the activation of Janus kinase (JAK)/phosphatidylinositol 3-kinase (PI3K) signaling pathway contributes to the effects of IL-6 on the pathogenesis of Bone Cancer pain. Therefore, suppression of functional upregulation of TRPV1 in DRG neurons by the inhibition of JAK/PI3K pathway, either before surgery or after surgery, reduces the hyperexcitability of DRG neurons and pain hyperalgesia in Bone Cancer rats. We here disclose a novel intracellular pathway, the IL-6/JAK/PI3K/TRPV1 signaling cascade, which may underlie the development of peripheral sensitization and Bone Cancer-induced pain.
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upregulation of p2x3 receptors by neuronal calcium sensor protein vilip 1 in dorsal root ganglions contributes to the Bone Cancer pain in rats
Pain, 2013Co-Authors: Min Liu, You Wan, Dong Fang, Jie Cai, Jisheng Han, Huan Yang, Jingjing Yang, Dehua ChuiAbstract:Primary and metastatic Cancers that affect Bone are frequently associated with severe and intractable pain. The mechanisms underlying the development of Bone Cancer pain are largely unknown. In this study, we first demonstrated that a functional upregulation of P2X3 receptors in dorsal root ganglion (DRG) neurons is closely associated with the neuronal hyperexcitability and the Cancer-induced Bone pain in MRMT-1 tumor cell-inoculated rats. Second, we revealed that visinin-like protein 1 (VILIP-1), a member of visinin-like proteins that belong to the family of neuronal calcium sensor proteins is responsible for the observed upregulation of P2X3 receptors in DRG neurons. The interaction between the amino terminus of VLIP-1 and the carboxyl terminus of the P2X3 receptor is critical for the surface expression and functional enhancement of the receptor. Finally, overexpression of VILIP-1 increases the expression of functional P2X3 receptors and enhances the neuronal excitability in naive rat DRG neurons. In contrast, knockdown of VILIP-1 inhibits the development of Bone Cancer pain via downregulation of P2X3 receptors and repression of DRG excitability in MRMT-1 rats. Taken together, these results suggest that functional upregulation of P2X3 receptors by VILIP-1 in DRG neurons contributes to the development of Cancer-induced Bone pain in MRMT-1 rats. Hence, P2X3 receptors and VILIP-1 could serve as potential targets for therapeutic interventions in Cancer patients for pain management. Pharmacological blockade of P2X3 receptors or knockdown of VILIP-1 in DRGs would be used as innovative strategies for the treatment of Bone Cancer pain.
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suppression of kcnq m kv7 potassium channels in dorsal root ganglion neurons contributes to the development of Bone Cancer pain in a rat model
Pain, 2013Co-Authors: Qin Zheng, You Wan, Dong Fang, Min Liu, Jie Cai, Jisheng Han, Guogang XingAbstract:Bone Cancer pain has a strong impact on the quality of life of patients, but is difficult to treat. Better understanding of the pathogenic mechanisms underlying Bone Cancer pain will likely lead to the development of more effective treatments. In the present study, we investigated whether inhibition of KCNQ/M channels contributed to the hyperexcitability of primary sensory neurons and to the pathogenesis of Bone Cancer pain. By using a rat model of Bone Cancer pain based on intratibial injection of MRMT-1 tumour cells, we documented a prominent decrease in expression of KCNQ2 and KCNQ3 proteins and a reduction of M-current density in small-sized dorsal root ganglia (DRG) neurons, which were associated with enhanced excitability of these DRG neurons and the hyperalgesic behaviours in Bone Cancer rats. Coincidently, we found that inhibition of KCNQ/M channels with XE-991 caused a robust increase in the excitability of small-sized DRG neurons and produced an obvious mechanical allodynia in normal rats. On the contrary, activation of the KCNQ/M channels with retigabine not only inhibited the hyperexcitability of these small DRG neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in Bone Cancer rats, and all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. These results suggest that repression of KCNQ/M channels leads to the hyperexcitability of primary sensory neurons, which in turn causes Bone Cancer pain. Thus, suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of Bone Cancer pain.
Guogang Xing - One of the best experts on this subject based on the ideXlab platform.
