Physiologic and Antinociceptive Effects of Intrathecal Resiniferatoxin in a Canine Bone Cancer Model

Brown, Dorothy Cimino; Iadarola, Michael J.; Perkowski, Sandra Z.; Erin, Hardam; Shofer, Frances S.; Laszlo, Karai J.; Oláh, Zoltán; Mannes, Andrew J.

doi:10.1097/00000542-200511000-00020

Cited by 159 publications

(168 citation statements)

References 23 publications

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“…It is also worth noting that while pain due to cancer may only partly arise from neuropathy, TRPV1 antagonists have exhibited effectiveness in models of cancer pain [117,118].…”

Section: Pre-clinical Overview Of Trpv1 Antago-nistsmentioning

confidence: 99%

TRPV1 Antagonists as Analgesic Agents

Trevisani

Gatti²

2013

TOPAINJ

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Abstract:The last decade (2001 -2010), declared as the Decade of Pain Control and Research by the United States Congress, brought significantly advances in our understanding of pain biology. Unfortunately, this has not translated into additional effective treatments of chronic pain conditions. Chronic pain is a debilitating and complex clinical state usually associated with diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. Standard pain drugs, even narcotic opioid analgesic agents, often provide unsatisfactory pain relief while causing important side-effect such as sedation, tolerance, dependence, respiratory depression and constipation. Furthermore, the effective management of chronic pain needs a multidisciplinary management approach and still represents one of the most urgent unmet medical need. Recently, preclinical research has uncovered new molecular mechanisms underlying the generation and transduction of pain, many of which represent new targets for innovative pharmacological interventions. This review focuses on Transient Receptor Potential (TRP) Vanilloid Type 1 (TRPV1) channel as a target for treating chronic pain. TRPV1 is a multifunctional ion channel involved in thermosensation (heat) and taste perception. Importantly, TRPV1 also functions as a molecular integrator for a broad variety of seemingly unrelated noxious stimuli. Indeed, TRPV1 is thought to be a major transducer of the thermal hyperalgesia that follows inflammation and/or tissue injury. Desensitization to topical TRPV1 agonists (e.g. capsaicin creams and patches) has been in clinical use for decades to treat chronic painful conditions like diabetic neuropathy. Most recently, a number of potent, small molecule TRPV1 antagonists have been advanced into clinical trials for pain relief. Perhaps not unexpectedly given the prominent role of TRPV1 in thermosensation, some of these antagonists showed worrisome adverse effects (hyperthermia and impaired noxious heat sensation) in humans, leading to their withdrawal from clinical trials. However, recent reports of TRPV1 antagonists that do not affect core body temperature in preclinical species suggest a potential opportunity to reduce at least this important side effect.

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“…It is also worth noting that while pain due to cancer may only partly arise from neuropathy, TRPV1 antagonists have exhibited effectiveness in models of cancer pain [117,118].…”

Section: Pre-clinical Overview Of Trpv1 Antago-nistsmentioning

confidence: 99%

TRPV1 Antagonists as Analgesic Agents

Trevisani

Gatti²

2013

TOPAINJ

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“…We have divided our discussion to address models for pain due to bone cancer, nonbone cancer, cancer invasion, cancer chemotherapy-related peripheral neuropathy; and spontaneously occurring cancer. 19,76,100,185 The most commonly used animal models of cancer pain have been developed in rodents, and therefore much of this review focuses on rodent models. However, recently described naturally occurring tumor models in dogs and cats have been developed, and these models also will be presented.…”

Section: New Approaches Using Animal Modelsmentioning

confidence: 99%

Animal Models of Cancer Pain

Pacharinsak

Beitz²

2010

Animal Models of Pain

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220Pain is one of the most common and distressing symptoms experienced by both human and veterinary oncology patients with advanced cancer. In humans, unrelieved pain can disrupt and interfere with activities of daily living, quality of life, and mood, 26,173 and domestic animals typically are euthanized when pain is no longer adequately controlled. 138 New developments in cancer detection and therapy have occurred over the past decade. These developments are contributing to longer life expectancies and have raised important issues related to quality of life, as attention has focused increasingly on how to manage cancer pain effectively. 91,115,134 This increased attention is true in the fields of both human and veterinary medicine. Human cancer patients who are in advanced stages of the disease, particularly those with bone metastasis, report that they experience significant pain, and pain intensity appears to be related to the degree of bone destruction. Similarly, pain secondary to cancer in domestic animals is a key concern in veterinary practice and should be addressed promptly to alleviate suffering, stress, and anxiety and to improve quality of life. Not only do cancer patients have to deal with persistent pain, they also often experience 'breakthrough pain.' Breakthrough pain-intermittent episodes of extreme pain-occurs spontaneously or after movement or weight-bearing of the affected leg. 114,133 Canine osteosarcoma has many clinical and biological similarities to human osteosarcoma, and affected dogs show signs of both ongoing and breakthrough pain. 37 In addition to cancer-induced pain, human patients also experience pain caused by the very therapies used to treat the cancer. Almost 30% of adult cancer patients and 60% of pediatric cancer patients who have undergone treatments that include radiation, chemotherapy, or surgery also have experienced pain resulting from these therapeutic procedures. 49,174 Whether radiation treatment and chemotherapy also induce pain in domestic animals is virtually impossible to address, because carefully controlled studies have not examined this issue.Pain intensity varies among cancer patients and is dependent on a patient's pain sensitivity, the type of cancer, and the tumor location. 48,49 Cancer treatment guidelines provided by the World Health Organization have been used in oncology and pain treatment clinics. 20,25,92,113,117,119,163 Treatment of human cancer patients include the use of opioids, nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, local anesthetics, antidepressants, and anticonvulsants either alone or in combination. Similarly in veterinary medicine, the goal of palliative therapy in cancer patients is to control pain from an incurable tumor and to support overall quality of life. 165 Therefore, opioids, NSAIDs, and bisphosphonates are used in addition to surgery and radiation therapy and are the drugs of choice in treating domestic animals with cancer pain, particularly those suffering from osteosarcoma and other forms of bone cancer. 1...

