Characterisation of ultraviolet-B-induced inflammation as a model of hyperalgesia in the rat.
TL;DR: It is concluded that UVB inflammation produces a dose‐dependent hyperalgesic state sensitive to established analgesics, which suggests thatUVB inflammation in the rat may represent a useful translational tool in the study of pain and the testing of analgesic agents.
Abstract: In humans, the acute inflammatory reaction caused by ultraviolet (UV) radiation is well studied and the sensory changes that are found have been used as a model of cutaneous hyperalgesia. Similar paradigms are now emerging as rodent models of inflammatory pain. Using a narrowband UVB source, we irradiated the plantar surface of rat hind paws. This produced the classical feature of inflammation, erythema, and a significant dose-dependent reduction in both thermal and mechanical paw withdrawal thresholds. These sensory changes peaked 48 h after irradiation. At this time there is a graded facilitation of noxious heat evoked (but not basal) c-fos-like immunoreactivity in the L4/5 segments of the spinal cord. We also studied the effects of established analgesic compounds on the UVB-induced hyperalgesia. Systemic as well as topical application of ibuprofen significantly reduced both thermal and mechanical hyperalgesia. Systemic morphine produced a dose-dependent and naloxone sensitive reversal of sensory changes. Similarly, the peripherally restricted opioid loperamide also had a dose-dependent anti-hyperalgesic effect, again reversed by naloxone methiodide. Sequestration of NGF, starting at the time of UVB irradiation, significantly reduced sensory changes. We conclude that UVB inflammation produces a dose-dependent hyperalgesic state sensitive to established analgesics. This suggests that UVB inflammation in the rat may represent a useful translational tool in the study of pain and the testing of analgesic agents.
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TL;DR: Mechanisms by which NGF activation of its cognate receptor, tropomyosin-related kinase A receptor, regulates a host of ion channels, receptors, and signaling molecules to enhance acute and chronic pain are outlined.
Abstract: Nerve growth factor (NGF) was originally discovered as a neurotrophic factor essential for the survival of sensory and sympathetic neurons during development. However, in the adult NGF has been found to play an important role in nociceptor sensitization after tissue injury. The authors outline mechanisms by which NGF activation of its cognate receptor, tropomyosin-related kinase A receptor, regulates a host of ion channels, receptors, and signaling molecules to enhance acute and chronic pain. The authors also document that peripherally restricted antagonism of NGF-tropomyosin-related kinase A receptor signaling is effective for controlling human pain while appearing to maintain normal nociceptor function. Understanding whether there are any unexpected adverse events and how humans may change their behavior and use of the injured/degenerating tissue after significant pain relief without sedation will be required to fully appreciate the patient populations that may benefit from these therapies targeting NGF.
289 citations
Cites background from "Characterisation of ultraviolet-B-i..."
...ministration of a TrkA-IgG fusion protein minimized behavioral symptoms of hyperalgesia induced by carrageenan(112,113) or ultraviolet B radiation.(62) In addition, although not consid-...
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...Moreover, NGF is up-regulated in experimental models of inflammation, including those induced by carrageenan, formalin, and complete Freund’s adjuvant, as well as in models of autoimmune arthritis(61) and ultraviolet-B-radiation–induced acute inflammation.(62) Cutaneous administration of NGF to rodents(63) and humans(64) causes hyperalgesia within 1 or 3 h, respectively, suggesting that NGF leads to a relatively rapid sensitization of cutaneous nociceptors....
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TL;DR: This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons.
Abstract: Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excit...
256 citations
Cites background from "Characterisation of ultraviolet-B-i..."
...A topically applied COX inhibitor reduced both heat and mechanical hyperalgesia induced by ultraviolet B irradiation in the rat hindpaw (57)....
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TL;DR: The calcium-permeable TRPV4 ion channel in skin epithelial cells is identified as critical for translating the UVB stimulus into intracellular signals and also into signals from epithelial skin cell to sensory nerve cell that innervates the skin, causing pain.
Abstract: At our body surface, the epidermis absorbs UV radiation. UV overexposure leads to sunburn with tissue injury and pain. To understand how, we focus on TRPV4, a nonselective cation channel highly expressed in epithelial skin cells and known to function in sensory transduction, a property shared with other transient receptor potential channels. We show that following UVB exposure mice with induced Trpv4 deletions, specifically in keratinocytes, are less sensitive to noxious thermal and mechanical stimuli than control animals. Exploring the mechanism, we find that epidermal TRPV4 orchestrates UVB-evoked skin tissue damage and increased expression of the proalgesic/algogenic mediator endothelin-1. In culture, UVB causes a direct, TRPV4-dependent Ca2+ response in keratinocytes. In mice, topical treatment with a TRPV4-selective inhibitor decreases UVB-evoked pain behavior, epidermal tissue damage, and endothelin-1 expression. In humans, sunburn enhances epidermal expression of TRPV4 and endothelin-1, underscoring the potential of keratinocyte-derived TRPV4 as a therapeutic target for UVB-induced sunburn, in particular pain.