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interleukin 6 mediated functional upregulation of trpv1 receptors in dorsal root ganglion neurons through the activation of jak pi3k signaling pathway roles in the development of Bone Cancer pain in a rat model
Pain, 2015Co-Authors: Dong Fang, Jie Cai, Jisheng Han, Lingyu Kong, Xiaodan Liu, Guogang XingAbstract:Primary and metastatic Cancers that affect Bone are frequently associated with severe and intractable pain. The mechanisms underlying the pathogenesis of Bone Cancer pain still remain largely unknown. Previously, we have reported that sensitization of primary sensory dorsal root ganglion (DRG) neurons contributes to the pathogenesis of Bone Cancer pain in rats. In addition, numerous preclinical and clinical studies have revealed the pathological roles of interleukin-6 (IL-6) in inflammatory and neuropathic hyperalgesia. In this study, we investigated the role and the underlying mechanisms of IL-6 in the development of Bone Cancer pain using in vitro and in vivo approaches. We first demonstrated that elevated IL-6 in DRG neurons plays a vital role in the development of nociceptor sensitization and Bone Cancer-induced pain in a rat model through IL-6/soluble IL-6 receptor (sIL-6R) trans-signaling. Moreover, we revealed that functional upregulation of transient receptor potential vanilloid channel type 1 (TRPV1) in DRG neurons through the activation of Janus kinase (JAK)/phosphatidylinositol 3-kinase (PI3K) signaling pathway contributes to the effects of IL-6 on the pathogenesis of Bone Cancer pain. Therefore, suppression of functional upregulation of TRPV1 in DRG neurons by the inhibition of JAK/PI3K pathway, either before surgery or after surgery, reduces the hyperexcitability of DRG neurons and pain hyperalgesia in Bone Cancer rats. We here disclose a novel intracellular pathway, the IL-6/JAK/PI3K/TRPV1 signaling cascade, which may underlie the development of peripheral sensitization and Bone Cancer-induced pain.
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suppression of kcnq m kv7 potassium channels in dorsal root ganglion neurons contributes to the development of Bone Cancer pain in a rat model
Pain, 2013Co-Authors: Qin Zheng, You Wan, Dong Fang, Min Liu, Jie Cai, Jisheng Han, Guogang XingAbstract:Bone Cancer pain has a strong impact on the quality of life of patients, but is difficult to treat. Better understanding of the pathogenic mechanisms underlying Bone Cancer pain will likely lead to the development of more effective treatments. In the present study, we investigated whether inhibition of KCNQ/M channels contributed to the hyperexcitability of primary sensory neurons and to the pathogenesis of Bone Cancer pain. By using a rat model of Bone Cancer pain based on intratibial injection of MRMT-1 tumour cells, we documented a prominent decrease in expression of KCNQ2 and KCNQ3 proteins and a reduction of M-current density in small-sized dorsal root ganglia (DRG) neurons, which were associated with enhanced excitability of these DRG neurons and the hyperalgesic behaviours in Bone Cancer rats. Coincidently, we found that inhibition of KCNQ/M channels with XE-991 caused a robust increase in the excitability of small-sized DRG neurons and produced an obvious mechanical allodynia in normal rats. On the contrary, activation of the KCNQ/M channels with retigabine not only inhibited the hyperexcitability of these small DRG neurons, but also alleviated mechanical allodynia and thermal hyperalgesia in Bone Cancer rats, and all of these effects of retigabine could be blocked by KCNQ/M-channel antagonist XE-991. These results suggest that repression of KCNQ/M channels leads to the hyperexcitability of primary sensory neurons, which in turn causes Bone Cancer pain. Thus, suppression of KCNQ/M channels in primary DRG neurons plays a crucial role in the development of Bone Cancer pain.
Ana Baamonde - One of the best experts on this subject based on the ideXlab platform.
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spinal and peripheral analgesic effects of the cb2 cannabinoid receptor agonist am1241 in two models of Bone Cancer induced pain
British Journal of Pharmacology, 2010Co-Authors: Verdad Curtoreyes, Agustín Hidalgo, Sara Llames, L Menendez, Ana BaamondeAbstract:Background and purpose: The activation of CB2 receptors induces analgesia in experimental models of chronic pain. The present experiments were designed to study whether the activation of peripheral or spinal CB2 receptors relieves thermal hyperalgesia and mechanical allodynia in two models of Bone Cancer pain. Experimental approach: NCTC 2472 osteosarcoma or B16-F10 melanoma cells were intratibially inoculated to C3H/He and C57BL/6 mice. Thermal hyperalgesia was assessed by the unilateral hot plate test and mechanical allodynia by the von Frey test. AM1241 (CB2 receptor agonist), AM251 (CB1 receptor antagonist), SR144528 (CB2 receptor antagonist) and naloxone were used. CB2 receptor expression was measured by Western blot. Key results: AM1241 (0.3–10 mg·kg−1) abolished thermal hyperalgesia and mechanical allodynia in both tumour models. The antihyperalgesic effect was antagonized by subcutaneous, intrathecal or peri-tumour administration of SR144528. In contrast, the antiallodynic effect was inhibited by systemic or intrathecal, but not peri-tumour, injection of SR144528. The effects of AM1241 were unchanged by AM251 but were prevented by naloxone. No change in CB2 receptor expression was found in spinal cord or dorsal root ganglia. Conclusions and implications: Spinal CB2 receptors are involved in the antiallodynic effect induced by AM1241 in two neoplastic models while peripheral and spinal receptors participate in the antihyperalgesic effects. Both effects were mediated by endogenous opiates. The use of drugs that activate CB2 receptors could be a useful strategy to counteract Bone Cancer-induced pain symptoms.
