Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Local analgesic effects of exogenous opioid agonists are particularly prominent in painful inflammatory conditions and are mediated by opioid receptors on peripheral sensory nerves. The endogenous ligands of these receptors, opioid peptides, have been demonstrated in resident immune cells within inflamed tissue of animals and humans. Here we examine in vivo and in vitro whether interleukin 1 beta (IL-1) or corticotropin-releasing factor (CRF) is capable of releasing these endogenous opioids and inhibiting pain. When injected into inflamed rat paws (but not intravenously), IL-1 and CRF produce antinociception, which is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively, and by the immunosuppressant cyclosporine A. In vivo administration of antibodies against opioid peptides indicates that the effects of IL-1 and CRF are mediated by beta-endorphin and, in addition, by dynorphin A and [Met]enkephalin, respectively. Correspondingly, IL-1 effects are inhibited by mu-, delta-, and kappa-opioid antagonists, whereas CRF effects are attenuated by all except a kappa-antagonist. Finally, IL-1 and CRF produce acute release of immunoreactive beta-endorphin in cell suspensions freshly prepared from inflamed lymph nodes. This effect is reversible by IL-1 receptor antagonist and alpha-helical CRF, respectively. These findings suggest that IL-1 and CRF activate their receptors on immune cells to release opioids that subsequently occupy multiple opioid receptors on sensory nerves and result in antinociception. beta-Endorphin, mu- and delta-opioid receptors play a major role, but IL-1 and CRF appear to differentially release additional opioid peptides.
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PMID:Interleukin 1 beta and corticotropin-releasing factor inhibit pain by releasing opioids from immune cells in inflamed tissue. 791 Apr 3

The hypothalamic-pituitary adrenocortical (HPA) system and sympathoneural and adrenomedullary systems are major effector systems that serve to maintain homeostasis during stress. Corticotropin-releasing hormone (CRH) in the paraventricular nucleus (PVN) of the hypothalamus, a determinant of both HPA and autonomic responses to stress, is under the control of many neurotransmitters and neuropeptides. Norepinephrine (NE) potently stimulates CRH neurons in the PVN; however, the physiologic role of NE in stress-induced activation of the HPA is unknown. In the present study we exposed animals to various stressors (immobilization (IMMO), cold (COLD), hemorrhage (HEM), hypoglycemia elicited by insulin administration (INS), pain and tissue damage caused by formalin injection (FORM) and sc injection of physiological saline (SAL), all of which are known to activate the HPA axis. Injection of physiological saline iv was used as a control. In vivo microdialysis was used to assess stressor- and intensity-specific activation of the PVN noradrenergic system, based on measurements of NE, its intraneuronal metabolite dihydroxyphenylglycol (DHPG), and the dopamine metabolite, dihydroxyphenylacetic acid (DOPAC). Simultaneously with microdialysate collections, blood samples were obtained via catheters in the femoral artery to measure plasma ACTH and corticosterone (CORT) levels as dependent measures, to assess stress-induced activation of the HPA axis. At their highest intensities, all the stressors significantly increased levels of PVN microdialysate NE, DHPG, and DOPAC, and plasma ACTH and CORT. PVN NE levels varied across stressors, with IMMO and FORM more potent than INS, COLD, or HEM. INS and HEM evoked proportionately larger plasma ACTH responses than did IMMO, FORM, and COLD. Plasma CORT responses were largest during IMMO, FORM, and HEM. Except for COLD and HEM, there was a strong correlation of plasma ACTH levels with levels of NE, DHPG, and DOPAC in PVN microdialysate. The data suggest that, except for COLD or HEM, there is a strong positive correlation of PVN noradrenergic activation and activity of the HPA axis. With stressors such as IMMO and FORM, NE synthesis, reflected by DOPAC changes, is strongly positively correlated with activity of the HPA axis. Furthermore, the results indicate substantial stressor specificity of PVN catecholaminergic and of HPA responses to different stressors and are inconsistent with a founding tenet of Selye's stress theory, the doctrine of nonspecificity, which defines stress as the nonspecific response of the body to any demand.
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PMID:Effects of various stressors on in vivo norepinephrine release in the hypothalamic paraventricular nucleus and on the pituitary-adrenocortical axis. 859 92

Immune cell-derived opioid peptides can activate opioid receptors on peripheral sensory nerves to inhibit inflammatory pain. The intrinsic mechanisms triggering this neuroimmune interaction are unknown. This study investigates the involvement of endogenous corticotropin-releasing factor (CRF) and interleukin-1beta (IL-1). A specific stress paradigm, cold water swim (CWS), produces potent opioid receptor-specific antinociception in inflamed paws of rats. This effect is dose-dependently attenuated by intraplantar but not by intravenous alpha-helical CRF. IL-1 receptor antagonist is ineffective. Similarly, local injection of antiserum against CRF, but not to IL-1, dose-dependently reverses this effect. Intravenous anti-CRF is only inhibitory at 10(4)-fold higher concentrations and intravenous CRF does not produce analgesia. Pretreatment of inflamed paws with an 18-mer 3'-3'-end inverted CRF-antisense oligodeoxynucleotide abolishes CWS-induced antinociception. The same treatment significantly reduces the amount of CRF extracted from inflamed paws and the number of CRF-immunostained cells without affecting gross inflammatory signs. A mismatch oligodeoxynucleotide alters neither the CWS effect nor CRF immunoreactivity. These findings identify locally expressed CRF as the predominant agent to trigger opioid release within inflamed tissue. Endogenous IL-1, circulating CRF or antiinflammatory effects, are not involved. Thus, an intact immune system plays an essential role in pain control, which is important for the understanding of pain in immunosuppressed patients with cancer or AIDS.
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PMID:Expression of corticotropin-releasing factor in inflamed tissue is required for intrinsic peripheral opioid analgesia. 865 Feb 25

