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.

Muscle fatigue is an exercise-induced reduction in maximal voluntary muscle force. It may arise not only because of peripheral changes at the level of the muscle, but also because the central nervous system fails to drive the motoneurons adequately. Evidence for “central” fatigue and the neural mechanisms underlying it are reviewed, together with its terminology and the methods used to reveal it. Much data suggest that voluntary activation of human motoneurons and muscle fibers is suboptimal and thus maximal voluntary force is commonly less than true maximal force. Hence, maximal voluntary strength can often be below true maximal muscle force. The technique of twitch interpolation has helped to reveal the changes in drive to motoneurons during fatigue. Voluntary activation usually diminishes during maximal voluntary isometric tasks, that is central fatigue develops, and motor unit firing rates decline. Transcranial magnetic stimulation over the motor cortex during fatiguing exercise has revealed focal cha...

Spinal and Supraspinal Factors in Human Muscle Fatigue

The sensation of pain alerts us to real or impending injury and triggers appropriate protective responses. Unfortunately, pain often outlives its usefulness as a warning system and instead becomes chronic and debilitating. This transition to a chronic phase involves changes within the spinal cord and brain, but there is also remarkable modulation where pain messages are initiated - at the level of the primary sensory neuron. Efforts to determine how these neurons detect pain-producing stimuli of a thermal, mechanical or chemical nature have revealed new signalling mechanisms and brought us closer to understanding the molecular events that facilitate transitions from acute to persistent pain.

Molecular mechanisms of nociception

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The induction of pain: an integrative review

Skin plays an important role in mediating our interactions with the world. Recreating the properties of skin using electronic devices could have profound implications for prosthetics and medicine. The pursuit of artificial skin has inspired innovations in materials to imitate skin's unique characteristics, including mechanical durability and stretchability, biodegradability, and the ability to measure a diversity of complex sensations over large areas. New materials and fabrication strategies are being developed to make mechanically compliant and multifunctional skin-like electronics, and improve brain/machine interfaces that enable transmission of the skin's signals into the body. This Review will cover materials and devices designed for mimicking the skin's ability to sense and generate biomimetic signals.

Pursuing prosthetic electronic skin.

Although information from sense organs is used by all animals, only man can verbally report his sensory experience. A brief consideration of these experiences may be useful in providing insight into cutaneous sensory mechanisms. Nonnoxious deformation of the human skin with a stimulator having a small surface area (2–3 mm2) evokes sensations usually referred to as “touch”. If the stimulator remains stationary, the sensation fades. Movement of the stimulator perpendicular to the skin produces changes in the sensory process which allow even rapidly repeated stimuli (e.g. 500 Hz) to be distinguished from stationary ones. When larger stimulators are used, some appreciation of texture can be obtained, and this is enhanced by movement of the stimulating surface across the skin. A smooth stimulator or an insect moving slowly and gently over the skin evokes distinctive sensations usually referred to as “tickle”. A sharp object such as a pin lightly pressed against certain points in the skin leads to an unpleasant experience which differs from touch but is equivocally painful; when the pin is pressed against the skin more firmly it usually elicits pain. Thus, sensations induced by mechanical events can be diverse. Moreover, common experience indicates that they may occur with greater or lesser intensity. On the other hand, neurophysiological experiments defining the properties of cutaneous sense organs have most often been done on animals other than man.

Cutaneous Mechanoreceptors and Nociceptors

1. The characteristics of receptors from the hairy skin of the hind limb of cat were studied by recording from single primary afferent fibres with fine micropipettes. The distinctive features of 513 fibres conducting under 51 m/sec are described.

2. Seventy-four fibres conducting between 6 and 37 m/sec were classified as nociceptors because they responded only to damaging mechanical stimulation of the skin. These fibres responded maximally to pinching the skin with a serrated forceps or to cutting the skin. Noxious heat, noxious cold, acid applied to the receptive field and bradykinin injected into skin cuts did not evoke discharges from such receptors. Typically their receptive fields were 2-5 cm long by 1-2·5 cm wide and consisted of responsive spots (under 1 mm diameter) separated by unresponsive areas. There was a tendency for the most slowly conducting fibres so classified to be the least sensitive.

3. Other afferent fibres had receptive fields similar to the nociceptors; however, they were excited by substantial but not noxious mechanical deformation. Their conduction velocities overlapped those of the nociceptors and extended upwards to 51 m/sec; the most rapidly conducting fibres tended to be the most sensitive to mechanical stimuli. These insensitive mechanoreceptors or moderate pressure receptors adapted more slowly than the nociceptors.

4. The majority of fine myelinated axons originated from hair receptors and had conduction velocities concentrated between 14 and 22 m/sec.

5. The possible relation of these observations to pain and reactions typical of pain is considered.

Myelinated afferent fibres responding specifically to noxious stimulation of the skin

1. The conduction velocities of 278 posterior articular nerve fibres studied in dorsal root filaments ranged from 10 to 110 m/sec. The conduction velocities were distributed similarly to posterior articular nerve fibre diameters determined histologically.

2. Two hundred and nine fibres were slowly adapting. Of these, 140 responded only at both marked flexion and marked extension, forty-seven responded only during flexion and twelve only during extension. Four slowly adapting fibres were activated specifically at intermediate joint positions. Outward twist of the tibia (abducting the foot) enhanced the discharge of most slowly adapting joint fibres.

3. Two rapidly adapting receptor types were noted. Pacinian corpuscle-like receptors (fourteen fibres) responded transiently to joint movement in any direction regardless of initial position. Phasic joint receptors (thirty fibres) were rapidly adapting at most joint positions but could give a low rate sustained discharge when strongly stimulated.

4. Six slowly adapting posterior articular nerve fibres responded to succinylcholine, suggesting that they originated from muscle spindles. Spindle-like receptors were usually tonically active at intermediate joint positions.

5. Eleven slowly conducting myelinated fibres responded only to extreme joint movement, which was probably noxious.

https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/jphysiol.1969.sp008866

Characteristics of knee joint receptors in the cat.

The relative position of our skeletal body parts is determined by the angles of our joints. In the absence of visual cues, joint angle information becomes conscious through a mental image of our body (body image). Introspective attention to the body image indicates that we have the following sensory information concerning a particular joint: knowledge of 1. the angle both when the joint is moving and stationary, and an awareness of 2. the direc­ tion and 3. the speed of angular changes. These three types of information can vary independently (e.g. a given position can be reached by movements

Paul R. Burgess

Papers

Cutaneous Mechanoreceptors and Nociceptors

Myelinated afferent fibres responding specifically to noxious stimulation of the skin

Characteristics of knee joint receptors in the cat.

Signaling of Kinesthetic Information by Peripheral Sensory Receptors

Receptor types in cat hairy skin supplied by myelinated fibers.