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

Corticotropin-releasing factor receptor CRF1 has been implicated in the neurobiological mechanisms of anxiety and depression. The amygdala plays an important role in affective states and disorders such as anxiety and depression. The amygdala is also emerging as a neural substrate of pain affect. However, the involvement of the amygdala in the interaction of pain and anxiety remains to be determined. This study tested the hypothesis that CRF1 receptors in the amygdala are critically involved in pain-related anxiety. Anxiety-like behavior was determined in adult male rats using the elevated plus maze (EPM) test. The open-arm preference (ratio of open arm entries to the total number of entries) was measured. Nocifensive behavior was assessed by measuring hindlimb withdrawal thresholds for noxious mechanical stimulation of the knee. Measurements were made in normal rats and in rats with arthritis induced in one knee by intraarticular injections of kaolin/carrageenan. A selective CRF1 receptor antagonist (NBI27914) or vehicle was administered systemically (i.p.) or into the central nucleus of the amygdala (CeA, by microdialysis). The arthritis group showed a decreased preference for the open arms in the EPM and decreased hindlimb withdrawal thresholds. Systemic or intraamygdalar (into the CeA) administration of NBI27914, but not vehicle, inhibited anxiety-like behavior and nocifensive pain responses, nearly reversing the arthritis pain-related changes. This study shows for the first time that CRF1 receptors in the amygdala contribute critically to pain-related anxiety-like behavior and nocifensive responses in a model of arthritic pain. The results are a direct demonstration that the clinically well-documented relationship between pain and anxiety involves the amygdala.
Mol Pain 2007 Jun 05
PMID:Pain-related anxiety-like behavior requires CRF1 receptors in the amygdala. 1755 May 94

It is accepted that inflammatory mediators released from leukocytes contribute to the generation of pain. However, it is less well known that immune cells also produce mediators that can effectively counteract pain. These include anti-inflammatory cytokines and opioid peptides. This article concentrates on recent evidence that interactions between leukocyte-derived opioid peptides and their receptors on peripheral sensory neurons can result in potent, clinically relevant inhibition of pathological pain. Inflammation of peripheral tissues leads to increased synthesis and axonal transport of opioid receptors in dorsal root ganglion neurons. This results in opioid receptor upregulation and enhanced G-protein coupling at peripheral sensory nerve terminals. These events are dependent on neuronal electrical activity, production of proinflammatory cytokines and nerve growth factor within the inflamed tissue. Together with the disruption of the perineurial barrier, all these changes lead to an enhanced peripheral analgesic efficacy of opioids. The major source of local endogenous opioid ligands (beta-endorphin, enkephalins, endomorphins and dynorphin) are leukocytes. These cells contain and upregulate signal-sequence encoding mRNA of the beta-endorphin precursor proopiomelanocortin and the entire enzymatic machinery necessary for its processing into the functionally active peptide. Opioid-containing immune cells extravasate using adhesion molecules and chemokines to accumulate in inflamed tissues. Upon stressful stimuli or in response to releasing agents such as corticotropin-releasing factor, cytokines, chemokines and catecholamines, leukocytes secrete opioids. Depending on the cell type, this release is contingent on extracellular Ca(2+) or on inositol triphosphate receptor-triggered release of Ca(2+) from endoplasmic reticulum. Once secreted opioid peptides activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. These effects occur without central untoward side effects such as depression of breathing, clouding of consciousness or addiction. Future aims include the selective targeting of opioid-containing leukocytes to sites of painful injury and the augmentation of opioid peptide and receptor synthesis.
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PMID:Targeting of opioid-producing leukocytes for pain control. 1764 Jul 27

Corticotropin-releasing factor (CRF) binds to membrane-bound CRF receptors (CRF-Rs). Among the actions mediated by activated CRF-Rs is beta-endorphin (END) release from immune cells, increasing peripheral antinociception. For assessment of inflammatory regulation of CRF-R expression, rats underwent pulp exposure of left, first mandibular molars and recovered for 6 days. Control pulpal tissue consisted of contralateral, uninjured molars and left, first mandibular molars of uninjured animals. Pulp tissue specimens were incubated with antibodies directed against CRF-R (both isoforms), neurofilament, CD45, and END. We observed (1) increases in pulp CRF-R immunoreactivity after injury, (2) increased CRF-R immunoreactivity expressed in 3 distinct zones in relation to the injury, and (3) increased CD45 and END immunoreactivity in regions surrounding the pulpal abscess. CRF-Rs might provide an additional target for novel analgesics to treat pulpal pain.
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PMID:Localized increases in corticotropin-releasing factor receptors in pulp after dental injury. 1796 55