Opioid peptides derived from immune cells produce analgesia by activating opioid receptors on peripheral sensory nerves in inflammation. Corticotropin-releasing hormone (CRH) and interleukin-1 beta (IL-1 beta) can release these opioids. Here we show that both corticotropin-releasing hormone and interleukin-1 beta elicit receptor-specific antinociception in inflamed paws of rats by an opioid-mediated mechanism. Autoradiographic studies demonstrate 125I-CRH and 125I-IL-1 beta binding sites on immune cells in lymph nodes and inflamed paws. This binding is of high affinity and displaceable by the respective unlabeled agonist and antagonist ligands but not by opioid or adrenergic compounds. 125I-CRH and 125I-IL-1 beta binding sites are absent on nerves and in non-inflamed subcutaneous tissue but their number is greatly enhanced in inflamed paws and lymph nodes. This upregulation of binding sites for the opioid-releasing agents corticotropin-releasing hormone and interleukin-1 beta likely represents part of the body's local response to combat inflammatory pain.
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PMID:Local upregulation of corticotropin-releasing hormone and interleukin-1 receptors in rats with painful hindlimb inflammation. 889 3

Corticotropin-releasing factor (CRF) plays a major role at the level of the hypothalamus and pituitary to control the body's response mechanisms to stressful stimuli. The recent discovery of CRF outside the central nervous system suggests that CRF may well play a similar role in peripheral tissues, most likely in a paracrine manner. While its effects in many other peripheral tissues is not known yet, CRF and its receptors are upregulated in inflammatory pain states pointing to a key role under these circumstances. Indeed, locally expressed CRF seems to act on CRF receptors on immune cells which have migrated into the area of the inflamed tissue, and induce the release of opioid peptides synthesized within these immune cells. These opioids subsequently act on peripheral opioid receptors located on peripheral sensory nerves to inhibit the transmission of painful stimuli. CRF may also affect the inflammatory response; however, these data are still controversial. The peripheral paracrine effects of CRF may be similar to those of hypothalamic CRF, i.e., to counterbalance local stressful events, such as inflammation and pain, so that they do not threaten the homeostasis of the body. Interestingly, CRF-like peptides have been identified not only in mammalians, but also in species such as the frog (Stenzel-Poore et al., 1992, Mol. Endocrinol. 6, 1716) and the teleost fish (Okawara et al., 1988, Proc. Natl. Acad. Sci. USA 85, 8439) indicating that this is a peptide that has been conserved over a long period (200 million years) across species (Lederis et al., 1990, Prog. Clin. Biol. Res. 342, 467) and that the release of ACTH-like peptides by peptides of the CRF family may represent an ancestral type of stress response (Ottaviani et al., 1992, Gen. Comp. Endocrinol. 87, 354; Tran et al., 1990, Gen. Comp. Endocrinol. 78, 351).
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PMID:Corticotropin-releasing factor in antinociception and inflammation. 910 70

Localized inflammation of a rat's hindpaw elicits an accumulation of beta-endorphin-(END) containing immune cells. We investigated the production, release, and antinociceptive effects of lymphocyte-derived END in relation to cell trafficking. In normal animals, END and proopiomelanocortin mRNA were less abundant in circulating lymphocytes than in those residing in lymph nodes (LN), suggesting that a finite cell population produces END and homes to LN. Inflammation increased proopiomelanocortin mRNA in cells from noninflamed and inflamed LN. However, END content was increased only in inflamed paw tissue and noninflamed LN-immune cells. Accordingly, corticotropin-releasing factor and IL-1beta released significantly more END from noninflamed than from inflamed LN-immune cells. This secretion was receptor specific, calcium dependent, and mimicked by potassium, consistent with vesicular release. Finally, both agents, injected into the inflamed paw, induced analgesia which was blocked by the co-administration of antiserum against END. Together, these findings suggest that END-producing lymphocytes home to inflamed tissue where they secrete END to reduce pain. Afterwards they migrate to the regional LN, depleted of the peptide. Consistent with this notion, immunofluorescence studies of cell suspensions revealed that END is contained predominantly within memory-type T cells. Thus, the immune system is important for the control of inflammatory pain. This has implications for the understanding of pain in immunosuppressed conditions like cancer or AIDS.
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PMID:Immune cell-derived beta-endorphin. Production, release, and control of inflammatory pain in rats. 920 66

