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)

The most efficient drugs to alleviate severe pain are opioid compounds. However, their chronic use could be associated with serious drawbacks, such as tolerance, respiratory depression and constipation. Therefore, there is a need for compounds able to efficiently alleviate inflammatory and neurogenic pain following chronic treatment. The discovery that the endogenous opioid peptides, enkephalins, are inactivated by two metallopeptidases, neutral endopeptidase and aminopeptidase N, which can be blocked by synthetic dual inhibitors, represents a promising way to develop 'physiological' analgesics devoid of morphine side effects. These dual inhibitors also have antidepressant-like properties through enkephalin-related activation of delta-opioid receptors. This is expected to reduce the emotional component of pain in humans. This article reviews the promising data obtained for future development of a new class of analgesic that could be of major interest in a number of severe and chronic pain syndromes.
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PMID:Protection of endogenous enkephalin catabolism as natural approach to novel analgesic and antidepressant drugs. 1722 31

Tibia fracture in rats evokes nociceptive, vascular, and bone changes resembling complex regional pain syndrome (CRPS). Substance P (SP) signaling contributes to the hindpaw warmth, increased vascular permeability, and edema observed in this model, suggesting that neurogenic inflammatory responses could be enhanced after fracture. Four weeks after tibia fracture we measured SP and calcitonin gene-related peptide (CGRP) protein levels in the sciatic nerve and serum. Hindpaw skin extravasation responses and SP receptor (NK1), CGRP receptor (calcitonin receptor-like receptor, CRLR) and neutral endopeptidase (NEP) protein levels were also determined. Gene expression levels of these peptides, receptors, and peptidase were examined in the DRG and skin. Spontaneous and intravenous SP-evoked extravasation responses were increased ipsilateral, but not contralateral to the fracture. Fracture increased SP and CGRP gene expression in the ipsilateral L4,L5 DRG and neuropeptide protein levels in the sciatic nerve and in serum, but had no effect on electrically evoked SP and CGRP release. NK1 receptor expression was increased in the ipsilateral hindpaw skin keratinocytes and endothelial cells after injury, but CRLR and NEP expression were unchanged. Fracture also increased epidermal thickness, but had no effect on epidermal skin neurite counts. These results demonstrate that spontaneous and intravenous SP-evoked extravasation responses are enhanced in the ipsilateral hindlimb after fracture and that fracture chronically increases the expression of endothelial and keratinocyte NK1 receptors in the injured limb. We postulate that SP activation of these up-regulated NK1 receptors results in skin warmth, protein leakage, edema, and keratinocyte proliferation in the injured limb.
Pain 2009 Aug
PMID:Post-junctional facilitation of Substance P signaling in a tibia fracture rat model of complex regional pain syndrome type I. 1946 18

Complex regional pain syndrome (CRPS) is a condition that is characterized by severe pain and exaggerated neurogenic inflammation, which may develop after injury or surgery. Neurogenic inflammation is mediated by neuropeptides, such as calcitonin gene-related peptide (CGRP) and substance P (SP) that are released from nociceptors. Genetic factors may play a role in CRPS as was suggested by the occurrence of familial cases and several genetic association studies investigating mainly the human leukocyte antigen (HLA) system. Here we investigated the role of neutral endopeptidase (NEP), a key enzyme in neuropeptide catabolism. NEP dysfunction resulting in reduced inactivation of neuropeptides may be a possible pathomechanism in CRPS. To this end, we tested a GT-repeat polymorphism in the NEP promoter region as well as 18 tag-SNPs in six linkage disequilibrium (LD) blocks in the NEP gene region in 320 CRPS patients and 376 controls. No significant genetic association was observed. Thus, we conclude that the NEP gene does not seem to be a major risk factor for CRPS.
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PMID:Lack of genetic association of neutral endopeptidase (NEP) with complex regional pain syndrome (CRPS). 2010 52

