Mechanisms of Cancer Pain

Pacharinsak, Cholawat; Beitz, Alvin J.

doi:10.1002/9781118999196.ch3

Cited by 7 publications

(9 citation statements)

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“…Here, we have used a rodent model of cancer-induced bone pain to study the mechanisms driving the analgesic effect of tapentadol observed in cancer patients with bone pain complications. The model and varia- tions of it are based on the implantation of cancer cells into bone in rodents (Pacharinsak and Beitz, 2008;Falk et al, 2012;Currie et al, 2013). This results in a set of peripheral and central changes with a slowly developing behavioural hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

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Spinal neuronal correlates of tapentadol analgesia in cancer pain: A back‐translational approach

Falk

Patel

Heegaard

et al. 2014

European Journal of Pain

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Background: Pain is a common and highly debilitating complication for cancer patients significantly compromising their quality of life. Cancer-induced bone pain involves a complex interplay of multiple mechanisms including both inflammatory and neuropathic processes and also some unique changes. Strong opioids are a mainstay of treatments but side effects are problematic and can compromise optimal pain control. Tapentadol is a novel dual-action drug, both stimulating inhibitory μ-opioid receptors (MOR) and mediating noradrenaline reuptake inhibition (NRI) leading to activation of the inhibitory α-2 adrenoceptor. It has been demonstrated to treat effectively both acute and chronic pain. We here demonstrate the efficacy in a model of cancer-induced bone pain. Methods: MRMT-1 mammary carcinoma cells were inoculated into the tibia of 6-week-old rats and 2 weeks after, the neuronal responses to a wide range of peripheral stimulation were evaluated. The recordings were made from wide-dynamic range neurons in lamina V of the dorsal horn before and after administration of tapentadol as well as antagonists of the two mechanisms, naloxone or atipamezole. Results: We found marked inhibitions of the neuronal activity with efficacy against mechanical, thermal and electrically evoked activity following tapentadol administration. In addition, the effects of the drug were fully reversible by naloxone and partly by atipamezole, supporting the idea of MOR-NRI dual actions. Conclusions: These findings add to the mechanistic understanding of cancer-induced bone pain and support the sparse clinical data indicating a possible use of the drug as a therapeutic alternative for cancer patients with metastatic pain complication.

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Section: Discussionmentioning

confidence: 99%

“…tions of it are based on the implantation of cancer cells into bone in rodents (Pacharinsak and Beitz, 2008;Falk et al, 2012;Currie et al, 2013). This results in a set of peripheral and central changes with a slowly developing behavioural hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Spinal neuronal correlates of tapentadol analgesia in cancer pain: A back‐translational approach

Falk

Patel

Heegaard

et al. 2014

European Journal of Pain

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“…Standardized behaviour tests, commonly used for pain quantification in CIBP and SNI, were used to validate successful implementation of the models (4,(16)(17)(18)(19)(20). In the CIBP model, scoring of limb use demonstrated a significant decrease in limb use on day 18 post surgery ( Figure 1A).…”

Section: Validation Of Pain Condition By Standardized Behaviour Testmentioning

confidence: 99%

Grid-climbing Behaviour as a Pain Measure for Cancer-induced Bone Pain and Neuropathic Pain

