Descending control of nociception: Specificity, recruitment and plasticity.
TL;DR: Analysis of the circuitry within the RVM reveals that the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain.
About: This article is published in Brain Research Reviews.The article was published on 2009-04-01 and is currently open access. It has received 808 citations till now. The article focuses on the topics: Rostral ventromedial medulla & Periaqueductal gray.
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TL;DR: The dorsal horn provides numerous potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation.
Abstract: Neurons in the spinal dorsal horn process sensory information, which is then transmitted to several brain regions, including those responsible for pain perception. The dorsal horn provides numerous potential targets for the development of novel analgesics and is thought to undergo changes that contribute to the exaggerated pain felt after nerve injury and inflammation. Despite its obvious importance, we still know little about the neuronal circuits that process sensory information, mainly because of the heterogeneity of the various neuronal components that make up these circuits. Recent studies have begun to shed light on the neuronal organization and circuitry of this complex region.
1,111 citations
TL;DR: Current work in this field is providing researchers with a more thorough understanding of nociceptor cell biology at molecular and systems levels and insight that will allow the targeted design of novel pain therapeutics.
Abstract: Specialized peripheral sensory neurons known as nociceptors alert us to potentially damaging stimuli at the skin by detecting extremes in temperature and pressure and injury-related chemicals, and transducing these stimuli into long-ranging electrical signals that are relayed to higher brain centers. The activation of functionally distinct cutaneous nociceptor populations and the processing of information they convey provide a rich diversity of pain qualities. Current work in this field is providing researchers with a more thorough understanding of nociceptor cell biology at molecular and systems levels and insight that will allow the targeted design of novel pain therapeutics.
955 citations
Cites background from "Descending control of nociception: ..."
...itization of pain perception relative to other competing behavioral needs and homeostatic demands (39)....
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TL;DR: This review focuses on the molecular determinants of network plasticity in the central nervous system (CNS) and discusses their relevance to the development of new therapeutic approaches.
Abstract: Chronic pain is a major challenge to clinical practice and basic science. The peripheral and central neural networks that mediate nociception show extensive plasticity in pathological disease states. Disease-induced plasticity can occur at both structural and functional levels and is manifest as changes in individual molecules, synapses, cellular function and network activity. Recent work has yielded a better understanding of communication within the neural matrix of physiological pain and has also brought important advances in concepts of injury-induced hyperalgesia and tactile allodynia and how these might contribute to the complex, multidimensional state of chronic pain. This review focuses on the molecular determinants of network plasticity in the central nervous system (CNS) and discusses their relevance to the development of new therapeutic approaches.
648 citations
TL;DR: The presence of sensory loss and signs of hypersensitivity in the painful area in patients with CPSP might indicate the dual combination of deafferentation and the subsequent development of neuronal hyperexcitability.
Abstract: Summary Central post-stroke pain (CPSP) is a neuropathic pain syndrome that can occur after a cerebrovascular accident. This syndrome is characterised by pain and sensory abnormalities in the body parts that correspond to the brain territory that has been injured by the cerebrovascular lesion. The presence of sensory loss and signs of hypersensitivity in the painful area in patients with CPSP might indicate the dual combination of deafferentation and the subsequent development of neuronal hyperexcitability. The exact prevalence of CPSP is not known, partly owing to the difficulty in distinguishing this syndrome from other pain types that can occur after stroke (such as shoulder pain, painful spasticity, persistent headache, and other musculoskeletal pain conditions). Future prospective studies with clear diagnostic criteria are essential for the proper collection and processing of epidemiological data. Although treatment of CPSP is difficult, the most effective approaches are those that target the increased neuronal hyperexcitability.
493 citations
TL;DR: Preclinical studies coupled with clinical pharmacologic and neuroimaging investigations have advanced the understanding of brain circuits that modulate pain and suggest that diminished descending inhibition is likely to be an important element in determining whether pain may become chronic.
