Evidence for a central component of post-injury pain hypersensitivity
TL;DR: An animal model is developed where changes occur in the threshold and responsiveness of the flexor reflex following peripheral injury that are analogous to the sensory changes found in man, and shows that it in part arises from changes in the activity of the spinal cord.
Abstract: Noxious skin stimuli which are sufficiently intense to produce tissue injury, characteristically generate prolonged post-stimulus sensory disturbances that include continuing pain, an increased sensitivity to noxious stimuli and pain following innocuous stimuli. This could result from either a reduction in the thresholds of skin nociceptors (sensitization)1,2 or an increase in the excitability of the central nervous system so that normal inputs now evoke exaggerated responses3,4. Because sensitization of peripheral receptors occurs following injury5–7, a peripheral mechanism is widely held to be responsible for post-injury hypersensitivity. To investigate this I have now developed an animal model where changes occur in the threshold and responsiveness of the flexor reflex following peripheral injury that are analogous to the sensory changes found in man. Electrophysiological analysis of the injury-induced increase in excitability of the flexion reflex shows that it in part arises from changes in the activity of the spinal cord. The long-term consequences of noxious stimuli result, therefore, from central as well as from peripheral changes.
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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
Journal Article•
4,241 citations
TL;DR: Here, a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain is developed, identifying distinct forms of Plasticity, which are term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.
Abstract: We describe those sensations that are unpleasant, intense, or distressing as painful. Pain is not homogeneous, however, and comprises three categories: physiological, inflammatory, and neuropathic pain. Multiple mechanisms contribute, each of which is subject to or an expression of neural plasticity-the capacity of neurons to change their function, chemical profile, or structure. Here, we develop a conceptual framework for the contribution of plasticity in primary sensory and dorsal horn neurons to the pathogenesis of pain, identifying distinct forms of plasticity, which we term activation, modulation, and modification, that by increasing gain, elicit pain hypersensitivity.
3,543 citations
TL;DR: Genetic, electrophysiological, and pharmacological studies are elucidating the molecular mechanisms that underlie detection, coding, and modulation of noxious stimuli that generate pain.
3,394 citations
Cites background from "Evidence for a central component of..."
...Persistent Pain: Central Mechanisms Central sensitization refers to the process through which a state of hyperexcitability is established in the central nervous system, leading to enhanced processing of nociceptive (pain) messages (Woolf, 1983)....
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...Central sensitization refers to the process through which a state of hyperexcitability is established in the central nervous system, leading to enhanced processing of nociceptive (pain) messages (Woolf, 1983)....
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TL;DR: 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.
Abstract: 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.
3,331 citations
Cites background from "Evidence for a central component of..."
...In 1983 I published a study indicating that many features of the pain hypersensitivity accompanying peripheral tissue injury or inflammation were the direct result of an augmentation of sensory signaling in the central nervous system [255]....
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...Published by du study on stimulus–response relations in the spinal cord was that the afferent activity induced by peripheral injury triggered a long-lasting increase in the excitability of spinal cord neurons, profoundly changing the gain of the somatosensory system [255]....
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References
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TL;DR: The results support the conclusion that altered activity in CMH nociceptors is a major peripheral determinant of cutaneous hyperalgesia following a mild heat injury to the skin.
Abstract: Pain thresholds in humans were determined for heat stimulations of the skin before and after a mild injury induced by a single conditioning stimulus (CS) of 50 degrees C and 100 sec duration. The same stimuli were delivered to the receptive fields of C fiber and A fiber mechanoheat-sensitive nociceptors (CMH and AMH nociceptors, respectively) and of low threshold warm and cold receptors in the anesthetized monkey and to the receptive fields of CMH nociceptors recorded percutaneously from the peroneal nerve of awake humans. Pain thresholds in normal skin were matched only by the response thresholds of CMH and not AMH nociceptors. Immediately following heat injury, some pain thresholds and CMH response thresholds were elevated, but by 5 to 10 min after the CS, pain and CMH thresholds were lowered to 2 to 6 degrees C below normal (hyperalgesia and nociceptor sensitization). No other type of cutaneous receptor studied exhibited changes in threshold similar to those observed for pain and for CMH nociceptors. The magnitude of hyperalgesia in humans and the magnitude of sensitization of CMH nociceptors in monkeys following heat injury were greater for hairy than for glabrous skin. The time course of the development of hyperalgesia was not altered by ischemia or conduction block in A fibers. The results support the conclusion that altered activity in CMH nociceptors is a major peripheral determinant of cutaneous hyperalgesia following a mild heat injury to the skin.
285 citations
TL;DR: Cutaneous hyperalgesia occurring in undamaged tissues adjacent to and at some distance from the site of an injury or a site of noxious stimulation is concerned.
Abstract: Hyperalgesia may be defined as a state of increased intensity of pain sensation induced by either noxious or ordinarily non-noxious stimulation of peripheral tissue. Hyperalgesia occurs in both superficial and deep tissues, in areas with pain thresholds that are normal, lowered or raised (1, 2). As seen at the bedside there are apparently several varieties of hyperalgesia, and few clinical phenomena are more difficult to understand and to evaluate. The literature on the subject includes work of a distinguished roster of investigators (3-8). As a result of these studies two classes of hyperalgesia have been loosely formulated, namely, that occurring at the site of injury, and that associated with the injury but occurring in undamaged tissue. Failure to outline clearly the characteristics of these two varieties of hyperalgesia has resulted in a controversy as regards the alterations responsible for the hyperalgesia occurring in undamaged tissue. One group holds that this hyperalgesia is attributable to changes in the periphery, whereas the other maintains that changes in the central nervous system are responsible. Due to the lack of quantitative methods of measuring perception, progress has been slow in clarifying an understanding of the underlying mechanisms. This communication is concerned primarily with that cutaneous hyperalgesia occurring in undamaged tissues adjacent to and at some distance from the site of an injury or a site of noxious stimulation.
271 citations
214 citations
TL;DR: It was shown that the low heat thresholds of some CMHs were not due to sensitization by preceding heat stimuli, and it was argued that low-frequency discharges observed in some nociceptiveCMHs of the rat at non-noxious temperatures are insignificant for nocICEption.
151 citations
TL;DR: Results show normal sensitization of polymodal nociceptor units with unmyelinated axons isolated from rabbit sural nerves on repeated heating of their receptive fields, measured here as a drop in mean heat threshold.
Abstract: 1. Ninety-three polymodal nociceptor units with unmyelinated axons were isolated from rabbit sural nerves. Twenty-three were used for control data. These showed normal sensitization on repeated heating of their receptive fields, measured here as a drop in mean heat threshold. 2. Small injuries were made 5 (n = 15) or 10 (n = 12) mm outside the receptive fields of some polymodal nociceptors. This resulted in the development of spontaneous firing and lowered thresholds to heating of the receptive field. 3. Local anaesthetic previously injected into the site of injury blocked this spread of heat sensitization. Previous injection of saline had no effect. 4. Antidromic stimulation of the sural nerve, proximal to the recording site, also resulted in heat sensitization of polymodal nociceptors (n = 10). 5. Possible mechanisms for the spread of sensitization of polymodal nociceptors from nearby injury are discussed. Analogies are drawn between these results and those of Lewis (1935--36) on the spread of cutaneous ;yperalgesia around a skin injury in man.
110 citations