Opioid-containing immune cells migrate preferentially to inflamed sites, where they release beta-endorphin which activates peripheral opioid receptors to inhibit pain. Immunocyte recruitment is a multistep, sequential engagement of various adhesion molecules located on immune cells and vascular endothelium. Selectins mediate the initial phase of immunoctye extravasation into inflamed sites. Here we show that anti-selectin treatment abolishes peripheral opioid analgesia elicited either endogenously (by stress) or by corticotropin-releasing factor. This results from a blockade of the infiltration of immunocytes containing beta-endorphin and the consequent decrease of the beta-endorphin content in the inflamed tissue. These findings indicate that the immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain in injured tissue. Thus, pain is exacerbated by measures inhibiting the immigration of opioid-producing cells or, conversely, analgesia might be conveyed by adhesive interactions that recruit those cells to injured tissue.
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PMID:Pain control in inflammation governed by selectins. 984 66

Chronic pelvic pain (CPP) is a frequent and often unexplained gynecological complaint. We attempted to evaluate stress history, psychological features and hypothalamic-pituitary-adrenal (HPA) axis function in a group of patients suffering from CPP associated with pelvic adhesions. We recruited 10 patients with CPP and adhesions and 14 painfree, infertile control patients who underwent gynecological examination and diagnostic laparoscopy in a general hospital. Psychological assessment included structured interviews on sexual and physical abuse experiences and major life events as well as questionnaires on pain characteristics and depression. To evaluate HPA axis function, we measured plasma adrenocorticotropin (ACTH) and salivary cortisol responses to the administration of 100 micrograms human corticotropin-releasing factor (CRF). Results revealed high, but not statistically increased, prevalence rates of sexual and physical abuse for patients with CPP and adhesions as compared to controls. Patients with CPP and adhesions reported a significantly higher total number of major life events. Mean depression scores were normal in both groups. Patients with CPP and adhesions demonstrated normal plasma ACTH, but decreased salivary cortisol levels in the CRF stimulation test. These preliminary findings suggest that stress and neuroendocrine changes may also contribute to the pathophysiology of CPP with an identified organic correlate.
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PMID:Psychological and endocrine correlates of chronic pelvic pain associated with adhesions. 1021 83

Corticotropin-releasing factor (CRF) is a peptide that is released from the hypothalamus and in widespread areas of the brain following exposure to stressors. It is considered to be a mediator of many of the effects of stress, and its analgesic properties have been demonstrated in many studies. However, for primarily methodological reasons, the effects of CRF in the central nervous system have been neglected whereas the peripheral effects of CRF have been overemphasized. We present evidence that: (1) CRF can act at all levels of the neuraxis to produce analgesia; (2) the release of beta-endorphin does not explain the analgesia following intravenous or intracranial CRF administration; (3) inflammation must be present for local CRF to evoke analgesia and (4) the analgesic effects of CRF show specificity for prolonged pain. These findings suggest that CRF may have a significant role in chronic pain syndromes associated with hypothalamic-pituitary-adrenal axis abnormalities. Furthermore, CRF may represent a new class of analgesics that merits further study. Implications for the relationship between stress and pain are discussed.
Pain 2000 Jan
PMID:The role of corticotropin-releasing factor in pain and analgesia. 1060 67

Cyclic vomiting syndrome (CVS) remains a mysterious disorder despite our increasing knowledge since its classic description by Gee in 1882. Its hallmark feature of recurrent, explosive bouts of vomiting punctuating periods of normal health causes substantial medical morbidity (50% of patients require intravenous therapy), as well as significant time lost from school (20 school absences per year) and work. Limited epidemiologic data indicate that CVS may occur more commonly than previously thought, affecting as many as 1.9% of school-aged children. Besides the relentless vomiting, the child usually has pallor (87%), lethargy (91%), anorexia (74%), nausea (72%), and abdominal pain (80%). There is evidence of clinical and physiologic overlap among CVS, abdominal migraine, and migraine headaches. We propose revised criteria for abdominal migraine that include pain as the predominant and consistent symptom, lack of abnormal screening tests, and in retrospect, either subsequent development of migraines or positive response to antimigraine medication. Besides migraines, other etiologic possibilities include mitochondrial DNA mutations, ion channelopathies, excessive hypothalamic-pituitary-adrenal axis activation, and heightened autonomic reactivity. The differential diagnosis includes idiopathic CVS (88%); gastrointestinal disorders (7%), including serious surgical disorders (e.g., malrotation); and extraintestinal disorders (5%), including serious surgical (brain stem neoplasm) and metabolic disorders (e.g., fatty acid oxidation disorder). Within the idiopathic group, there may be migraine, Sato's neuroendocrine, mitochondrial, and other subgroups. Treatment includes avoidance of triggers, prophylactic medication, supportive care, abortive medication, and family support. In the future, investigation into mitochondrial DNA mutations, ion channel defects, corticotropin-releasing factor, and serotonin and tachykinin receptor physiology and pharmacology may help discover the etiology and pathogenesis of this disorder.
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PMID:Cyclic vomiting syndrome: evolution in our understanding of a brain-gut disorder. 1095 42


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