203 citations
TL;DR: Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA, and the sequestration of NGF using TrkAd5, a soluble receptor protein that binds NGF with picomolar affinity.
Abstract: Chronic pain presents a huge economic and social burden, with existing treatments largely unable to satisfy medical needs. Recently, studies have shown that nerve growth factor (NGF) is a major mediator of inflammatory and neuropathic pain, providing a new therapeutic target. Although originally discovered as a trophic factor for sympathetic and sensory neurons during development, it now appears that in adults, levels of NGF are elevated in many acute and chronic pain conditions. Furthermore, preclinical animal models of inflammatory and neuropathic pain also show increased NGF levels, while the sequestration of NGF alleviates the associated hyperalgesia. The molecular mechanisms involved are being elucidated. This review briefly examines pain signaling pathways and describes currently available analgesics. It then investigates the approaches taken in targeting NGF-mediated pain. Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA (also known as neurotrophic tyrosine kinase receptor, type 1 [NTRK1]), and the sequestration of NGF using TrkA domain 5 (TrkAd5), a soluble receptor protein that binds NGF with picomolar affinity. Administration of either antibodies or TrkAd5 has been shown to be effective in a number of preclinical models of pain, including cystitis, osteoarthritis, UV irradiation (sunburn), and skeletal bone pain due to fracture or cancer. Other possible future therapies examined in this review include small-molecule TrkA antagonists, which target either the extracellular NGF binding domain of TrkA or its intracellular tyrosine kinase domain.
170 citations
TL;DR: A broad range of pharmacological and non-pharmacological strategies to prevent or treat pain is described in depth and the important issue of humane endpoints is central to any strategy dedicated to reduce or avoid unnecessary pain and distress, without compromising the scientific validity of the studies.
Abstract: Over the last few years, there has been an increasing interest in the ethical aspects related to the use of animals in research, with particular attention to pain and distress associated with experimental procedures. Back in 1992, the National Research Council (NRC) published the report Recognition and Alleviation of Pain and Distress in Laboratory Animals. Although pain and distress are often addressed together as components of the animal’s wellbeing, they differ from the physiological and management point of view. The significant scientific progress made since the publication of the first report made an update necessary, and quite rightly, the NRC decided to address both arguments separately. In 2008 it published Recognition and Alleviation of Distress in Laboratory Animals and now comes the present title that deals with the recognition and alleviation of pain in various vertebrate species used in research. The two reports can be read independently but readers interested in animal welfare should benefit from reading both together. Contributions to the book came from members of the NRC’s Committee on Recognition and Alleviation of Pain in Laboratory Animals, and the draft report was peerreviewed by a group of individuals chosen for their diverse perspectives and technical expertise. This extensive review procedure combined with the participation of professionals in the field with different backgrounds ensures that the final report represents a broad view within the laboratory animal science community. The book starts with a very practical Glossary of commonly used terms followed by a brief Summary and Introduction that sets the background and states the purpose of the report. The report itself is organized into five chapters and takes the reader through a logical sequence. The first chapter introduces the definition of pain, underlining the differences between nociception and pain, and analyses the evidence available to support the underlying premise of the book that all vertebrates can experience (conscious) pain. The main argument dealt with on the second chapter is the physiological and anatomical basis of nociception and pain, helping to thoroughly understand the difference between both, and more importantly the implications for animal welfare. In the last part of the book, the authors deal with the more practical aspects and dedicate the next two chapters to recognize and assess the intensity of pain in animals and the strategies adopted to effectively manage pain in a research setting. The review includes all methods currently available such as behavioural assessment, measurement of nociceptive responses (analgesiometry tests), use of biomarkers and brain activity imaging. A broad range of pharmacological and non-pharmacological strategies to prevent or treat pain is described in depth. Last but certainly not least comes a chapter covering the important issue of humane endpoints, which in a research setting is central to any strategy dedicated to reduce or avoid unnecessary pain and distress, without compromising the scientific validity of the studies. In addition, specific issues in each chapter are further developed within boxes, and the chapter ends up with concise conclusions and recommendations, as well as an updated list of references. This structure has the advantage of allowing different reading levels according to the needs and interests of the readers. The book is well written and easy to follow, even for those readers not familiar with the subject. Each chapter can be read independently, with the disadvantage that some of basic concepts are treated more than once making it redundant on occasions (particularly at the beginning). The Commission has included information on the treatment and management of pain for the less common laboratory animal species (birds, fish, reptiles and amphibians) based on the wider availability of practical data for the most common species. I feel that the addition of an appendix including such data for all laboratory species would improve the final result and allow this report to become a reference handbook in the field. Although the conclusions and recommendations section at the end of each chapter represents the view of the authoring committee, the report leaves space to different views and to debate the more controversial or undefined issues. This approach together with the large number of references given allows the reader to enter into the arguments and develop a personal view. I would highly recommend this book to a wide audience, from laboratory animal veterinarians who need to keep abreast of new developments in the field, to researchers who want to find a deeper insight into the behaviour of the animals they use.
