Foreword and Preface
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Pain—particularly chronic pain—continues to destroy the lives of millions of people worldwide. There is no nobler goal than achieving the relief of pain and suffering.
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Despite advancing knowledge in the field, the burden of pain remains unacceptably high. Epidemiological studies, many reviewed in this book, point to the high prevalence of chronic pain across the world associated with staggering socioeconomic costs. Unfortunately, existing therapies fail to offer good (let alone complete) pain relief to the majority of these sufferers.
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A good understanding of pain and pain mechanisms can lead to effective therapies.
Section I: Neurobiology of Pain
Chapter 1: Peripheral Mechanisms of Cutaneous Nociception
1.1 SUMMARY
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Nociceptors are a specialized class of primary afferents that respond to intense, noxious stimuli.Unmyelinated nociceptors signal the burning pain from intense heat stimuli applied to the glabrous skin of the hand, as well as the pain from sustained pressure.Myelinated nociceptors signal the sharp pain from heat stimuli applied to hairy skin and from sharp mechanical stimuli. Both myelinated and unmyelinated nociceptors signal pain from chemical stimuli.
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Following a cutaneous injury, enhanced pain in response to cutaneous stimuli, called hyperalgesia, develops at the site of injury (primary hyperalgesia) and in the surrounding uninjured skin (secondary hyperalgesia). Tissue injury leads to enhanced responsiveness of nociceptors, called sensitization, which accounts for primary hyperalgesia. This sensitization is due to the local release of inflammatory mediators. Secondary hyperalgesia is due to sensitization of neurons in the central nervous system.
1.2 INTRODUCTION
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We concentrate on the skin for three reasons. First, sensory receptors in the skin have been more thoroughly studied than receptors in any other tissue. Second, the opportunity to perform correlative psychophysical studies in animals and humans allows powerful inferences to be made regarding function. Third, cutaneous pain sensation is of great clinical significance.
- In the case of the sensory capacity of the skin, cutaneous stimuli may evoke a sense of cooling, warmth, or touch. Warm fibers, which are predominately unmyelinated, are exquisitely sensitive to gentle warming of their punctate receptive fields. Similarly, a subpopulation of the thinly myelinated, Aδ fibers respond selectively to gentle cooling stimuli and encode the sense of cooling. For the sense of touch, different classes of mechanoreceptive afferent fibers are exquisitely sensitive to deformations of the skin.
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mong the many varieties of sensory receptors, nociceptors are distinctive in that they typically respond to the multiple energy forms that produce injury (thermal, mechanical, and chemical stimuli) and provide information to the CNS regarding the location and intensity of noxious stimuli.
- Tissue damage results in a cascade of events that lead to enhanced pain in response to natural stimuli, termed hyperalgesia. A corresponding increase in the responsiveness of nociceptors, called sensitization, occurs.
1.3 PROPERTIES OF NOCICEPTORS IN UNINJURED SKIN
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CMH and AMH is often used to refer to C-fiber mechano-heat–sensitive nociceptors and A-fiber mechano-heat–sensitive nociceptors, respectively.
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CMHs and AMHs may also be referred to as polymodal nociceptors.
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A selection bias occurs: nociceptors with lower thresholds are more likely to be studied.
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Mechanically sensitive afferents (MSAs) and mechanically insensitive afferents (MIAs).
1.3.1 C-Fiber Nociceptors
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Activity of sufficient magnitude in CMHs fibers is thought to evoke a burning pain sensation. Most CMHs respond to chemical stimuli.
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One ion channel involved in the transduction of heat at nerve terminals is thought to be the TRPV1**.
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Signal transduction molecules on keratinocytes may also play a role in heat transduction by inducing the ATP.
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Two types of heat response are observed following a stepped heat stimulus: Quick C (QC) fibers and slow C (SC) fibers.
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(1) the heat threshold of CMHs depends on the temperature at the depth of the receptor and not the rate of increase in temperature, (2) transduction of heat stimuli (conversion of heat energy to action potentials) occurs at different skin depths for different CMHs, and (3) suprathreshold responses of CMHs vary directly with the rate of increase in temperature.
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Given that the depth of CMH terminals varies widely, true heat thresholds are obtained when the rate of increase in temperature is very gradual or when the duration of the stimulus is very long.
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The heat threshold of the majority of CMHs is in a remarkably narrow range of 39–41°C.
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The response of CMHs is also strongly influenced by the stimulus history. Both fatigue and sensitization are observed.