2017

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Abstract. Despite Chronic pain affects up to 40% of the general population and consequently has a major socio-economic impact on our society (1, 2). Despite affecting millions of people, chronic pain is generally insufficiently treated, leaving a large number of patients with inadequate pain-relief (2, 3). The low success rate for development of new analgesic therapy has been linked to a poor translation from preclinical findings to clinical effects (4, 5), which have led to extensive criticism of the predictive value of the animal models of chronic pain (5-7). However, animal models are currently the best available tool for testing the analgesic potential of new drugs. A way to increase the probability of successful translation could, therefore, be to rethink the way models are used. There is currently an extensive mismatch between preclinical and clinical assessment of pain, and it likely reduces the chances of translation from preclinical findings to clinical efficacy.Most preclinical research relies on detection of responses to mechanical or thermal stimuli, hence the evaluation of evoked pain. In contrast, clinical research aims at quantifying the subjective pain experience, mainly evaluated by self-reporting systems, such as the numeric or visual analogue scales (8), and hence quantifying ongoing pain. Consequently, preclinical research is focused on stimulus-based evoked responses, mainly mediated by spinal processes, whereas clinical studies are evaluating the pain experience, including perception at supraspinal levels. Rodents are still the primary choice for in vivo models of various pain conditions, and although tradition has favoured quantification of evoked responses, rodents do display aversive motivational states that are similar to aspects of human pain perception (9, 10). Aversive affective functions in animals are likely adaptive survival mechanisms, and are based on the ability to alter behavioural decisions or suspend normal behaviour in order to avoid injury or permit faster healing of a damaged body part. Development of behavioural tests designed to quantify suspension of normal behaviour is, therefore, likely a more relevant readout for human pain assessment, and validation and implementation of such tests might ease the translation from in vivo model to patient.In this study we tested if sparing of the affected leg during grid climbing behaviour can be used as a non-stimuli-evoked behavioural test to quantify neuropathic-spared nerve injury (SNI) and cancer-induced bone (CIBP) pain. The test is based on suspension of the animal's normal behaviour, and hence reflects how the ongoing pain affects that animal's natural behaviour. In addition, the tests are based on objective measures, which reduces the variability that can be associated with application of a given stimuli and interpretation of responses by the experimenter. Materials and MethodsAnimals. Six-week-old male and female C3H/HeNRj mice (Taconic, Tornbjerg, Denmark) were group-housed in Type III IVC cages (Scanbur A/S, Karlslunde...

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“…tactile allodynia) and cold. Paclitaxel is a commonly used chemotherapeutic that increases the expression of Na V 1.7 in the nociceptive afferents 63,64 and induces a robust allodynia in the animal models [65][66][67] . Finally, ATP (adenosine triphosphate) by an action on a variety of purine receptors expressed on afferent terminals and second order neurons and non neuronal cells has been broadly implicated in inflammatory, visceral and neuropathic pain states [57][58][59][60] .…”

Section: Introductionmentioning

confidence: 99%

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Moreno

Catroli

Alemán

et al. 2019

Preprint

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One sentence summary:In situ epigenome engineering approach for genomically scarless, durable, and non-addictive management of pain. ABSTRACTCurrent treatments for chronic pain rely largely on opioids despite their unwanted side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing, with the voltage-gated sodium channel, Na V 1.7 (SCN9A), being perhaps the most promising candidate for analgesic drug development.Specifically, a hereditary loss-of-function mutation in Na V 1.7 leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence similarity between Na V subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na V 1.7 via genome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins as a potential treatment for chronic pain.Towards this end, we first optimized the efficiency of Na V 1.7 repression in vitro in Neuro2A cells, and then by the lumbar intrathecal route delivered both genomeengineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain and BzATP-induced pain. Our results demonstrate: one, effective repression of Na V 1.7 in lumbar dorsal root ganglia; two, reduced thermal hyperalgesia in the inflammatory state; three, decreased tactile allodynia in the neuropathic state; and four, no changes in normal motor function. We anticipate this genomically scarless and non-addictive pain amelioration approach enabling Long-lasting Analgesia via Targeted in vivo Epigenetic Repression of Nav1.7, a methodology we dub pain LATER, will have significant therapeutic potential, such as for preemptive administration in 2 anticipation of a pain stimulus (pre-operatively), or during an established chronic pain state.

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Mechanisms of Cancer Pain

Cited by 7 publications

References 100 publications

Spinal neuronal correlates of tapentadol analgesia in cancer pain: A back‐translational approach

Spinal neuronal correlates of tapentadol analgesia in cancer pain: A back‐translational approach

Grid-climbing Behaviour as a Pain Measure for Cancer-induced Bone Pain and Neuropathic Pain

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

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