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“…Administration of a vanilloid agonist, such as capsaicin or its ultrapotent analog RTX [31], can cause calcium-induced cytotoxicity and lead to a TRPV1-selective axonopathy that spares surrounding non-TRPV1-expressing somatosensory proprioceptive afferent and motor efferent nerve fibers. The potency and selectivity of vanilloid agonists for TRPV1 afferents has been demonstrated repeatedly in vivo [8,[32][33][34][35][36][37][38][39][40]. For example, ablation of TRPV1 + nerve terminals occurring after a single subcutaneous injection of RTX into the rat hind paw results in prolonged but reversible analgesia that can be detected for one to several weeks and induces up-regulation of molecular markers for axon damage/repair in neuronal perikarya of the dorsal root ganglia [8,32].…”

Section: Introductionmentioning

confidence: 99%

“…While the actions of peripherally administered RTX are localized and reversible, RTX given intrathecally produces a spatially broader effect over multiple dermatomes with permanent pain relief [33,34,36]. The therapeutic efficacy of intrathecal RTX is especially evident in veterinary canine patients with naturally-occurring osteosarcoma [34], and RTX delivered intrathecally to treat advanced cancer pain in humans is currently in a Phase I clinical trial (<http:// clinicalstudies.info.nih.gov/detail/A_2009-D-0039.html>).…”

Section: Introductionmentioning

confidence: 99%

“…Because TRPV1 agonists are painful initially upon application, in general, administration of a TRPV1 agonist necessitates pretreatment with a local anesthetic and, in the case of intrathecal administration, general anesthesia, which requires the patient to be either in the clinic or in the operating room. In addition, while capsaicin is effective when administered focally to treat Morton's neuroma or osteoarthritis [45] and RTX is effective when administered intrathecally to treat osteosarcoma [34], they generally cannot be given systemically in large doses since they produce a decrease in core body temperature and may be cardiotoxic, although there is a much larger safety margin for RTX [29]. Thus while some conditions may be amenable to local, interventional TRPV1 agonist administration, other pain conditions, where pain is more diffuse or delocalized, may not be appropriate candidates for treatment with localized therapies.…”

Section: Introductionmentioning

confidence: 99%

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Positive allosteric modulation of TRPV1 as a novel analgesic mechanism

Lebovitz

Kaszás

Keller

et al. 2012

The Journal of Pain

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Background: The prevalence of long-term opiate use in treating chronic non-cancer pain is increasing, and prescription opioid abuse and dependence are a major public health concern. To explore alternatives to opioid-based analgesia, the present study investigates a novel allosteric pharmacological approach operating through the cation channel TRPV1. This channel is highly expressed in subpopulations of primary afferent unmyelinated C-and lightly-myelinated Aδ-fibers that detect low and high rates of noxious heating, respectively, and it is also activated by vanilloid agonists and low pH. Sufficient doses of exogenous vanilloid agonists, such as capsaicin or resiniferatoxin, can inactivate/deactivate primary afferent endings due to calcium overload, and we hypothesized that positive allosteric modulation of agonist-activated TRPV1 could produce a selective, temporary inactivation of nociceptive nerve terminals in vivo. We previously identified MRS1477, a 1,4-dihydropyridine that potentiates vanilloid and pH activation of TRPV1 in vitro, but displays no detectable intrinsic agonist activity of its own. To study the in vivo effects of MRS1477, we injected the hind paws of rats with a non-deactivating dose of capsaicin, MRS1477, or the combination. An infrared diode laser was used to stimulate TRPV1-expressing nerve terminals and the latency and intensity of paw withdrawal responses were recorded. qRT-PCR and immunohistochemistry were performed on dorsal root ganglia to examine changes in gene expression and the cellular specificity of such changes following treatment.

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Physiologic and Antinociceptive Effects of Intrathecal Resiniferatoxin in a Canine Bone Cancer Model

Abstract: Intrathecal resiniferatoxin elicits transient hemodynamic effects. In controls, a profound and sustained blockade of thermal stimuli is produced in a dose-dependent fashion. Similar administration in dogs with bone cancer produces a prolonged antinociceptive response.

Cited by 159 publications

References 23 publications

TRPV1 Antagonists as Analgesic Agents

TRPV1 Antagonists as Analgesic Agents

Animal Models of Cancer Pain

Positive allosteric modulation of TRPV1 as a novel analgesic mechanism

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