Abstract: Purpose of review Chronic pain is an important public health problem that negatively impacts quality of life of affected individuals and exacts an enormous socio-economic cost. Currently available therapeutics provide inadequate management of pain in many patients. Acute pain states generally resolve in most patients. However, for reasons that are poorly understood, in some individuals, acute pain can transform to a chronic state. Our understanding of the risk factors that underlie the development of chronic pain is limited. Recent studies have suggested an important contribution of dysfunction in descending pain modulatory circuits to pain 'chronification'. Human studies provide insights into possible endogenous and exogenous factors that may promote the conversion of pain into a chronic condition. Recent findings Descending pain modulatory systems have been studied and characterized in animal models. Human brain imaging techniques, deep brain stimulation and the mechanisms of action of drugs that are effective in the treatment of pain confirm the clinical relevance of top-down pain modulatory circuits. Growing evidence supports the concept that chronic pain is associated with a dysregulation in descending pain modulation. Disruption of the balance of descending modulatory circuits to favour facilitation may promote and maintain chronic pain. Recent findings suggest that diminished descending inhibition is likely to be an important element in determining whether pain may become chronic. This view is consistent with the clinical success of drugs that enhance spinal noradrenergic activity, such as serotonin/norepinephrine reuptake inhibitors (SNRIs), in the treatment of chronic pain states. Consistent with this concept, a robust descending inhibitory system may be normally engaged to protect against the development of chronic pain. Imaging studies show that higher cortical and subcortical centres that govern emotional, motivational and cognitive processes communicate directly with descending pain modulatory circuits providing a mechanistic basis to explain how exogenous factors can influence the expression of chronic pain in a susceptible individual. Summary Preclinical studies coupled with clinical pharmacologic and neuroimaging investigations have advanced our understanding of brain circuits that modulate pain. Descending pain facilitatory and inhibitory circuits arising ultimately in the brainstem provide mechanisms that can be engaged to promote or protect against pain 'chronification'. These systems interact with higher centres, thus providing a means through which exogenous factors can influence the risk of pain chronification. A greater understanding of the role of descending pain modulation can lead to novel therapeutic directions aimed at normalizing aberrant processes that can lead to chronic pain.
487 citations
Cites background from "Descending control of nociception: ..."
...The existence of oncells and off-cells with descending projections to the spinal dorsal horns provides a neuronal context for positive and negative pain modulation from the PAG/RVM system [60]....
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...Moreover, opioids inhibit on-cells and cause excitation of off-cells, and the latter effect is considered ‘necessary and sufficient’ to produce analgesia [57,60]....
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...to the spinal dorsal horns as well as the trigeminal nucleus caudalis [57,59,60]....
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...Moreover, as this system receives inputs from higher cortical sites, it also provides a mechanism whereby homeostatic or existential priorities may tone down or augment nociceptive inputs [60]....
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...com noxious stimuli and prior to a nociceptive reflex, whereas ‘off-cells’ ceased firing immediately prior to the tail-flick [57,59,60]....
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References
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TL;DR: It was concluded that focal brain stimulation in this region can induce analgesia in the absence of diffusely applied "whole brain" stimulation.
Abstract: Chronic monopolar electrodes were implanted in the region of the midbrain central gray in eight rats. In three rats, continuous 60 cycle-per-second sine-wave stimulation resulted in an electrical analgesia defined by the elimination of responses to aversive stimulation while general motor responsiveness was retained. Exploratory laparotomy was carried out in these animals during continuous brain stimulation without the use of chemical anesthetics. Following surgery, brain stimulation was terminated, and responses to aversive stimuli returned. Electrodes effective in inducing electrical analgesia at the lowest currents were located at the dorsolateral perimeter of the midbrain central gray. It was concluded that focal brain stimulation in this region can induce analgesia in the absence of diffusely applied "whole brain" stimulation.
1,315 citations
"Descending control of nociception: ..." refers background in this paper
...…including different components of the pain signal In the 40 years since Reynolds first described the phenomenon of stimulation-produced analgesia (Reynolds, 1969), the therapeutic potential of descending control has fuelled intense investigation of how descending systems interface with…...
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TL;DR: Before any cytokine or hormone can be characterized as an EP or EC (or, for that matter, as being involved in any of the acute phase responses), clearly established rules must be followed, which are patterned after the traditional criteria used by Koch to distinguish a pathogenic microorganism from a benign one.
Abstract: The biology of cytokines is one of the most rapidly growing areas of biomedical research. It is understandable why the assumption was made several years ago that EP was equivalent to IL-1 (both alpha and beta) and subsequently to IL-1 alpha, IL-1 beta, and TNF. However, as more data have been obtained, it has become clearer that many cytokines and hormones are capable of participating in the febrile response. It is also becoming apparent that EPs and ECs might influence body temperature during nonpathological states, perhaps contributing to the elevation in temperature during or after exercise, the circadian variation in temperature, and others. Medical textbooks have begun to list IL-1 as the EP. As I attempted to make clear in this review, evidence that IL-1 alpha is a circulating EP is poor. The evidence is considerably stronger that IL-1 beta is an EP, at least during LPS-induced fever in rodents. The point I have tried to emphasize is that before any cytokine or hormone can be characterized as an EP or EC (or, for that matter, as being involved in any of the acute phase responses), clearly established rules must be followed, which are patterned after the traditional criteria used by Koch to distinguish a pathogenic microorganism from a benign one. As summarized in Tables 4 and 5, there are many candidates for EPs and ECs, but much more experimental evidence is essential before we gain a clear understanding of the relationship between contact with an exogenous pyrogen, the release of EPs and ECs, and the development of fever.
