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Central Sensitization (central + sensitization)
Selected AbstractsSensitization of meningeal nociceptors: inhibition by naproxenEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2008Dan Levy Abstract Migraine attacks associated with throbbing (manifestation of peripheral sensitization) and cutaneous allodynia (manifestation of central sensitization) are readily terminated by intravenous administration of a non-selective cyclooxygenase (COX) inhibitor. Evidence that sensitization of rat central trigeminovascular neurons was also terminated in vivo by non-selective COX inhibition has led us to propose that COX inhibitors may act centrally in the dorsal horn. In the present study, we examined whether COX inhibition can also suppress peripheral sensitization in meningeal nociceptors. Using single-unit recording in the trigeminal ganglion in vivo, we found that intravenous infusion of naproxen, a non-selective COX inhibitor, reversed measures of sensitization induced in meningeal nociceptors by prior exposure of the dura to inflammatory soup (IS): ongoing activity of A,- and C-units and their response magnitude to mechanical stimulation of the dura, which were enhanced after IS, returned to baseline after naproxen infusion. Topical application of naproxen or the selective COX-2 inhibitor N -[2-(cyclohexyloxy)-4-nitrophenyl]-methanesulfonamide (NS-398) onto the dural receptive field of A,- and C-unit nociceptors also reversed the neuronal hyper-responsiveness to mechanical stimulation of the dura. The findings suggest that local COX activity in the dura could mediate the peripheral sensitization that underlies migraine headache. [source] Plateau potential-dependent windup of the response to primary afferent stimuli in rat dorsal horn neuronsEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 9 2000Valérie Morisset Abstract In the spinal cord, repetitive stimulation of nociceptive afferent fibres induces a progressive build-up of dorsal horn neuron (DHN) responses. This ,action potential windup' is used as a cellular model of central sensitization to pain. It partly relies on synaptic plasticity, being reduced after blocking NMDA and neurokinin receptors. Using intracellular recordings in a slice preparation of the rat spinal cord, we have analysed the implication of an additional non-synaptic component of windup. Primary afferent fibres were electrically stimulated in the dorsal root. Of 47 responding deep DHNs, 17 (36%) produced action potential windup and afterdischarge during consecutive periods of repeated stimuli (0.4,1 Hz) activating high- (n = 13 neurons) and low-threshold (n = 6 neurons) afferent fibres. When the NMDA receptors were blocked, the rate of windup did not change. In all neurons, there was an absolute correlation between expression of windup and the production of calcium-dependent plateau potentials. Sensitization of the DHN response, similar to the synaptically induced windup, was obtained by repetitive intracellular injection of depolarizing current pulses. This intracellularly induced windup had the same pharmacology as the plateau potential. Synaptically induced windup was also abolished by nifedipine, an L-type calcium-channel blocker. Expression of plateau properties in DHNs is therefore a critical component of windup, operating downstream of synaptic processes. Being associated with calcium influx, generation of plateau potentials could be a link between short-term plasticity and the long-term modification of DHN excitability associated with central sensitization. [source] From Migraine To Chronic Daily Headache: The Biological Basis of Headache TransformationHEADACHE, Issue 8 2007Ian D. Meng PhD Migraine headache carries the potential of transforming into chronic daily headache (CDH) over a period of time. Although several risk factors for migraine progression to CDH have been identified, the biological basis of this transformation is unknown. In this review, the consequences of stressful life events and medication overuse, 2 risk factors associated with the development of CDH, on brain processes involved in headache are examined. The extensive overlap in both neural circuitry and cellular events that occur with stress, medication overuse, and migraine provide insight into potential mechanisms that may lead to CDH. Particular attention is devoted to the effect of stress and medication overuse on peripheral and central neuroimmune interactions that can facilitate pain signaling. These interactions include the degranulation of mast cells in the dura, causing the sensitization of primary afferent neurons, as well as the activation of glial cells in the brain that can lead to central sensitization. It is hypothesized that the biological processes involved in migraine headache are directly impacted by stress, medication overuse, and other risk factors, resulting in a reduced threshold for induction of headache and transformation of episodic migraine to CDH. [source] Change of Excitability in Brainstem and Cortical Visual Processing in Migraine Exhibiting