158 citations
References
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TL;DR: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals.
Abstract: The Committee for Research and Ethical Issues of the International Association for the Study of Pain (IASP®) is concerned with the ethical aspects of studies producing experimental pain and any suffering it may cause in animals. Such studies are essential if new and clinically relevant knowledge about the mechanisms of pain is to be acquired. Investigations in conscious animals intended to stimulate chronic pain in man are being performed. Such experiments require careful planning to avoid or at least minimize pain in the animals.
7,443 citations
Additional excerpts
...The guidelines of the Committee for Research and Ethical Issues of the IASP (Zimmermann, 1983) were followed....
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...The guidelines of the Committee for Research and Ethical Issues of the IASP (Zimmermann, 1983) were followed....
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TL;DR: Both the thermal method and the Randall‐Selitto mechanical method detected dose‐related hyperalgesia and its blockade by either morphine or indomethacin, but the Thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
Abstract: A method to measure cutaneous hyperalgesia to thermal stimulation in unrestrained animals is described. The testing paradigm uses an automated detection of the behavioral end-point; repeated testing does not contribute to the development of the observed hyperalgesia. Carrageenan-induced inflammation resulted in significantly shorter paw withdrawal latencies as compared to saline-treated paws and these latency changes corresponded to a decreased thermal nociceptive threshold. Both the thermal method and the Randall-Selitto mechanical method detected dose-related hyperalgesia and its blockade by either morphine or indomethacin. However, the thermal method showed greater bioassay sensitivity and allowed for the measurement of other behavioral parameters in addition to the nociceptive threshold.
4,829 citations
"Characterisation of ultraviolet-B-i..." refers methods in this paper
...Thermal response latencies were tested using the method described by Hargreaves et al. (1988)....
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Journal Article•
4,241 citations
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TL;DR: Part 1 Basic aspects: peripheral - peripheral neural mechnaisms of nociception, the course and termination of primary afferent fibres, teh pathophysiology of damaged peripheral nerves, functional chemistry ofPrimary afferent neurons central - the dorsal horn.
Abstract: Introduction. SECTION ONE. . Basic Aspects. Peripheral & Central. . Peripheral Mechanisms of Nociceptors, R.A. Meyer. Inflammatory Pain (Including Cytokines) , J. Levine. Cellular Properties, S. Bevan. Neurotrophins, S.B. Mcmahon. Damaged Peripheral Nerve, M. Devor. Dorsal Horn , C.J. Woolf. Medulla to Thalamus, J. Dostrovsky. Cortex Imaging, M. Ingvar. Fetal -- Neonatal, M. Fitzgerald. Central Pharmacology, T. Yaksh. Dorsal Horn Plasticity, R. Dubner. CNS Modulation, H. Fields. Psychology. Emotions & Psychobiology, K.D. Craig. Cognition, M. Weisenberg. Measurement. Animals, R. Dubner. Children, P.J. Mcgrath. Normal People, R. Gracely. People in Pain, R. Melzack. Other Measures of Pain and Disability, A. De C.Williams, . SECTION TWO: CLINICAL STATES. Soft Tissue, Joints, And Bones. Postoperative Pain, M. Cousins. Osteoarthritis, P.Creamer. Rheumatoid Arthritis, M. Jayson. Muscle and Tendons , D. Newham. Low Back Pain, D.M. Long. Upper Extremity & Neck, A. E. Sola. Fibromyalgia , R. Bennett, . Deep and Visceral Pain. Abdominal, L. Blendis . Heart/Vascular (Including Haemopathies), Procacci. (A), Gynaecology , A.J. Rapkin. (B), Obstetrics, J.S. Mcdonald. Genitourinary, V. Wesselmann. Head. Orofacial, Y. Sharav. Trigeminal, Eye, Ear., J. Zakrzewska. Headache , J. Schoenen. Nerve and Root Damage. Amputation, T.S. Jensen. Peripheral Neuropathies , , J. Scadding. RSD, SMP. Nerve Roots and Arachnoiditis, D. Dubuisson. . Special Cases. (A) , Gender, K. Berkely. (B), Children, C. Berde. Elderly, L. Gagliese. Animals, C.E. Short. Cancer , R.K. Portenoy. (A), Psychiatry and Cancer, W. Breitbart. (B), Pain and Impending Death, C. Saunders. Central Nervous System. Central Pain, J. Boive. Spinal Cord Damage, A. Beric. Pain - Psychological Medicine, H. Merskey. SECTION THREE: THERAPEUTIC ASPECTS. Pharmacology. Methods of Therapeutic Trials, H. Mcquay, . Non-Narcotic Analgesics, K. Brune. Psychotropic Drugs, R.C. Monks. Opioids, R.G. Twycross. Local and Regional Anesthesia, H. Mcquay, . Other Drugs Including Sy
3,121 citations