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

This study examines the contribution of central corticotropin-releasing factor (CRF) to pain behavior. CRF is the principal modulator of the hypothalamo-pituitary-adrenal (HPA) axis, in addition to acting on many other areas of the central nervous system. We compared nociceptive thresholds (heat and mechanical) and pain behavior in response to a sustained stimulus (formalin test) between Fischer and Lewis rats that have different HPA axis activity. Intracerebroventricular (i.c.v.) administration of CRF produced dose-dependent antinociception at a lower dose in Lewis (40 ng, paw pinch 71+/-0 g) compared to Fischer rats (200 ng, 112+/-3 g). The antinociceptive effect of CRF was mostly preserved in adrenalectomized Fischer rats. The i.c.v. administration of the CRF receptor antagonist, astressin, had a hyperalgesic effect, suggesting that CRF is tonically active. Lewis rats required higher doses of astressin (5 ng, paw pinch 51+/-1 g) to show nociceptive effects compared to Fischer rats (1 ng, 79+/-1 g). Only Lewis rats vocalized during mechanical stimulus, and this behavior was prevented by diazepam or morphine but was worsened by CRF, despite its antinociceptive property. In the formalin test, CRF and astressin had the largest effect on the interphase suggesting that they act on the endogenous pain inhibitory system. CRF also increased anxiety/fear-like behaviors in the forced swim and predator odor tests. Our results establish that central CRF is a key modulator of pain behavior and indicates that CRF effects on nociception are largely independent of its mood modulating effect as well as its control of the HPA axis.
Pain 2006 Apr
PMID:Analgesia and hyperalgesia from CRF receptor modulation in the central nervous system of Fischer and Lewis rats. 1649 7

Endomorphins (EMs) are endogenous selective mu-opioid receptor agonists. Their role in inflammatory pain has not been fully elucidated. Here we examine peripheral antinociception elicited by exogenously applied EM-1 and EM-2 and the contribution of EM-containing leukocytes to stress- and corticotropin-releasing factor (CRF)-induced antinociception. To this end, we applied behavioral (paw pressure) testing, radioligand binding, immunohistochemistry, and flow cytometry in rats with unilateral hindpaw inflammation induced with Freund's adjuvant. EMs injected directly into both hindpaws produced antinociception exclusively in inflamed paws. This was blocked by locally applied mu-receptor-selective (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) but not kappa-receptor-selective (nor-binaltorphimine) antagonists. Delta-receptor antagonists (naltrindole and N,N-diallyl-Tyr-Aib-Aib-Phe-Leu) did not influence EM-1-induced but dose-dependently decreased EM-2-induced antinociception. Antibodies against beta-endorphin, methionine-enkephalin, or leucine-enkephalin did not significantly change EM-2-induced antinociception. Both EMs displaced binding of [3H]-[D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin to mu-receptors in dorsal root ganglia (DRG). Using [3H]-naltrindole or [(125)I]-[D-Pen2,5]-enkephalin, no detectable delta-binding was found in DRG of inflamed hindlimbs. Numerous beta-endorphin-containing and fewer EM-1- and EM-2-containing leukocytes were detected in subcutaneous tissue of inflamed paws. Leukocyte-depleting serum decreased the number of immigrating opioid-containing immune cells and attenuated swim stress- and CRF-induced antinociception in inflamed paws. Both forms of antinociception were strongly attenuated by anti-beta-endorphin and to a lesser degree by anti-EM-1 and anti-EM-2 antibodies injected into inflamed paws. Together, exogenously applied and immune cell-derived EMs alleviate prolonged inflammatory pain through selective activation of peripheral opioid receptors. Exogenous EM-2 in addition to mu-receptors also activates peripheral delta-receptors, which does not involve actions via other opioid peptides.
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PMID:Peripheral antinociceptive effects of exogenous and immune cell-derived endomorphins in prolonged inflammatory pain. 1662 55

