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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The neurobiology of pain had a notable interest in research focused on the study of neuronal plasticity development, nociceptors, molecular identity, signaling mechanism, ionic channels involved in the generation, modulation and propagation of action potential in all type of excitable cells. All the findings open the possibility for developing new therapeutic treatment. Nociceptive/inflammatory pain and neuropathic pain represent two different kinds of persistent chronic pain. We have reviewed the different mechanism suggested for the maintenance of pain, like descending nociceptive mechanism and their changes after tissue damage, including suppression and facilitation of defence behavior during pain. The role of these changes in inducing NMDA and AMPA receptors gene expression, after prolonged inflammation is emphasized by several authors. Furthermore, a relation between a persistent pain and amygdale has been shown. Molecular biology is the new frontier in the study of neurobiology of pain. Since the entire genome has been studied, we will able to find new genes involved in specific condition such as pain, because an altered gene expression can regulate neuronal activity after inflammation or tissue damage.
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PMID:Neurobiology of pain. 1674 73

Blockade of Ca2+-permeable AMPA receptors in the rat spinal cord diminishes the development of hyperalgesia and allodynia associated with peripheral injury. Cobalt uptake studies reveal that Ca2+-permeable AMPA receptors are expressed by some substance P receptor-expressing (NK1R+) neurons in lamina I, as well as other neurons throughout the superficial dorsal horn. Selective elimination of NK1R+ neurons in lamina I and lamina III/IV of the dorsal horn also suppresses development of hyperalgesia and allodynia. These observations raise the possibility that Ca2+-permeable AMPA receptors contribute to excitatory synaptic drive onto the NK1R+ neurons associated with allodynia and hyperalgesia. The first synapse in the pain pathway is the glutamatergic excitatory drive from the primary afferent fibres onto dorsal horn neurons. Therefore, we tested whether Ca2+-permeable AMPA receptors are located on lamina I and lamina III/IV NK1R+ neurons postsynaptic to primary afferent fibres, using inward rectification and polyamine toxins for receptor identification. We examined three different populations of dorsal horn neurons; lamina I NK1R+ neurons, including projection neurons, and non-NK1R+ (NK1R-) neurons including interneurons, and lamina III/IV NK1R+ neurons, believed to contribute to the low-threshold mechanosensory pathway. The majority of synapses in all three groups had rectification indices less than 1.0 and greater than 0.4, indicating that the AMPA receptors at these synapses are a mixture of Ca2+-permeable and -impermeable forms. Lamina III/IV NK1R+ neurons and lamina I NK1R- neurons have a significantly higher proportion of postsynaptic Ca2+-permeable AMPA receptors than lamina I NK1R+ neurons. Thus synaptically positioned Ca2+-permeable AMPA receptors directly contribute to low-threshold sensory afferent drive into the dorsal horn, and can mediate afferent input onto interneurons such as GABAergic neurons. These receptors also contribute to high-threshold primary afferent drive onto NK1R+ neurons in the superficial dorsal horn, but do so less consistently.
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PMID:Both Ca2+-permeable and -impermeable AMPA receptors contribute to primary synaptic drive onto rat dorsal horn neurons. 1676 2

Secondary mechanical hyperalgesia has been demonstrated in postoperative patients indicating that central sensitization occurs after surgery. However, the underlying mechanisms are unknown. Here, we studied the role of spinal AMPA/kainate receptors for pain behaviors indicating secondary hyperalgesia caused by gastrocnemius incision in the rat. These were reduced by NBQX, a selective antagonist of AMPA/kainate receptors. However, administration of NMDA receptor antagonists caused no or only a modest decrease in behaviors for secondary hyperalgesia but produced associated motor deficits and supraspinal side effects. We further determined that only secondary mechanical hyperalgesia was reversed by JSTX, a selective antagonist of calcium-permeable AMPA receptor; primary mechanical hyperalgesia and guarding behavior were unchanged. These findings indicate that JSTX influenced a spinal amplification process that leads to secondary hyperalgesia but does not contribute to primary hyperalgesia and guarding after incision. This amplification process likely requires Ca(2) influx through spinal AMPA/KA (but not NMDA) receptors. Behaviors for secondary mechanical hyperalgesia after incision can be inhibited without affecting primary mechanical hyperalgesia and guarding. Mechanisms for central sensitization causing secondary hyperalgesia in postoperative patients may therefore be separated from spontaneous pain and hyperalgesia that arises adjacent to the area of the incision.
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PMID:[Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision]. 1676 60

