Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Capsaicin is a neurotoxin that can deplete sensory nerves of their content of substance P and interfere with certain sensory functions, such as responses of animals to noxious heat stimuli. In adult guinea pigs, a species that is susceptible to the effects of capsaicin on both substance P content and sensory function, capsaicin induces selective depletion of substance P from dorsal root ganglia and the dorsal spinal cord, sites of the cell bodies and central terminals of primary afferent neurons, respectively. As the onset of thermal analgesia in guinea pigs precedes depletion of substance P, direct neural actions of capsaicin probably account for its effects on sensory function. Capsaicin interferes with the retrograde transport of nerve growth factor (NGF) to the cell bodies of sensory nerves. Decreased availability of NGF at the site of neural protein synthesis leads to decreased synthesis of substance P. After failure of synthesis of substance P, the content of the peptide in sensory nerves gradually decreases until depletion occurs.
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PMID:Mechanisms of depletion of substance P by capsaicin. 258 20

Distal symmetrical peripheral neuropathy is a common adverse experience in persons with HIV infection. This condition, which presents as a pain, numbness. burning and/or dysaethesia initially in the feet, is often multi-factorial in its origin. Nucleoside analogue reverse transcriptase inhibitors represent an important contributor to peripheral neuropathy. Specifically, around 10% of patients receiving stavudine or zalcitabine and 1 to 2% of didanosine recipients may have to discontinue therapy with these agents due to neuropathy. Prompt withdrawal of these therapies enables gradual resolution of signs and symptoms in most patients, although a period of symptom intensification may occur shortly after withdrawal. Risk factors for developing peripheral neuropathy during nucleoside analogue therapy include low CD4+ cell count (<100 cells/mm3), a prior history of an AIDS defining illness or neoplasm, a history of peripheral neuropathy, use of other neurotoxic agents including high alcohol (ethanol) consumption and nutritional deficiencies such as low serum hydroxocobalamin levels. Thus, patients at increased risk of peripheral neuropathy should potentially avoid the use of the neurotoxic nucleoside analogues or be more carefully monitored during therapy. Management of this problem includes patient education. prompt withdrawal of the likely causative agent (giving consideration not to leave the patient on a sub-optimal therapy regimen) and simple analgesia. with augmentation with tricyclic antidepressants or anticonvulsant agents when pain is severe. New agents that may assist in managing this condition include levacecarnine (acetyl-L-carnitine) and nerve growth factors such as recombinant human nerve growth factor.
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PMID:Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. 988 91

Plasticity of the central nervous system has been shown to be an important correlate in the generation of chronic pain. However, there is now also increasing evidence for profound changes of the primary sensory neurons including nociceptors throughout the life of an organism and these changes account for clinically relevant alterations of pain perception. During development sensory neurons require one or more growth factors that rescue neurons during critical periods of programmed cell death and growth factors also play an important role for the development of the appropriate phenotype. Neurotrophin-3 may initially have an effect on proliferation of many subtypes of sensory neurons including cells destined to become nociceptors during early development. During a critical period of late prenatal development nerve growth factor (NGF) signalling through its cognate high affinity receptor trkA has been shown to be the main survival factor during a critical period of prenatal development. Humans deficient of trkA suffer from the rare disorder of congenital analgesia. Postnatally, the subpopulation of non-peptidergic nociceptors lose their ability to respond to NGF, start to express receptor element for and begin to respond to glial cell line-derived neurotrophic factor (GDNF). Both NGF and GDNF have also been shown to regulate the sensitivity of nociceptors to heat and capsaicin in the adult. Changes in the levels of endogenous trophic factors have also been implicated for the generation of ongoing activity and sensitisation to heat that are the hallmark of nociceptors innervating inflamed tissue. Whereas the development of ongoing activity correlates with the intensity of ongoing pain, sensitisation of nociceptors to heat can explain the hyperalgesia to heat that typically accompanies inflammatory lesions in the skin. Dramatic changes of nociceptor phenotype occur following nerve injury. Sensory neurons, including nociceptors, start to express adrenoceptors and become responsive for catecholamines and these changes appear to be responsible for the development of sympathetically maintained pain in some patients.
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PMID:The changing sensitivity in the life of the nociceptor. 1049 77