The involvement of the peripheral opioid system in modulating inflammatory pain has been well documented. This study aimed to investigate the possibility of electroacupuncture (EA)-mediated peripheral opioid release. Rats were injected with complete Freund's adjuvant in one of the hind paws to induce localized inflammatory pain. The pain behavioral changes were measured by paw withdrawal latency (PWL) to a noxious thermal stimulus. At day 5 of inflammation, rats received a second injection of saline or opioid antagonists into the inflamed paw, followed by EA at 30 Hz, 2 mA, and 0.1 ms for 30 minutes. The EA was conducted at acupuncture point GB30. A control was used in which needles were inserted at GB30 but no electrical stimulation was applied. Rats receiving EA showed a significantly longer PWL as compared with the control from 30 minutes to three hours after EA treatment. Intraplantar but not intraperitoneal injection of naloxone methiodide, a peripherally acting opioid receptor antagonist, eliminated the analgesic effect at 30 minutes after EA treatment. Intraplantar injection of an antibody against beta-endorphin and a corticotropin-releasing factor antagonist also produced a reduction in PWL in rats receiving EA. These data strongly suggest that peripheral opioids are released by EA at the inflammatory site.
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PMID:Involvement of peripheral opioid mechanisms in electroacupuncture analgesia. 1678 67

Colorectal hyperalgesia has been supposed to be one of the key pathophysiological roles in irritable bowel syndrome (IBS). Recent animal models have demonstrated that neonatal maternal deprivation (stress memory) or repetitive rectal distension (pain memory) in neonatal animal triggers long-term hypersensitivity to rectal distension, indicating that negative events including abuse or maternal separation in childhood may play a crucial role on development of IBS. Several molecules such as corticotropin-releasing factor, serotonin, nerve growth factor, myosin light chain kinase, chemical mediators from mast cell, substance P and calcitonin gene-related peptide released from transient receptor potential vanilloid receptor 1 (TRPV1)-positive primary afferent nerves have been proved to induce visceral hyperalgesia. Novel drugs based on these findings have been developed.
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PMID:[Visceral hypersensitivity]. 1689 10

Previous studies have identified stress system dysregulation in fibromyalgia (FM) patients; such dysregulation may be involved in the generation and/or maintenance of pain and other symptoms. Corticotropin-releasing factor (CRF) is the principal known central nervous system mediator of the stress response; however, to date no studies have examined cerebrospinal fluid (CSF) CRF levels in patients with FM. The relationship between CSF CRF level, heart rate variability (HRV), and pain, fatigue, and depressive symptoms was examined in patients with FM. Among participants (n=26), CSF CRF levels were associated with sensory pain symptoms (r=0.574, p=0.003) and affective pain symptoms (r=0.497, p=0.011), but not fatigue symptoms. Increased HRV was also strongly associated with increased CSF CRF and FM pain. In multivariate analyses adjusting for age, sex, and depressive symptoms, the association between CSF CRF and sensory pain symptoms (t=2.54, p=0.027) persisted. Women with FM who reported a history of physical or sexual abuse had lower CSF CRF levels than women who did not report such a history. CSF CRF levels are associated with both pain symptoms and variation in autonomic function in FM. Differences in CSF CRF levels among women with and without a self-reported history of physical or sexual abuse suggest that subgroups of FM patients may exist with different neurobiological characteristics. Further studies are needed to better understand the nature of the association between CSF CRF and pain symptoms in FM.
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PMID:Cerebrospinal fluid corticotropin-releasing factor concentration is associated with pain but not fatigue symptoms in patients with fibromyalgia. 1693 2