AllodyniaHEADACHE, Issue 10 2006Koichi Shibata MD Background.,Clinical and neurophysiological manifestations of information processing associated with central sensitization are little known. Allodynic migraine (AM) can be caused by the sensitization of trigeminal neuron, but no study has reported on AM between attacks using blink reflex (BR) and pattern-reversal visual evoked potentials (PVEPs). Objective.,We explored the characteristics of AM between attacks associated with central sensitization using BR and PVEP. Methods.,We recruited 13 patients with interictal AM and 15 patients with nonallodynic migraine (NA), and 30 healthy subjects (HS). BRs were obtained using paired pulses delivered at the interstimulus interval (ISI) of 150, 300, and 500 ms. The ratio of the area in the R2 of the second to R2 of the first shock was measured for each ISI. PVEP were recorded with 2 spatial frequencies (0.5 and 4.0 cpd) and 2 low and high contrasts (29% and 98%, respectively). Amplitudes of P100 were measured. Results.,For BR, there were no significant differences in the ratio of the area of the R2 between the sides of stimulation, and the sides of headache. AM patients had less suppression of the R2 at the ISI of 150 and 300 ms when compared with the NA patients and HS. For PVEP, at 0.5, there were significant differences of amplitude between AM patients and HS, and between NA patients and HS in low and high contrast. At 4.0 cpd, there were significant differences of amplitude between AM patients and HS in low contrast, and between AM patients and HS, and NA patients and HS in high contrast. In AM patients, there was a significant difference of amplitude ratio between 0.5 and 4.0 cpd. Conclusions.,Our BR and PVEP study showed that migraine patients exhibiting allodynia may show central sensitization of brainstem trigeminal neuron and have contrast modulating dysfunction during the cortical visual processing of striate and extrastriate on visual cortex in-between attacks. [source] Neurochemistry of Trigeminal Activation in an Animal Model of MigraineHEADACHE, Issue 2006Michael L. Oshinsky PhD Research techniques such as electrophysiology, cFos protein expression, and other measurements of neuronal activation provide insights into the pathophysiology of pain processing in migraine, but they do not indicate the specific neurotransmitter systems involved. This paper summarizes data from microdialysis experiments in which changes in the neurochemistry of the trigeminal nucleus caudalis (TNC) were monitored during dural stimulation. Microdialysis allows the measurement of extracellular concentrations of neurotransmitters in a small area of the brain, in vivo, by means of a probe equipped with a semipermeable membrane. Microdialysis enables direct measurement of changes in extracellular concentrations of neurotransmitters in the intact animal over time in response to dural inflammation. Following the activation of the dural nociceptors, changes in the extracellular amino acid neurotransmitters in the deep lamina of the TNC were tracked. A 5-minute application of inflammatory soup when compared with saline to the dura of rats induced a transient decrease in extracellular glutamate in the TNC at approximately 30 minutes postapplication. This short-lived decrease was followed by a continuous increase in extracellular glutamate to a level of approximately 3 times the baseline value at 3 hours after application of the inflammatory soup. The time course of this increase in extracellular glutamate correlated with changes in sensory thresholds on the face of the rat from electrophysiological recordings of secondary sensory neurons in the TNC. No significant differences between the inflammatory soup and saline conditions were observed for extracellular concentrations of aspartate (an excitatory amino acid) or the inhibitory neurotransmitters gamma-aminobutyric acid or glutamine. Results of these experiments support an integral role for glutamate in central sensitization of neurons in the TNC, and suggest an important contribution of glutamate to allodynia and hyperalgia in this animal model of migraine. [source] Evidence for Antinociceptive Activity of Botulinum Toxin Type A in Pain ManagementHEADACHE, Issue 2003K. Roger Aoki PhD The neurotoxin, botulinum toxin type A, has been used successfully, in some patients, as an analgesic for myofascial pain syndromes, migraine, and other headache types. The toxin inhibits the release of the neurotransmitter, acetylcholine, at the neuromuscular junction thereby inhibiting striated muscle contractions. In the majority of pain syndromes where botulinum toxin type A is effective, inhibiting muscle spasms is an important component of its activity. Even so, the reduction of pain often occurs before the decrease in muscle contractions suggesting that botulinum toxin type A has a more complex mechanism of action than initially hypothesized. Current data points to an antinociceptive effect of botulinum toxin type A that is separate from its neuromuscular activity. The common biochemical mechanism, however, remains the same between