Allodynia or hyperalgesia induced by peripheral nerve injury may be involved in changes in the sensitivity of neurotransmitters at the spinal cord level. In order to clarify the functional role of neurotransmitters in peripheral nerve injury, we used rats with nerve injury induced by chronic constriction of the sciatic nerve (CCI rat model) and estimated the effects of the intrathecal injection of drugs known to affect glutamate and tachykinin receptors. In sham-operated rats, the NMDA receptor agonist NMDA and AMPA-kinate receptor agonist RS-(5)-bromowillardin reduced withdrawal latency. The non-competitive NMDA receptor antagonist MK-801, competitive NMDA receptor antagonist AP-5 and AMPA-kinate receptor antagonist NBQX increased withdrawal latency. Substance P (SP) increased the withdrawal latency but only transitorily. The NK1 receptor antagonist RP67580 increased withdrawal latency, but the NK2 receptor antagonist SR48968 did not show an effect. In CCI rats, RS-(5)-bromowillardin reduced withdrawal latency, but NMDA did not show an effect. NBQX increased withdrawal latency, while MK-801 and AP-5 showed little or no effect. SP reduced withdrawal latency, and both RP67580 and SR48968 increased it. These results indicate that the alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in the spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain.
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PMID:Alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain. 1690 66

L-glutamate is considered the main excitatory neurotransmitter in the mammalian brain. Paradoxically, L-glutamate is also the most important excitotoxin pivotally involved in the aetiology of several neurodegenerative diseases such as stroke, Alzheimer, Parkinson, amyotropic lateral sclerosis, Huntington and neuropathic pain. L-glutamate signalling is transduced both presynaptically and postsynaptically by metabotropic and ionotropic receptors. Three types of glutamate-gated channels integrate the synaptic signal, namely AMPA, kainate and NMDA receptors. Sustained activation of these receptors, and especially of the NMDA receptor, is a casuistic phenomenon that leads to the neuronal death underlying neurodegeneration. Thus, pharmacological intervention at these neuronal receptors and their synaptic protein complexes is a valuable therapeutic strategy. The approval of memantine, a safe, well-tolerated uncompetitive NMDA antagonist for the treatment of moderate to severe Alzheimer dementia validates ionotropic glutamate receptors as key therapeutic targets of neurodegenerative diseases in humans. As a consequence, an enormous effort is being carried out to identify and develop safe and potent antagonists for the clinics. In this review, we will describe progress in this important arena of human health.
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PMID:Pharmacological intervention at ionotropic glutamate receptor complexes. 1707 61

Pain is an important survival and protection mechanism for animals. However, chronic/persistent pain may be differentiated from normal physiological pain in that it confers no obvious advantage. An accumulating body of pharmacological, electrophysiological, and behavioral evidence is emerging in support of the notion that glutamate receptors play a crucial role in pain pathways and that modulation of glutamate receptors may have potential for therapeutic utility in several categories of persistent pain, including neuropathic pain resulting from injury and/or disease of central (e.g., spinal cord injury) or peripheral nerves (e.g., diabetic neuropathy, radiculopathy) and inflammatory or joint-related pain (e.g., rheumatoid arthritis, osteoarthritis). This review focuses on the role of glutamate receptors, including both ionotropic (AMPA, NMDA and kainate) and metabotropic (mGlu1-8) receptors in persistent pain states with particular emphasis on their expression patterns in nociceptive pathways and their potential as targets for pharmacological intervention strategies.
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PMID:Glutamate receptors and pain. 1711 Jan 39