The characterization of the corticotropin-releasing factor (CRF) family of neuroendocrine regulatory peptides, the cloning and pharmacological characterization of two CRF receptor subtypes (CRF(1) and CRF(2)), and the development of selective CRF receptor antagonists provided new insight to unravel the mechanisms of stress and the potential involvement of the CRF system in different pathophysiological conditions, including functional gastrointestinal disorders, mainly irritable bowel syndrome (IBS), and psychopathologies such as anxiety/depression. Compelling pre-clinical data showed that brain CRF administration mimics acute stress-induced colonic responses and enhances colorectal distension-induced visceral pain in rats through CRF(1) receptors. Similarly, peripheral CRF reduced the pain threshold to colonic distension and increased colonic motility in humans and rodents. These observations mimic the manifestations of IBS, characterized by abdominal bloating/discomfort and altered bowel habits. Moreover, CRF-CRF(1) pathways have been implicated in the development of anxiety/depression. These psychopathologies, together with stressful life events, have high comorbidity with IBS, and are considered significant components of the disease. From these observations, CRF(1) receptors have been suggested as a target to treat IBS. Peripherally acting CRF(1) antagonists might directly improve IBS symptoms, as related to motility, secretion and immune response. On the other hand, central actions will be beneficial as to prevent the psychopathologies that co-exist with IBS and as a way to modulate the central processing of stress- and visceral pain-related signals. Here, we review the pre-clinical and clinical data supporting these assumptions, and address the efforts done at a pharmaceutical level to develop effective therapies targeting CRF(1) receptors for functional gastrointestinal disorders.
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PMID:CRF1 receptors as a therapeutic target for irritable bowel syndrome. 1710 Jun 12

Corticotropin-releasing hormone (CRH) is a major mediator of stress response in the brain-gut axis. Irritable bowel syndrome (IBS) is presumed to be a disorder of the brain-gut link associated with exaggerated response to stress. We first showed that peripheral administration of CRH aggravated visceral sensorimotor function as well as adrenocorticotropic hormone (ACTH) response in IBS patients. We then administered alpha-helical CRH (alphahCRH), a non-selective CRH receptor antagonist among IBS patients. Electrical stimulation of the rectum induced significantly higher motility indices of the colon in IBS patients than in the controls. This response was significantly suppressed in IBS patients but not in the controls after administration of alphahCRH. Administration of alphahCRH induced a significant increase in the barostat bag volume of the controls but not in that of IBS patients. alphahCRH significantly reduced the ordinate scale of abdominal pain and anxiety evoked by electrical stimulation in IBS patients. Plasma ACTH and serum cortisol were generally not suppressed by alphahCRH. Last, administration of CRH1-receptor (CRH-R1) specific antagonist blocked colorectal distention-induced sensitization of the visceral perception in rats. Moreover, pretreatment with CRH-R1 antagonist blocked colorectal distention-induced anxiety, which was measured with elevated plus-maze, in rats. Evidence supporting the concept that peripheral CRH and CRH-R1 play important roles in brain-gut sensitization is increasing. Several studies have identified immunoreactive CRH and urocortin as well as CRH-R1 and CRH-R2 mRNAs in human colonic mucosa. In addition, reverse transcription-polymerase chain reaction has revealed the expression of CRH-R1 mRNA in both the myenteric and submucosal plexus in the guinea pig. Application of CRH has been shown to evoke depolarizing responses associated with elevated excitability in both myenteric and submucosal neurons. On the other hand, peripheral injection of CRH has been reported to induce discrete effects on colonic secretory and motor function, and permeability. There are functional differences between CRH-R1 and CRH-R2. For instance, activation of CRH-R1 causes a proinflammatory response, whereas stimulation of CRH-R2 provokes anti-inflammatory changes. In addition, there is evidence of the contrasting roles of CRH-R1 and CRH-R2 in visceral nociception. While CRH-R1 is involved in the pro-nociceptive effects of visceral pain, CRH-R2 mediates an anti-nociceptive response. These findings suggest the major role of CRH in stress-related pathophysiology of IBS and possibly in inflammation of the intestinal mucosa.
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PMID:Role of corticotropin-releasing hormone in irritable bowel syndrome and intestinal inflammation. 1723 26

Ramosetron is a potent and selective serotonin (5-HT)(3) receptor antagonist that has been shown to affect abnormal colonic function and abdominal pain in animals. Ramosetron (0.3 to 100 microg/kg, p.o.) has been found to significantly suppress abnormal defecation induced by conditioned-fear stress (CFS), restraint stress, corticotropin releasing factor (CRF) and 5-HT in rats and mice, and these effects were more potent than those of alosetron, cilansetron or loperamide. On the other hand, ramosetron (3,000 microg/kg, p. o., once daily for 7 days) did not inhibit normal defecation in dogs while tiquizium significantly inhibited it. Ramosetron (3 to 100 microg/kg, p. o.) also significantly prevented CFS-induced acceleration of colonic transit and CRF-induced abnormal water transport in rats, respectively. Moreover, ramosetron (0.3 to 3 microg/kg, p. o.) significantly suppressed restraint stress-induced decrease in colonic pain threshold, an effect not observed with loperamide. These results indicate that ramosetron produce beneficial clinical effects on IBS symptoms.
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PMID:Pharmacological profile of ramosetron, a novel therapeutic agent for IBS. 1732 87