There is great interest in discovering new targets for pain therapy since current methods of analgesia are often only partially successful. Although protein kinase C (PKC) enhances nociceptor function, it is not known which PKC isozymes contribute. Here, we show that epinephrine-induced mechanical and thermal hyperalgesia and acetic acid-associated hyperalgesia are markedly attenuated in PKCepsilon mutant mice, but baseline nociceptive thresholds are normal. Moreover, epinephrine-, carrageenan-, and nerve growth factor- (NGF-) induced hyperalgesia in normal rats, and epinephrine-induced enhancement of tetrodotoxin-resistant Na+ current (TTX-R I(Na)) in cultured rat dorsal root ganglion (DRG) neurons, are inhibited by a PKCepsilon-selective inhibitor peptide. Our findings indicate that PKCepsilon regulates nociceptor function and suggest that PKCepsilon inhibitors could prove useful in the treatment of pain.
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PMID:A novel nociceptor signaling pathway revealed in protein kinase C epsilon mutant mice. 1067 42

When tissue is destroyed, pain arises. Tissue destruction as well as wound healing are associated with an inflammatory reaction. This leads to activation of nociceptors ("pain receptors") which can cross-communicate with the inflammatory infiltrate. The following review will concentrate on pain-exaggerating (hyperalgesic) and pain-ameliorating (analgesic) mediators which arise from immune cells or the circulation during the inflammation. In the early stages of inflammation endogenous hyperalgesic mediators are produced, including the proinflammatory cytokines IL-1, IL-6 and TNF-alpha, nerve growth factor as well as bradykinin and prostaglandins. Simultaneously, analgesic mechanisms are activated. Opioid peptides such as endorphins, enkephalins and dynorphins are produced by immune cells and can be released locally in the inflamed tissue on stimulation with IL-1 or corticotropin releasing factor. Analgesia is elicited by binding of the opioid peptides to receptors on peripheral sensory neurons. During the course of an inflammatory process, peripheral opioid-mediated analgesia increases. In parallel, antiinflammatory cytokines such as IL-4, IL-10, IL-13 and IL-1ra are produced and reduce hyperalgesic effects of the proinflammatory cytokines initially produced. Inflammatory pain, therefore, is the result of an interplay between hyperalgesic and analgesic mediators. Drugs such as immunosuppressants influencing this interplay may also impair endogenous hyperalgesic and analgesic mechanisms.
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PMID:[Pain and the immune system: friend or foe?]. 1212 5

It is without dispute that the treatment of neuropathic pain is an area of largely unmet medical need. Available analgesics, such as morphine, either have minimal effects in neuropathic pain patients, or are not always well tolerated due to concurrent adverse effects. The chronicity of neuropathic pain is thought to be related to many neurochemical changes in the dorsal root ganglia (DRG) and spinal cord, including a reduction in the retrograde transport of nerve growth factor (NGF). In this study, we have determined the ability of chronic intrathecal (i.t.) infusion of NGF to reverse neuropathic pain symptoms and to restore morphine's effectiveness in an animal model of neuropathic pain. Seven days after sciatic nerve constriction injury, NGF was administered to the spinal cord by continuous infusion (125 ng/microl/h) via osmotic pumps attached to chronically implanted i.t. catheters. Spinal infusion of NGF did not affect the expression of tactile allodynia or thermal (hot) hyperalgesia in neuropathic rats, although it significantly increased cold water responses frequency at day 14. Following infusion of vehicle, i.t. morphine (20 microg) was ineffective in altering somatosensory thresholds in neuropathic rats. In contrast, morphine substantially attenuated the neuropathy-induced warm and cold hyperalgesia, as well as tactile allodynia, in neuropathic rats chronically infused with i.t. NGF. In addition, we demonstrate that i.t. morphine-induced antinociception was augmented by a cholecystokinin (CCK) antagonist in animals chronically infused with i.t. antibodies directed against NGF. We hypothesize that NGF is critical in maintaining neurochemical homeostasis in the spinal cord of nociceptive neurons, and that supplementation may be beneficial in restoring and/or maintaining opioid analgesia in chronic pain conditions resulting from traumatic nerve injury.
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PMID:Intrathecal nerve growth factor restores opioid effectiveness in an animal model of neuropathic pain. 1290 15