botulinum toxin type A's effect on the motor nerve or the sensory nerve: enzymatic blockade of neurotransmitter release. The antinociceptive effect of the toxin was reported to block substance P release using in vitro culture systems.1 The current investigation evaluated the in vivo mechanism of action for the antinociceptive action of botulinum toxin type A. In these studies, botulinum toxin type A was found to block the release of glutamate. Furthermore, Fos, a product of the immediate early gene, c- fos, expressed with neuronal stimuli was prevented upon peripheral exposure to the toxin. These findings suggest that botulinum toxin type A blocks peripheral sensitization and, indirectly, reduces central sensitization. The recent hypothesis that migraine involves both peripheral and central sensitization may help explain how botulinum toxin type A inhibits migraine pain by acting on these two pathways. Further research is needed to determine whether the antinociceptive mechanism mediated by botulinum toxin type A affects the neuronal signaling pathways that are activated during migraine. [source] Nitric oxide and pain: ,Something old, something new'ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 9 2009A. MICLESCU Challenges have emerged following the revival of nitric oxide (NO) from ,something old', a simple gas derived from nitrogen and oxygen with a role in the early stages of evolution, into ,something new', an endogenously formed biological mediator regulating a wide variety of physiological functions. Although pain is a common sensation, it encompasses multiple neurobiologic components, of which NO is only one. In pain research, the study of NO is complicated by convoluted problems related mostly to the effects of NO, which are pro- or anti-nociceptive depending on the circumstances. This dual function reflects the multi-faceted roles of the NO molecule described in physiology. This review covers current information about NO and its implications in pain mechanisms. In addition, it follows the pain pathways, demonstrating the role of NO in peripheral nociceptive transmission as well in central sensitization. This knowledge may provide the scientific basis for developing new drugs that are indicated for different types of pain, drugs that may be related to the chemical links of NO. A comprehensive approach to understanding the effects of NO will help clinicians identify novel agents that combine the pharmacological profile of native drugs with a controllable manner of NO release. Inhibitors of NO synthesis may have analgesic effects and would be of interest for treating inflammatory and neuropathic pain. Unfortunately, only a few of these compounds have reached the stage of clinical pain trials. [source] Role of spinal cord glia in the central processing of peripheral pain perceptionNEUROGASTROENTEROLOGY & MOTILITY, Issue 5 2010S. Bradesi Abstract Background, The discovery that glial activation plays a critical role in the modulation of neuronal functions and affects the spinal processing of nociceptive signalling has brought new understanding on the mechanisms underlying central sensitization involved in chronic pain facilitation. Spinal glial activation is now considered an important component in the development and maintenance of allodynia and hyperalgesia in various models of chronic pain, including neuropathic pain and pain associated with peripheral inflammation. In addition, spinal glial activation is also involved in some forms of visceral hyperalgesia. Purpose, We discuss the signalling pathways engaged in central glial activation, including stress pathways, and the neuron,glia bidirectional relationships involved in the modulation of synaptic activity and pain facilitation. In this expanding field of research, the characterization of the mechanisms by which glia affect spinal neuro-transmission will increase our understanding of central pain facilitation, and has the potential for the development of new therapeutic agents for common chronic pain conditions. [source] Synergistic Interactions Between a KCNQ Channel Opener and an Opioid: Flupirtine and Morphine in Rat Pain Models Including Neuropathic PainPAIN MEDICINE, Issue 7 2007C Goodchild Purpose of the study:, Flupirtine is an established clinical analgesic for mild to moderate musculoskeletal pain states. It has recently been shown to be a KCNQ 2,3 potassium channel opener. These experiments were performed to see if this property could be useful in treating more severe pain states characterised by central sensitisation with the drug either given alone or in combination with morphine. Methods:, Experiments were performed in rats in an observer blinded fashion with vehicle controls. Non sedating doses of flupirtine, morphine and combinations containing both drugs were defined using the rotarod technique. Dose response relationships were determined for non sedating doses of both drugs given alone and together in combination in causing antinociception in three nociception paradigms: electrical pain; carrageenan paw inflammation; streptozotocin-induced diabetic