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themed issue cannabinoids research paper spinal and peripheral analgesic effects of the cb2 cannabinoid receptor agonist am1241 in two models of Bone Cancer induced pain
2010Co-Authors: Sara Llames, Agustín Hidalgo, L Menendez, Ana BaamondeAbstract:Background and purpose: The activation of CB2 receptors induces analgesia in experimental models of chronic pain. The present experiments were designed to study whether the activation of peripheral or spinal CB2 receptors relieves thermal hyperalgesia and mechanical allodynia in two models of Bone Cancer pain. Experimental approach: NCTC 2472 osteosarcoma or B16-F10 melanoma cells were intratibially inoculated to C3H/He and C57BL/6 mice. Thermal hyperalgesia was assessed by the unilateral hot plate test and mechanical allodynia by the von Frey test. AM1241 (CB2 receptor agonist), AM251 (CB1 receptor antagonist), SR144528 (CB2 receptor antagonist) and naloxone were used. CB2 receptor expression was measured by Western blot. Key results: AM1241 (0.3–10 mg·kg
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Analgesic effects of capsazepine and resiniferatoxin on Bone Cancer pain in mice.
Neuroscience Letters, 2005Co-Authors: Luis Menéndez, Lucía Juárez, Eva García, Olivia García-suárez, Agustín Hidalgo, Ana BaamondeAbstract:Abstract In the present paper, we describe the analgesic effects induced by the transient receptor potential vanilloid type 1 (TRPV1) antagonist, capsazepine, and the TRPV1 agonist, resiniferatoxin, on the thermal hyperalgesia induced by the presence of a tibial osteosarcoma or an inflammatory process in mice. The administration of capsazepine abolished the osteosarcoma-induced hyperalgesia at a dose range (3–10 mg/kg; s.c.) ineffective to inhibit the hyperalgesia elicited by the intraplantar administration of complete Freund's adjuvant (CFA). In contrast, the administration of resiniferatoxin (0.01–0.1 mg/kg; s.c.) inhibited both the osteosarcoma- and the CFA-induced hyperalgesia. Remarkably, a single dose of resiniferatoxin abolished the osteosarcoma-induced hyperalgesia for several days and completely prevented the instauration of thermal hyperalgesia when administered at the initial stages of osteosarcoma development. The potential of drugs acting through TRPV1 for the management of some types of Bone Cancer pain is proposed.
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initial thermal heat hypoalgesia and delayed hyperalgesia in a murine model of Bone Cancer pain
Brain Research, 2003Co-Authors: Luis Menéndez, Agustín Hidalgo, Sara Llames, Ana Lastra, Manuel F Fresno, Alvaro Meana, Ana BaamondeAbstract:Abstract The recent development of rodent models of Bone Cancer pain has started to provide the basis for demonstrating the particular neurochemical and behavioral entity of Cancer pain. Behaviourally, both spontaneous pain and hyperalgesia related to mechanical, but not thermal, noxious stimuli have been described in Cancer-bearing animals. We have carried out a histological and behavioural study focused on the reactivity to noxious heat in C3H/HeJ mice receiving an intratibial injection of 105 NCTC 2472 cells. These cells, able to induce an osteosarcoma, break through Bone into soft tissues 2 weeks after cell inoculation, producing a macroscopical increase of the limb size from the fourth week. Thermal reactivity is diminished during the first 2 weeks after cell implantation, this hypoalgesia being reversed by the administration of naloxone (10 mg/kg). In contrast, during the fourth and fifth weeks after NCTC 2472 cell implantation, an increased nociceptive heat reactivity, instead of hypoalgesia, was obtained. This thermal hyperalgesia was prevented by the systemic administration of morphine (15 mg/kg). Throughout the whole period studied, mice showed signs of spontaneous pain behaviour that reached its maximum 3 weeks after inoculation. In conclusion, we show that the presence of thermal heat hyperalgesia is preceded by an initial opioid-mediated hypoalgesic state, in this murine model of Bone Cancer pain.