This study tests the hypothesis that central sensitization initiated by nociceptive input can be maintained by repeated brief innocuous peripheral inputs. Capsaicin was injected intradermally into the hind paw of adult rats. Three different types of daily cutaneous mechanical stimulations (vibration, soft brush, or pressure) were applied to the capsaicin-injected paw for a period of 2 weeks. Daily stimulation consisted of a 10-s stimulation repeated every 30s for 30 min. Foot withdrawal thresholds to von Frey stimuli applied to the paw were measured once a day for 4 weeks. The capsaicin-only group (control rats without daily stimulation) showed hyperalgesia lasting for 3 days. In contrast, hyperalgesia persisted for 2 weeks in the group that received vibration stimulation. Neither the soft brush nor the pressure group showed a significant difference in mechanical threshold from the control group (capsaicin only). The vibration-induced prolonged hyperalgesia was significantly reduced by systemic injection of ifenprodil, an NMDA-receptor antagonist, but it was not influenced by either an AMPA-receptor blocker or a reactive oxygen species (ROS) scavenger. Furthermore, a dorsal column lesion did not interfere with the prolongation of hyperalgesia. Data suggest that vibration-induced prolongation of hyperalgesia is mediated by spinal NMDA-receptors, and a similar mechanism may underlie some forms of chronic pain with no obvious causes, such as complex regional pain syndrome type 1 (CRPS-1).
Pain 2007 May
PMID:Prolonged maintenance of capsaicin-induced hyperalgesia by brief daily vibration stimuli. 1713 33

The nucleus cuneiformis (CnF), located just ventrolateral to the periaqueductal gray, is part of the descending pain modulatory system. Neurons in the CnF project to medullary nucleus raphe magnus (NRM), which plays an important role on pain modulation. In this study, we investigated the effect of microinjection of the non-competitive NMDA receptor antagonist MK-801, the competitive NMDA receptor antagonist AP-7, and the kainate/AMPA receptor antagonist DNQX, alone or in combination with morphine into the nucleus cuneiformis on morphine-induced analgesia to understand the role of glutamatergic receptors in the modulating activity of morphine. Antinociception was assessed with the tail-flick test. Morphine (10, 20, 40 microg in 0.5 microl saline) had an antinociceptive effect, increasing tail-flick latency in a dose-dependent manner. Microinjection of MK-801 (10 microg/0.5 microl saline) and AP7 (3 microg/0.5 microl saline) prior to morphine microinjection (10 microg/0.5 microl saline) attenuated the antinociceptive effects of morphine, whereas DNQX (0.5 microg/0.5 microl saline) showed a partial antinociceptive effect and potentiated the analgesic effect of morphine. These results indicated that the NMDA receptor partially potentiates the antinociceptive effect of morphine. Our results suggest that NMDA but not non-NMDA receptors are involved in the antinociception produced by morphine in the CnF. The non-NMDA receptors in this area may have a facilitatory effect on nociceptive transmission. The fact that morphine's effect was potentiated by NMDA receptor suggests that projection neurons within the CnF are under tonic, glutamatergic input and when the influence of this input is blocked, the descending inhibitory system is inactivated.
Eur J Pain 2007 Nov
PMID:Involvement of glutamatergic receptors in the nucleus cuneiformis in modulating morphine-induced antinociception in rats. 1729 98

The anterior cingulate cortex (ACC) is critical for brain functions including learning, memory, fear and pain. Long-term synaptic potentiation (LTP), a cellular model for learning and memory, has been reported in the ACC neurons. Unlike LTP in the hippocampus and amygdala, two key structures for memory and fear, little is known about the synaptic mechanism for the expression of LTP in the ACC. Here we use whole-cell patch clamp recordings to demonstrate that cingulate LTP requires the functional recruitment of GluR1 AMPA receptors; and such events are rapid and completed within 5-10 min after LTP induction. Our results demonstrate that the GluR1 subunit is essential for synaptic plasticity in the ACC and may play critical roles under physiological and pathological conditions.
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PMID:Time-dependent postsynaptic AMPA GluR1 receptor recruitment in the cingulate synaptic potentiation. 1744 4

Ionotropic glutamate receptors contain three subtypes: NMDA, AMPA and kainate receptors. The former two receptor subtypes have well defined roles in nociception, while the role of kainate receptors in pain is not as well characterized. Kainate receptors are expressed in nociceptive pathways, including the dorsal root ganglion, spinal cord, thalamus and cortex. Electrophysiological studies show that functional kainate receptors are located postsynaptically, where they mediate a portion of excitatory synaptic transmission, or are located presynaptically, where they modulate excitatory or inhibitory neurotransmission. Recent genetic and pharmacological studies suggest that kainate receptors can regulate nociceptive responses. These results highlight kainate receptors as a target for the development of new treatments for chronic pain.
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PMID:Kainate receptors and pain: from dorsal root ganglion to the anterior cingulate cortex. 1750 52


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