There is conflicting evidence on the antinociceptive effects of corticotropin-releasing factor (CRF) along the neuraxis of pain transmission and the responsible anatomical sites of CRF's action at the level of the brain, spinal cord and periphery. In an animal model of tonic pain, that is, Freunds complete adjuvant (FCA) hindpaw inflammation, we systematically investigated CRF's ability to modulate inflammatory pain at those three levels of pain transmission by algesiometry following the intracerebroventricular, intrathecal, and intraplantar application of low, systemically inactive doses of CRF. At each level, CRF elicits potent antinociceptive effects, which are dose dependent and antagonized by local, but not systemic CRF receptor antagonist alpha-helical CRF indicating CRF receptor specificity. Consistently, we have identified by immunohistochemistry multiple brain areas, inhibitory interneurons within the dorsal horn of the spinal cord as well as immune cells within subcutaneous tissue--but not peripheral sensory neurons--that coexpress both CRF receptors and opioid peptides. In line with these anatomical findings, local administration of CRF together with the opioid receptor antagonist naloxone dose-dependently reversed CRF's antinociceptive effects at each of these three levels of pain transmission. Therefore, local application of low, systemically inactive doses of CRF at the level of the brain, spinal cord and periphery inhibits tonic inflammatory pain most likely through an activation of CRF receptors on cells that coexpress opioid peptides which results in opioid-mediated pain inhibition. Future studies have to delineate whether endogenous CRF at these three levels contributes to the body's response to cope with the stressful stimulus pain in an opioid-mediated manner.
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PMID:Inhibition of inflammatory pain by CRF at peripheral, spinal and supraspinal sites: involvement of areas coexpressing CRF receptors and opioid peptides. 1737 37

As a hormone in the hypothalamic-pituitary-adrenocortical (HPA) axis corticotropin-releasing factor (CRF) mediates stress responses. CRF can also act as a neuromodulator of synaptic transmission outside the HPA axis. A major site of extrahypothalamic expression of CRF and its G-protein-coupled receptors is the amygdala, a key player in affect-related disorders such as anxiety. The laterocapsular division of the central nucleus of the amygdala (CeLC) is important for the modulation of pain affect. This study determined the effects of CRF1 and CRF2 receptor antagonists in CeLC neurons in an arthritis pain model. Extracellular single-unit recordings were made from CeLC neurons in anesthetized adult rats. All neurons responded more strongly to noxious than to innocuous mechanical stimulation (compression) of peripheral tissues, including the knee. Evoked responses and background activity were measured before and during the development of a kaolin/carrageenan-induced knee joint arthritis. Drugs were administered into the CeLC by microdialysis before and/or after arthritis induction. All CeLC neurons showed increased responses to mechanical stimuli ("sensitization") 5-6 h postinduction of arthritis. A selective CRF1 receptor antagonist (NBI27914; 1-100 microM, concentration in microdialysis probe; 15 min) inhibited evoked responses and background activity in arthritis (n = 9) but had no effect under normal conditions before arthritis (n = 9). In contrast, a selective CRF2 receptor antagonist (Astressin-2B; 1-100 microM, 15 min) had no effect in arthritis (n = 7) but increased the neurons' responses under normal conditions (n = 8). These data suggest that CRF1 receptors in the amygdala contribute to pain-related sensitization, whereas the normally inhibitory function of CRF2 receptors is lost in the arthritis pain model.
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PMID:Differential effects of CRF1 and CRF2 receptor antagonists on pain-related sensitization of neurons in the central nucleus of the amygdala. 1739 12


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