During inflammatory processes, the hypothalamic-pituitary axis is activated which can subsequently result in analgesia. For example, hypothalamic corticotrophin-releasing hormone (CRH) that is released during such activation has been attributed with analgesic actions. It is believed that the somatotrophic axis is also activated during inflammation. The aim of this study was to determine the analgesic actions of growth hormone-releasing hormone (GHRH), in a rat model of localized inflammatory hyperalgesia, induced by intraplantar (i.pl.) endotoxin (ET) injections. Pretreatment with intraperitoneal (i.p.) injections of GHRH (2, 5, 10 microg kg(-1)) 30 min before i.pl. ET injection (1.25 microg in 50 microl saline) prevented, in a dose-dependent manner, both mechanical hyperalgesia determined by the paw pressure (PP) test and thermal hyperalgesia determined by the hot plate (HP) and paw immersion (PI) tests. Pretreatment with GHRH had no significant effect on the elevated levels of the inflammatory mediators, interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6 and nerve growth factor (NGF) due to i.pl. ET injection. No significant effect was obtained by pretreatment with GHRH, on the increased expression of gelatinase B due to ET injection. In conclusion, GHRH reverses inflammatory hyperalgesia in the rat without affecting the upregulated inflammatory mediators and these actions may be clinically important.
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PMID:Growth hormone releasing hormone reverses endotoxin-induced localized inflammatory hyperalgesia without reducing the upregulated cytokines, nerve growth factor and gelatinase activity. 1527 87

When tissue is destroyed or invaded by leukocytes in inflammation, numerous mediators are delivered by the circulation and/or liberated from resident and immigrated cells at the site. Proalgesic mediators include proinflammatory cytokines, chemokines, protons, nerve growth factor, and prostaglandins, which are produced by invading leukocytes or by resident cells. Less well known is that analgesic mediators, which counteract pain, are also produced in inflamed tissues. These include anti-inflammatory cytokines and opioid peptides. Interactions between leukocyte-derived opioid peptides and opioid receptors can lead to potent, clinically relevant inhibition of pain (analgesia). Opioid receptors are present on peripheral endings of sensory neurons. Opioid peptides are synthesized in circulating leukocytes, which migrate to inflamed tissues directed by chemokines and adhesion molecules. Under stressful conditions or in response to releasing agents (e.g., corticotropin-releasing factor, cytokines, noradrenaline), leukocytes can secrete opioids. They activate peripheral opioid receptors and produce analgesia by inhibiting the excitability of sensory nerves and/or the release of excitatory neuropeptides. This review presents discoveries that led to the concepts of pain generation by mediators secreted from leukocytes and of analgesia by immune-derived opioids.
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PMID:Leukocytes in the regulation of pain and analgesia. 1620 36

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

Many treatments for neuropathic pain activate or augment norepinephrine release in the spinal cord, yet these treatments are less effective against acute nociceptive stimuli. We previously showed in mice that peripheral nerve injury results in sprouting of spinal noradrenergic fibers, possibly reflecting the substrate for this shift in drug efficacy. Here, we tested whether such sprouting also occurs in rats after nerve injury and examined one signal for such sprouting. Ligation of L5 and L6 spinal nerves unilaterally in rats resulted in hypersensitivity to tactile stimulation of the ipsilateral paw, and sprouting of noradrenergic fibers in the dorsal horn of the lumbar spinal cord. Brain derived nerve growth factor (BDNF) content increased in L4-L6 dorsal root ganglia ipsilateral to injury and in lumbar spinal cord following nerve injury, and intrathecal infusion of BDNF antiserum prevented spinal noradrenergic sprouting. This treatment also prevented the increased analgesic efficacy of intrathecal clonidine observed after nerve injury. Intraspinal injection of BDNF in non-injured rats mimicked the sprouting of spinal noradrenergic fibers seen after nerve injury. These results suggest that increased BDNF synthesis and release drives spinal noradrenergic sprouting following nerve injury, and that this sprouting may paradoxically increase the capacity for analgesia in the setting of neuropathic pain from drugs which utilize or mimic the noradrenergic pathway.
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PMID:Brain derived nerve growth factor induces spinal noradrenergic fiber sprouting and enhances clonidine analgesia following nerve injury in rats. 1782 49


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