Clostridial neurotoxins from the botulinum neurotoxin (BoNT) family are protein complexes, derived from the bacterium Clostridium botulinum, which potently inhibit acetylcholine release and result in a reversible blockade of the neuromuscular junction. This feature led to the clinical development of BoNT-A for a number of neuromuscular disorders. BoNT-A toxins are commercially available as three different preparations: Dysport/Azzalure, Botox/Vistabel, and Xeomin/Bocouture. Although BoNT-A preparations have not yet been approved for the treatment of pain, a substantial body of preclinical and clinical evidence shows that BoNT-A is effective in treating a number of different types of pain. It is thought to exert an analgesic effect both via muscle-relaxant properties and also directly, via inhibition of nociceptive neuropeptides. This review explores the mechanistic basis of this analgesic effect, summarizing current knowledge of the structure-function relationship of BoNT and discussing effects on both motor and pain neurons. For a complete picture of the analgesic properties of BoNT-A, clinical evidence of efficacy in myofascial pain and neuropathic pain is considered in tandem with a mechanistic rationale for activity. Patients experiencing chronic pain are clear candidates for treatment with a modified clostridial endopeptidase that would provide enduring inhibition of neurotransmitter release. A strong preclinical evidence base underpins the concept that re-engineering of BoNT could be used to enhance the analgesic potential of this neurotoxin, and it is hoped that the first clinical studies examining re-engineered BoNT-A will confirm this potential.
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PMID:Re-engineering clostridial neurotoxins for the treatment of chronic pain: current status and future prospects. 2046 83

Endometriosis is a condition in which endometrium or endometrium-like tissue grows in areas other than the endometrium and is often found within the pelvis such as in the uterus or ovary, but occasionally develops ectopically in the skin. In this paper, we report a case of cutaneous endometriosis in the umbilical region found in a 37-year-old woman with no history of pregnancy. The lesion was a brown, firm and elastic nodule, 9 mm x 7 mm in size, and caused bleeding as well as pain which increased during menstruation. Histopathological findings revealed that there were small and large glandular cavity structures in the dermis and the edematous interstitium around it. On immunohistochemical staining for estrogen and progesterone receptors, the cellular nuclei of glandular cavity walls were mainly found to be positive for both, and cells in the edematous interstitium around the glandular cavity were positive for CD10. Consequently, we diagnosed this case as cutaneous endometriosis in the umbilical region. CD10 was initially described as a tumor-specific antigen found in acute lymphoblastic leukemia. Recently, the usefulness of CD10 in diagnosing endometriosis in addition to various types of lymphoma or blood cancer has been confirmed, and in our case it also proved to be as useful as estrogen receptor or progesterone receptor in the definitive diagnosis of endometriosis.
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PMID:Cutaneous endometriosis in the umbilical region: the usefulness of CD10 in identifying the interstitium of ectopic endometriosis. 2053 70

Human opiorphin protects enkephalins from degradation by human neutral endopeptidase and aminopeptidase-N and inhibits pain perception in various behavioral rodent models of pain via endogenous enkephalin-related activation of opioidergic pathways. In addition to pain control, endogenous opioid pathways are also implicated in the modulation of emotion-related behaviors. Thus, we explored the dose-dependent motivational responses induced by opiorphin using the forced swim test, the standard rat model of depression. In addition, to further understand the endogenous events triggered by opiorphin, we investigated the specific involvement of mu- or delta-opioid receptor-dependent pathways. In parallel, the locomotor activity test was used to detect possible sedation or hyperactivity. Here, we report for the first time that at 1-2 mg/kg i.v. doses, opiorphin elicited antidepressant-like effects by activating endogenous delta-opioidergic pathways, since that activation was reversed by the selective delta-opioid antagonist naldrindole (10 mg/kg i.p.). The antidepressive behavioral responses exerted by opiorphin are specific at systemically active doses. Treated-rats did not develop either hypo- or hyper-active responses in a locomotor test or amnesic behavioral response in the passive avoidance rat model. In addition, opiorphin did not induce either anxiolytic-, or anxiogenic-like responses in the conditioned defensive burying test. Taking the data together, we conclude that opiorphin is able to elicit antidepressant-like effects, mediated via delta-opioid receptor-dependent pathways, by modulating the concentrations of endogenous enkephalin released in response to specific physical and/or psychological stimuli. Thus, opiorphin or optimized derivatives is a promising single candidate to treat disorders that include both pain and mood disorders, particularly depression.
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PMID:Human opiorphin is a naturally occurring antidepressant acting selectively on enkephalin-dependent delta-opioid pathways. 2061 Aug 67