neuropathy. Results:, Flupirtine and morphine when given alone caused slight to moderate antinociception in all three paradigms. Flupirtine also caused significant increases in morphine antinociception in all three models. In carrageenan paw inflammation complete reversal of carrageenan-induced hyperalgesia was caused by 10 mg/kg flupirtine in combination with 0.4 mg/kg morphine. These doses of the two drugs were ineffective when given alone but the combination caused complete antinociception in this model of inflammatory pain. In the diabetic neuropathy model (see figure) morphine 3.2 mg/kg given alone caused significant antinociception but the size of that response was significantly less than that caused by a lower dose of morphine (1.6 mg/kg shown to be ineffective when it was given alone) given in combination with flupirtine 10 mg/kg (p < 0.001; one way ANOVA). Conclusions:, Flupirtine should be investigated as an adjunct analgesic with opioids for the management of patients with severe pain states involving central sensitization. [source] Glutamate-mediated astrocyte-to-neuron signalling in the rat dorsal hornTHE JOURNAL OF PHYSIOLOGY, Issue 5 2010Rita Bardoni By releasing neuroactive agents, including proinflammatory cytokines, prostaglandins and neurotrophins, microglia and astrocytes are proposed to be involved in nociceptive transmission, especially in conditions of persistent, pathological pain. The specific action on dorsal horn neurons of agents released from astrocytes, such as glutamate, has been, however, poorly investigated. By using patch-clamp and confocal microscope calcium imaging techniques in rat spinal cord slices, we monitored the activity of dorsal horn lamina II neurons following astrocyte activation. Results obtained revealed that stimuli that triggered Ca2+ elevations in astrocytes, such as the purinergic receptor agonist BzATP and low extracellular Ca2+, induce in lamina II neurons slow inward currents (SICs). Similarly to SICs triggered by astrocytic glutamate in neurons from other central nervous system regions, these currents (i) are insensitive to tetrodotoxin (TTX), (ii) are blocked by the NMDA receptor (NMDAR) antagonist d -AP5, (iii) lack an AMPA component, and (iv) have slow rise and decay times. Ca2+ imaging also revealed that astrocytic glutamate evokes NMDAR-mediated episodes of synchronous activity in groups of substantia gelatinosa neurons. Importantly, in a model of peripheral inflammation, the development of thermal hyperalgesia and mechanical allodynia was accompanied by a significant increase of spontaneous SICs in dorsal horn neurons. The NMDAR-mediated astrocyte-to-neuron signalling thus represents a novel pathway that may contribute to the control of central sensitization in pathological pain. [source] Alteration of sensory neurons and spinal response to an experimental osteoarthritis pain modelARTHRITIS & RHEUMATISM, Issue 10 2010Hee-Jeong Im Objective To verify the biologic links between progressive cellular and structural alterations within knee joint components and development of symptomatic chronic pain that are characteristic of osteoarthritis (OA), and to investigate the molecular basis of alterations in nociceptive pathways caused by OA-induced pain. Methods An animal model of knee joint OA pain was generated by intraarticular injection of mono-iodoacetate (MIA) in Sprague-Dawley rats, and symptomatic pain behavior tests were performed. Relationships between development of OA with accompanying pain responses and gradual alterations in cellular and structural knee joint components (i.e., cartilage, synovium, meniscus, subchondral bone) were examined by histologic and immunohistologic analysis, microscopic examination, and microfocal computed tomography. Progressive changes in the dynamic interrelationships between peripheral knee joint tissue and central components of nociceptive pathways caused by OA-induced pain were examined by investigating cytokine production and expression in sensory neurons of the dorsal root ganglion and spinal cord. Results We observed that structural changes in components of the peripheral knee joint correlate with alterations in the central compartments (dorsal root ganglia and the spinal cord) and symptomatic pain assessed by behavioral hyperalgesia. Our comparative gene expression studies revealed that the pain pathways in MIA-induced knee OA may overlap, at least in part, with neuropathic pain mechanisms. Similar results were also observed upon destabilization of the knee joint in the anterior cruciate ligament transection and destabilization of the medial meniscus models of OA. Conclusion Our results indicate that MIA-induced joint degeneration in rats generates an animal model that is suitable for mechanistic and pharmacologic studies on nociceptive pain pathways caused by OA, and provide key in vivo evidence that OA pain is caused by central sensitization through communication between peripheral OA nociceptors and the central sensory system. Furthermore, our data suggest a mechanistic overlap between OA-induced pain and neuropathic pain. [source] | |||||||||||||