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      Effect of Peritumoral Bupivacaine on Primary and Distal Hyperalgesia in Cancer-Induced Bone Pain

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          Cancer-induced bone pain (CIBP) is a debilitating chronic pain condition caused by injury to bone nerve terminals due to primary or metastasized bone tumors. Pain manifests as enhanced sensitivity, not only over the affected bone site but also at distal areas that share common nerve innervation with the tumor. In this study, we aim to understand how tumor-induced primary and distal pain sensitivities are affected by bupivacaine-induced block of bone nerve endings in a rat model of CIBP.


          MRMT-1 breast cancer cells were injected into the proximal segment of tibia in female Sprague–Dawley rats. Radiograms and micro-CT images were obtained to confirm tumor growth. Bupivacaine was injected peritumorally at day 7 or day 14 post-tumor induction, and withdrawal thresholds in response to pressure and punctate mechanical stimulus were recorded from the knee and hind-paw, respectively. Immunohistochemical studies for the determination of ATF3 and GFAP expression in DRG and spinal cord sections were performed.


          Rats developed primary and distal hyperalgesia after MRMT-1 administration that was sustained for 2 weeks. Peritumoral administration of bupivacaine in 7-day post-tumor-induced (PTI) rats resulted in a reversal of both primary and distal hyperalgesia for 20–30 mins. However, bupivacaine failed to reverse distal hyperalgesia in 14 day-PTI rats. ATF3 and GFAP expression were much enhanced in 14 day-PTI animals, compared to 7 day-PTI group.


          Results from this study strongly suggest that distal hyperalgesia of late-stage CIBP demonstrates differential characteristics consistent with neuropathic pain as compared to early stage, which appears more inflammatory in nature.

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          Models and mechanisms of hyperalgesia and allodynia.

          Hyperalgesia and allodynia are frequent symptoms of disease and may be useful adaptations to protect vulnerable tissues. Both may, however, also emerge as diseases in their own right. Considerable progress has been made in developing clinically relevant animal models for identifying the most significant underlying mechanisms. This review deals with experimental models that are currently used to measure (sect. II) or to induce (sect. III) hyperalgesia and allodynia in animals. Induction and expression of hyperalgesia and allodynia are context sensitive. This is discussed in section IV. Neuronal and nonneuronal cell populations have been identified that are indispensable for the induction and/or the expression of hyperalgesia and allodynia as summarized in section V. This review focuses on highly topical spinal mechanisms of hyperalgesia and allodynia including intrinsic and synaptic plasticity, the modulation of inhibitory control (sect. VI), and neuroimmune interactions (sect. VII). The scientific use of language improves also in the field of pain research. Refined definitions of some technical terms including the new definitions of hyperalgesia and allodynia by the International Association for the Study of Pain are illustrated and annotated in section I.
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            Pain and nociception: mechanisms of cancer-induced bone pain.

            Cancer pain, especially pain caused by metastasis to bone, is a severe type of pain, and unless the cause and consequences can be resolved, the pain will become chronic. As detection and survival among patients with cancer have improved, pain has become an increasing challenge, because traditional therapies are often only partially effective. Until recently, knowledge of cancer pain mechanisms was poor compared with understanding of neuropathic and inflammatory pain states. We now view cancer-induced bone pain as a complex pain state involving components of both inflammatory and neuropathic pain but also exhibiting elements that seem unique to cancer pain. In addition, the pain state is often unpredictable, and the intensity of the pain is highly variable, making it difficult to manage. The establishment of translational animal models has started to reveal some of the molecular components involved in cancer pain. We present the essential pharmacologic and neurobiologic mechanisms involved in the generation and continuance of cancer-induced bone pain and discuss these in the context of understanding and treating patients. We discuss changes in peripheral signaling in the area of tumor growth, examine spinal cord mechanisms of sensitization, and finally address central processing. Our aim is to provide a mechanistic background for the sensory characteristics of cancer-induced bone pain as a basis for better understanding and treating this condition.
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              Molecular mechanisms of cancer pain.

              Pain is the most disruptive influence on the quality of life of cancer patients. Although significant advances are being made in cancer treatment and diagnosis, the basic neurobiology of cancer pain is poorly understood. New insights into these mechanisms are now arising from animal models, and have the potential to fundamentally change the way that cancer pain is controlled.

                Author and article information

                J Pain Res
                J Pain Res
                Journal of Pain Research
                02 June 2020
                : 13
                : 1305-1313
                [1 ]Center for Nanosciences & Molecular Medicine, Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham University , Kochi, Kerala 682041, India
                Author notes
                Correspondence: Sahadev A Shankarappa Center for Nanosciences and Molecular Medicine,Amrita Institute of Medical Sciences and Research Center, Amrita Vishwa Vidyapeetham University , Kochi, Kerala682041, IndiaTel +91 4842 801234 (Ext 8705) Email sahadevs@icloud.com

                These authors contributed equally to this work

                © 2020 Mathew et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 4, References: 49, Pages: 9
                M. Tech Nanomedical project grant (DST, Govt. of India) to SEM, CSIR fellowship (DST, Govt. of India) to PM, and grants 6242-P75/RGCB/PMD/DBT/SDSA/2015, BT/PR24515/MED/30/1926/2017 (DBT, Govt. of India), and the Ramalingaswami fellowship (DBT, Govt. of India) to SS.
                Original Research


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