Burkitt's lymphoma is not an uncommon malignancy in the paediatric population. It is a high-grade non-Hodgkin B-cell lymphoma which may present as endemic, sporadic and human immunodeficiency-associated subtypes. The African, or endemic, variant usually involves the maxilla and other facial bones while head and neck manifestations in sporadic Burkitt's lymphoma are rare. We described a case of oral Burkitt's lymphoma involving the right jaw in a 4-year-old boy. The patient presented with a rapidly-enlarging swelling of one month duration, toothache-like pain and radiographical appearance of 'floating teeth' in the right mandible. Incisional biopsy revealed small round tumour cells with scarce cytoplasm and multiple small nuclei interspersed by phagocytic macrophages. The tumour cells were immunopositivity for CD20 and CD10, expressed weak positivity for CD3, negative for CD5 and showed > 90% positivity for Ki-67. Tumour remission was achieved with six cycles of chemotherapy with the CHOP regime.
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PMID:Burkitt's lymphoma in a young Brazilian boy. 2061 28

Endometriosis is prevalent among women of reproductive age, and is most commonly found in the gynecologic organs themselves and the surrounding pelvic peritoneum. Endometriosis of the appendix, however, is rare. Preoperative diagnosis is difficult and a definitive diagnosis is usually established following histopathological examination of the appendix. We report a case of endometriosis of the appendix in a 29-year-old woman who presented with right lower quadrant abdominal pain. Rebound tenderness was localized to McBurney's point. Her WBC count was 12,300/mm3 and her CRP was 6.497 mg/dl. Ultrasound and computed tomography detected a calcified region inside the cecum and slight thickening of the wall of the appendix. Based on these findings, the patient was diagnosed with acute appendicitis and underwent an appendectomy. The appendix appeared mildly congested, but the mucosa of the appendix was nearly normal and without macroscopic inflammation. Histopathological examination demonstrated ectopic endometrial glands and stroma in the muscularis. These stroma cells were positive for CD10 on immunohistochemical staining, establishing a diagnosis of endometriosis of the appendix. The patient had a good clinical course and no residual pain postoperatively.
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PMID:A case of endometriosis of the appendix. 2063 87

Mucosa-associated lymphoma tissue (MALT) of the dura is extremely rare, with only a few reported cases worldwide. We present a unique case of a 61-year-old female who presented with neurologic symptoms of unsteady gait, dizziness, and sharp pain on her scalp for 3 weeks. A subsequent magnetic resonance imaging (MRI) of the brain demonstrated a dural-based mass radiographically consistent with meningioma. However, biopsy revealed the cells to be immunopositive for CD20 and CD79a, and immunonegative for CD5, CD10, CD43, and CD23. The neoplastic small lymphoid B cells were MUM1 positive and showed kappa light chain restriction, consistent with MALT of the dura. No evidence of systemic disease was found. The patient underwent radiation, which resulted in a complete response. MALT lymphoma, while rare, must be considered in the differential diagnosis in patients presenting radiographically with meningioma.
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PMID:Mucosa-associated lymphoma tissue of the dura presenting as meningioma. 2068 87

Human opiorphin QRFSR-peptide protects enkephalins from degradation by human neutral endopeptidase (hNEP) and aminopeptidase-N (hAP-N) and inhibits pain perception in a behavioral model of mechanical acute pain (1). Here, using two other pain rat models, the tail-flick and the formalin tests, we assess the potency and duration of the antinociceptive action of opiorphin with reference to morphine. The occurrence of adverse effects with emphasis on the side-effect profile at equi-analgesic doses was compared. We demonstrate that opiorphin elicits minimal adverse morphine-associated effects, at doses (1-2 mg/kg, i.v.) that produce a comparable analgesic potency in both spinally controlled thermal-induced acute and peripheral chemical-induced tonic nociception. The analgesic response induced by opiorphin in the formalin-induced pain model preferentially requires activation of endogenous mu-opioid pathways. However, in contrast to exogenous mu-opioid agonists such as morphine, opiorphin, does not develop significant abuse liability or antinociceptive drug tolerance after subchronic treatment. In addition, anti-peristaltism was not observed. We conclude that opiorphin, by inhibiting the destruction of endogenous enkephalins, which are released according to the painful stimulus, activates restricted opioid pathways specifically involved in pain control, thus contributing to a greater balance between analgesia and side-effects than found with morphine. Therefore, opiorphin could give rise to new analgesics endowed with potencies similar to morphine but with fewer adverse effects than opioid agonists. Its chemical optimization, to generate functional derivatives endowed with better bioavailability properties than the native peptide, could lead to a potent class of physiological type analgesics.
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PMID:Systemically active human opiorphin is a potent yet non-addictive analgesic without drug tolerance effects. 2081 77


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