In peripheral inflamed tissue interactions between leukocyte-derived opioid peptides and opioid receptors on sensory neurons lead to potent, clinically relevant inhibition of pain. Opioid receptors are present on peripheral terminals of sensory neurons and are upregulated in inflammation. Their endogenous ligands, opioid peptides, are synthesized in circulating immune cells, which migrate to injured tissues directed by chemokines and adhesion molecules. Under stressful stimuli or in response to releasing agents (e.g., corticotropin-releasing factor, cytokines, catecholamines) leukocytes can secrete opioids. These peptides activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. These effects occur without central opioid side effects such as depression of breathing, clouding of consciousness, or addiction. Future research should elucidate the selective targeting of opioid peptide-containing immune cells to sites of painful tissue injury and the augmentation of opioid peptide and receptor synthesis.
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PMID:Leukocyte-derived opioid peptides and inhibition of pain. 1804 Jul 94

Corticotropin-releasing factor (CRF) is not only a stress hormone but also acts as a neuromodulator outside the hypothalamic-pituitary-adrenocortical axis, playing an important role in anxiety, depression, and pain modulation. The underlying mechanisms remain to be determined. A major site of extra-hypothalamic expression of CRF and its receptors is the amygdala, a key player in affect-related disorders such as anxiety. The latero-capsular division of the central nucleus of the amygdala (CeLC) is also important for pain modulation and pain affect. This study analyzed the effects of CRF on nociceptive processing in CeLC neurons and the contribution of CRF1 and CRF2 receptors and protein kinases A and C. Extracellular single-unit recordings were made from CeLC neurons in anesthetized adult rats. All neurons responded more strongly to noxious than innocuous mechanical stimulation of the knee. Evoked responses and background activity were measured before and during administration of CRF into the CeLC by microdialysis. CRF was administered alone or together with receptor antagonists or protein kinase inhibitors. CRF (0.01-1 microM; concentrations in microdialysis probe; 15 min) facilitated the evoked responses more strongly than background activity; a higher concentration (10 microM) had inhibitory effects. Facilitation by CRF (0.1 microM) was reversed by a selective CRF1 receptor antagonist (NBI27914, 10 microM) but not a CRF2 receptor antagonist (astressin-2B, 100 microM) and by a protein kinase A (PKA) inhibitor (KT5720, 100 microM) but not a protein kinase C inhibitor (GF109203X, 100 microM). Inhibitory effects of CRF (10 microM) were reversed by astressin-2B. These data suggest that CRF has dual effects on amygdala neurons: CRF1 receptor-mediated PKA-dependent facilitation and CRF2 receptor-mediated inhibition.
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PMID:Pro- and anti-nociceptive effects of corticotropin-releasing factor (CRF) in central amygdala neurons are mediated through different receptors. 1817 11

In inflammation, resident cells and infiltrating leukocytes produce proalgesic mediators. Although these mediators induce pain, the role of specific cell populations is still controversial. In addition, resident cells and leukocytes also generate analgesic mediators that counteract inflammatory pain, including anti-inflammatory cytokines, endocannabinoids, and opioid peptides. Chemokines and adhesion molecules orchestrate the migration of opioid peptide-containing leukocytes to inflamed tissue. Leukocytes secrete opioid peptides under stressful conditions or in response to releasing agents (eg, corticotropin-releasing factor and chemokines). Secretion requires intracellular calcium mobilization and activation of phosphinositol-3 kinase and p38 mitogen activated kinase. Following release, opioid peptides bind to receptors on peripheral sensory neurons and produce analgesia in animal models and humans. This review presents recent findings on the role of leukocytes in the generation and inhibition of inflammatory pain.
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PMID:Leukocytes as mediators of pain and analgesia. 1817 5

A major site of extrahypothalamic expression of corticotropin-releasing factor (CRF) and its G-protein-coupled CRF1 and CRF2 receptors is the amygdala, a key player in emotions and affective disorders. Pain-related plasticity in the laterocapsular division of the central nucleus of the amygdala (CeLC) generates emotional-affective responses and anxiety-like behavior. CRF1 receptor antagonists have anxiolytic effects. Although both CRF1 and CRF2 receptors couple positively to adenylyl cyclase, they can have opposite effects, but the underlying mechanism is unknown. This study addressed CRF1 and CRF2 receptor functions and mechanisms in the amygdala in a model of arthritic pain. Using whole-cell patch-clamp recordings of CeLC neurons, we found that a selective CRF1 receptor antagonist (NBI27914 [5-chloro-4-(N-(cyclopropyl)methyl-N-propylamino)-2-methyl-6-(2,4,6-trichlorophenyl)]) amino-pyridine inhibited synaptic facilitation in brain slices from arthritic rats through a postsynaptic mechanism. Inhibition of the NMDA receptor-mediated synaptic component was occluded by a protein kinase A (PKA) inhibitor, consistent with our previous demonstration of PKA-dependent increased NMDA receptor function in arthritis pain-related plasticity. NBI27914 also decreased neuronal excitability through inhibition of highly tetraethylammonium (TEA)-sensitive ion channels that contribute to action potential repolarization and firing rate. In contrast, a CRF2 receptor antagonist (astressin-2B [cyclo(31-34) [d-Phe11,His12,C alphaMeLeu13,39, Nle17, Glu31, Lys34] Ac-Sauvagine(8-40)]) facilitated synaptic transmission through presynaptic inhibition of GABAergic transmission (disinhibition). NBI27914 inhibited arthritis pain-related behaviors (audible and ultrasonic vocalizations and hindlimb withdrawal reflexes). Astressin-2B had no significant behavioral effect. The data suggest that endogenous CRF1 receptor activation in the amygdala contributes to pain-related synaptic facilitation, increased excitability, and pain behavior through a postsynaptic mechanism involving activation of PKA and highly TEA-sensitive K(+)-currents. Presynaptic CRF2 receptor-mediated inhibition does not reach behavioral significance.
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PMID:Differential mechanisms of CRF1 and CRF2 receptor functions in the amygdala in pain-related synaptic facilitation and behavior. 1840 Aug 85

