I have developed "tennis elbow" from lugging this book around the past four weeks, but it is worth the pain, the effort, and the aspirin. It is also worth the (relatively speaking) bargain price. Including appendixes, this book contains 894 pages of text. The entire panorama of the neural sciences is surveyed and examined, and it is comprehensive in its scope, from genomes to social behaviors. The editors explicitly state that the book is designed as "an introductory text for students of biology, behavior, and medicine," but it is hard to imagine any audience, interested in any fragment of neuroscience at any level of sophistication, that would not enjoy this book. The editors have done a masterful job of weaving together the biologic, the behavioral, and the clinical sciences into a single tapestry in which everyone from the molecular biologist to the practicing psychiatrist can find and appreciate his or

Principles of Neural Science

Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.

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Central sensitization: implications for the diagnosis and treatment of pain.

Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

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Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

Repetitive stimulation of small diameter primary afferent fibres produces a progressive increase in action potential discharge (windup) and a prolonged increase in the excitability of neurones in the spinal cord following the stimulus. Previous studies have demonstrated that windup is the consequence of the temporal summation of slow synaptic potentials and that the slow potentials and windup are reduced by pretreatment with N-methyl-D-aspartic acid (NMDA) antagonists. We have now examined whether primary afferent induced hypersensitivity states in flexor motoneurones are also dependent on the activation of NMDA receptors and whether windup is a possible trigger for the production of the central hypersensitivity. Both a non-competitive (MK-801) and a competitive (D-CPP) NMDA antagonist, at doses that did not modify the baseline reflex, reduced the facilitation of the flexor reflex produced by either brief electrical stimulation of the sural nerve (1 Hz for 20 sec at C-fibre strength), or by the cutaneous application of the chemical irritant mustard oil. These antagonists also prevented windup from occurring in the motoneurones. When the the MK-801 and the D-CPP were administered once a state of central facilitation had been induced by prior treatment with mustard oil, they returned the facilitated reflex to its pretreatment level. These results indicate that NMDA receptors are involved in the induction and maintenance of the central sensitization produced by high threshold primary afferent inputs. Because central sensitization is likely to contribute to the post-injury pain hypersensitivity states in man, these data have a bearing both on the potential role of NMDA antagonists for pre-emptive analgesia and for treating established pain states.

The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states.

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The induction of pain: an integrative review

For the first time a book that addresses all aspects of muscle pain from basic science to clinical treatment. This book answers all possible questions regarding muscle pain--from local muscle soreness to the fibromyalgia syndrome. The unique concept behind the book is the combination of neuroanatomical and neurophysiological data with the clinical management of all diseases that exhibit muscle pain

Muscle Pain: Understanding Its Nature, Diagnosis and Treatment

Appearance of new receptive fields in rat dorsal horn neurons following noxious stimulation of skeletal muscle: a model for referral of muscle pain?

Sensory innervation of the thoracolumbar fascia in rats and humans.

Excitatory effects of 5-hydroxytryptamine, histamine and potassium ions on muscular group IV afferent units: a comparison with bradykinin.

Certain pathological types of afferent input are supposed to lead to long-term changes in the responsiveness of dorsal horn neurones. This mechanism might be of importance for the development of neurological disturbances such as chronic pain. The present study was undertaken in order to find out whether dorsal horn neurones— particularly those processing input from deep tissues— exhibit long-lasting changes in response behaviour after a short-lasting noxious stimulation of deep tissue. In anaesthetized cats, the impulse activity of single dorsal horn cells was recorded extracellularly with glass microelectrodes. In a small number of cells that had multiple receptive fields (RFs), the algesic agent bradykinin was injected into a muscle RF and the properties of all RFs retested at regular time intervals. Following noxious chemical stimulation of one RF, the injected and the other RFs of the same neurone often showed changes which consisted of an increase in size, a lowering of mechanical threshold and appearance of new RFs. In an attempt to assess the influence of a single noxious stimulus on the entire population of dorsal horn cells, the properties of a greater sample of neurones were compared before and after injection of bradykinin into the deep tissues of the hind limb. Every cell encountered was classified as being driven by (1) cutaneous receptors only, (2) deep receptors only, (3) both input sources, or (4) electrical stimulation only (cell without receptive field). Following injection of bradykinin, the proportion of cells with both deep and cutaneous input and of those having background activity rose, and the percentage of cells without a receptive field decreased. The data indicate that any noxious manipulation of the hind limb may elicit long-lasting changes in the response behaviour of dorsal horn neurones. This assumption was supported by the finding that in animals in which the hind limb had been operated on, the proportion of cells with deep and cutaneous input was significantly higher and that of cells with exclusively deep input lower than in animals with an intact hind limb. Transferring these findings to the clinical situation, the data suggest that the increase in size of the RFs and the appearance of new RFs after a noxious stimulus might reflect the spread or irradiation of deep pain. Likewise, the increase in convergence of deep and cutaneous afferents might be of relevance for the referral of deep pain to the skin, while the decrease in mechanical threshold of deep RFs remote to the location of the noxious stimulus might be the neurophysiological basis of referred tenderness.

Siegfried Mense

Papers

Muscle Pain: Understanding Its Nature, Diagnosis and Treatment

Appearance of new receptive fields in rat dorsal horn neurons following noxious stimulation of skeletal muscle: a model for referral of muscle pain?

Sensory innervation of the thoracolumbar fascia in rats and humans.

Excitatory effects of 5-hydroxytryptamine, histamine and potassium ions on muscular group IV afferent units: a comparison with bradykinin.

Long-term changes in discharge behaviour of cat dorsal horn neurones following noxious stimulation of deep tissues.