1,218 citations
"Descending control of nociception: ..." refers background in this paper
...This is of interest because themedial preoptic area is a primary site at which PGE2 acts to organize autonomic, neuroendocrine and behavioral elements of the sickness response (Elmquist et al., 1997; Ivanov and Romanovsky, 2004; Kluger, 1991)....
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TL;DR: The likelihood that sustained activation of descending modulatory pathways that facilitate pain transmission could underlie some states of chronic pain is examined.
935 citations
"Descending control of nociception: ..." refers background in this paper
...A shift in the balance ON- and OFF-cell populations such that ON-cells predominate for extended periods likely underlies the pro-nociceptive influence that this region develops during chronic inflammatory and nerve injury states (Heinricher et al., 2003; Porreca et al., 2002)....
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...In neuropathic models, mechanical allodynia and thermal hyperalgesia are maintained by the RVM (Porreca et al., 2002)....
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...Lesion or general inactivation of RVM neurons may produce modest hyperalgesia or have no effect under basal conditions, but raise the nociceptive threshold in acute and chronic hyperalgesic states (Heinricher and Kaplan, 1991; Kaplan and Fields, 1991; Porreca et al., 2002)....
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TL;DR: A model of fear and pain is presented in which the two are assumed to activate totally different classes of behavior, and it is assumed that fear triggers the endorphin mechanism, thereby inhibiting pain motivation and recuperative behaviors that might compete with effective defensive behavior.
Abstract: A model of fear and pain is presented in which the two are assumed to activate totally different classes of behavior. Fear, produced by stimuli that are associated with painful events, results in defensive behavior and the inhibition of pain and pain-related behaviors. On the other hand, pain, produced by injurious stimulation, motivates recuperative behaviors that promote healing. In this model injurious stimulation, on the one hand, and the expectation of injurious stimulation, on the other hand, activate entirely different motivational systems which serve entirely different functions. The fear motivation system activates defensive behavior, such as freezing and flight from a frightening situation, and its function is to defend the animal against natural dangers, such as predation. A further effect of fear motivation is to organize the perception of environmental events so as to facilitate the perception of danger and safety. The pain motivation system activates recuperative behaviors, including resting and body-care responses, and its function is to promote the animal's recovery from injury. Pain motivation also selectively facilitates the perception of nociceptive stimulation. Since the two kinds of motivation serve different and competitive functions, it might be expected that they would interact through some kind of mutual inhibition. Recent research is described which indicates that this is the case. The most important connection is the inhibition of pain by fear; fear has the top priority. This inhibition appears to be mediated by an endogenous analgesic mechanism involving the endorphins. The model assumes that fear triggers the endorphin mechanism, thereby inhibiting pain motivation and recuperative behaviors that might compete with effective defensive behavior.
761 citations
"Descending control of nociception: ..." refers background in this paper
...Depending on the behavioral context, signals related to noxious or potentially noxious input could receive enhanced attention or be subordinated to other bodily needs of higher priority (Bolles and Fanselow, 1980; Koyama et al., 2005; Quevedo and Coghill, 2007)....
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...…on these areas as sources of descending inhibitory control, with a role in endogenous analgesia (antinociception) in states of extreme stress(Bolles and Fanselow, 1980; Terman et al., 1984) or in creating contrast in sensory signals that sharpened the signalling of pain by ascending…...
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TL;DR: Stimulation at several mesencephalic and diencephalic sites abolished responsiveness to intense pain in rats while leaving responsiveness to other sensory modes relatively unaffected.
Abstract: Stimulation at several mesencephalic and diencephalic sites abolished responsiveness to intense pain in rats while leaving responsiveness to other sensory modes relatively unaffected. The peripheral field of analgesia was usually restricted to one-half or to one quadrant of the body, and painful stimuli applied outside this field elicited a normal reaction. Analgesia outlasted stimulation by up to 5 minutes. Most electrode placements that produced analgesia also supported self-stimulation. One placement supported self-stimulation only in the presence of pain.
744 citations
"Descending control of nociception: ..." refers background in this paper
...…reports of behavioral analgesia following stimulation in the PAG concluded that the effects of central stimulation were highly selective for behaviors evoked by noxious stimuli, and that animals continued to respond to non-noxious, tactile, stimuli and other non-aversive cues (Mayer et al, 1971)....
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