The aim of this study was to investigate the participation of glucocorticoid receptors and corticotropin releasing factor receptors of subtype 2 (CRF-2 receptors) in the analgesic effect of CRF on somatic pain sensitivity. The participation of glucocorticoid receptors and CRF-2 receptors in the CRF-induced analgesia was investigated by the receptors antagonists: RU38486 or astressin 2-B, respectively, in anaesthetized rats. For estimation of pain sensitivity the threshold of pain reaction induced by electrical stimulation of the rat' tail as tested before and during 30 min after the systemic injection of CRF. The CRF-induced analgesic effect was partly abolished by glucocorticoid receptor antagonist RU 38486 and completely abolished by CRF-2 receptor antagonist astressin 2-B. The data suggest that glucocorticoid receptors and CRF-2 receptors participate in the CRF-induced analgesic effect.
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PMID:[Analgesic effect of corticotropin releasing factor (CRF) on somatic pain sensitivity: participation of glucocorticoid and CRF-2 receptors]. 1906 25

Selye pioneered the concept of biological stress in 1936, culminating in the identification of the corticotropin-releasing factor (CRF) signaling pathways by Vale's group in the last two decades. The characterization of the 41 amino-acid CRF and other peptide members of the mammalian CRF family, urocortin 1, urocortin 2, and urocortin 3, and the cloning of CRF(1) and CRF(2) receptors, which display distinct affinity for CRF ligands, combined with the development of selective CRF receptor antagonists enable us to unravel the importance of CRF(1) receptor in the stress-related endocrine (activation of pituitary-adrenal axis), behavioral (anxiety/depression, altered feeding), autonomic (activation of sympathetic nervous system), and immune responses. The activation of CRF(1) receptors is also one of the key mechanisms through which various stressors impact the gut to stimulate colonic propulsive motor function and to induce hypersensitivity to colorectal distension as shown by the efficacy of the CRF(1) receptor antagonists in blunting these stress-related components. The importance of CRF(1) signaling pathway in the visceral response to stress in experimental animals provided new therapeutic approaches for treatment of functional bowel disorder such as irritable bowel syndrome, a multifactor functional disorder characterized by altered bowel habits and visceral pain, for which stress has been implicated in the pathophysiology and is associated with anxiety-depression in a subset of patients.
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PMID:From Hans Selye's discovery of biological stress to the identification of corticotropin-releasing factor signaling pathways: implication in stress-related functional bowel diseases. 1912 89

The analgesic effects of leukocyte-derived opioids have been exclusively demonstrated for somatic inflammatory pain, for example, the pain associated with surgery and arthritis. Neuropathic pain results from injury to nerves, is often resistant to current treatments, and can seriously impair a patient's quality of life. Although it has been recognized that neuronal damage can involve inflammation, it is generally assumed that immune cells act predominately as generators of neuropathic pain. However, in this study we have demonstrated that leukocytes containing opioids are essential regulators of pain in a mouse model of neuropathy. About 30%-40% of immune cells that accumulated at injured nerves expressed opioid peptides such as beta-endorphin, Met-enkephalin, and dynorphin A. Selective stimulation of these cells by local application of corticotropin-releasing factor led to opioid peptide-mediated activation of opioid receptors in damaged nerves. This ultimately abolished tactile allodynia, a highly debilitating heightened response to normally innocuous mechanical stimuli, which is symptomatic of neuropathy. Our findings suggest that selective targeting of opioid-containing immune cells promotes endogenous pain control and offers novel opportunities for management of painful neuropathies.
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PMID:Immune cell-derived opioids protect against neuropathic pain in mice. 1913 63


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