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)

Although Delta(9)-tetrahydrocannabinol (THC) produces analgesia, its effects on nociceptive primary afferents are unknown. These neurons participate not only in pain signaling but also in the local response to tissue injury. Here, we show that THC and cannabinol induce a CB(1)/CB(2) cannabinoid receptor-independent release of calcitonin gene-related peptide from capsaicin-sensitive perivascular sensory nerves. Other psychotropic cannabinoids cannot mimic this action. The vanilloid receptor antagonist ruthenium red abolishes the responses to THC and cannabinol. However, the effect of THC on sensory nerves is intact in vanilloid receptor subtype 1 gene knock-out mice. The THC response depends on extracellular calcium but does not involve known voltage-operated calcium channels, glutamate receptors, or protein kinases A and C. These results may indicate the presence of a novel cannabinoid receptor/ion channel in the pain pathway.
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PMID:Delta 9-tetrahydrocannabinol and cannabinol activate capsaicin-sensitive sensory nerves via a CB1 and CB2 cannabinoid receptor-independent mechanism. 1204 79

The central nervous system undergoes dynamic changes as it matures. However, until recently, very little was known about the impact of these changes on pain and analgesia. This study tested the hypothesis that the epsilon and gamma isozymes of protein kinase C (PKC) contribute to formalin-induced nociception in an age-dependent manner. Expression of epsilon and gamma PKC and the contributions of these isozymes in formalin-induced nociception was examined in postnatal day 7, 15, and 21 rats. epsilonPKC expression in dorsal root ganglion neurons and gammaPKC expression in lamina II of the spinal cord increased from the first to the third postnatal week. Coupling immunohistochemical and Western analysis, translocation of epsilonPKC followed intraplantar formalin in all ages. In contrast, formalin-induced gammaPKC translocation was observed only in postnatal day 21 rats. Behaviorally, intrathecal administration of the epsilonPKC-specific inhibitor (epsilonV1-2) attenuated phase 1 and phase 2 formalin behaviors at all ages. In contrast, intrathecal administration of the gammaPKC-specific inhibitor (gammaV5-3) attenuated only phase 2 responses in postnatal day 15 and 21 rats. Functionally, inhibition of epsilonPKC decreased capsaicin-stimulated release of glutamate and calcitonin gene-related peptide in spinal cords isolated from postnatal day 7 rats. These results suggest that epsilonPKC age independently mediates inflammatory pain produced by intraplantar formalin. In contrast, gammaPKC contributes to formalin-induced nociception in an age-dependent manner. Identifying the molecular mechanisms responsible for age-specific patterns of nociception is necessary for the rational development of novel therapeutic strategies for treating pediatric pain.
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PMID:Protein kinase C epsilon and gamma: involvement in formalin-induced nociception in neonatal rats. 1476 97

Galanin peptide in primary sensory neurons may confer analgesia following injury. Its presence in regenerative axon sprouts where pain may be initiated has not been examined. We examined very early outgrowth of peptidergic axon sprouts after sciatic nerve crush in mice with experimental streptozotocin-induced diabetes. Diabetic mice had a retarded wave of outgrowing galanin axons, but those expressing calcitonin gene-related peptide grew normally. Diabetic mice also developed early, then persistent excessive autotomy behaviour, an index of pain behaviour in complete nerve lesions. Diabetes is associated with variations in the early outgrowth of peptide-containing axons. A relative delay in galanin axon outgrowth could contribute to heightened neuropathic pain in diabetes.
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PMID:Heightened pain and delayed regeneration of galanin axons in diabetic mice. 1507 19

Although many clinical reviews are consistent with the view that hormone replacement therapy should be recommended for increasing bone mass of osteoporotic patients, calcitonin administration is preferable to hormone replacement therapy for the alleviation of pain accompanying osteoporosis, despite the fact that osteoporosis and the accompanying pain are accelerated by the reduction in estrogen levels. Distinct from the clinical view, animal studies have shown that estrogen treatment reduces ovariectomy-induced hyperalgesia, although the mechanism of this phenomenon is unknown. The discrepancy in clinical and animal study outcomes may be due to the timing of administration of estrogen after depletion of the hormone. To address this possibility, the anti-nociceptive effect of estrogen was compared with calcitonin using the tail withdrawal test in rats injected with estrogen or calcitonin at 3 weeks (short term) or 15 weeks (long term) after ovariectomy. Furthermore, we analyzed the change in [3H]8-OH-DPAT binding in the spinal cord, addressing whether estrogen exerts its anti-nociceptive effect by the expression of 5-HT receptors attributable to calcitonin-induced analgesia, as has been reported in our previous animal studies. The present study demonstrates that the administration of estrogen injected in the short term, but not long term, after ovariectomy mimicked the effects of calcitonin-induced anti-nociception and prevention of ovariectomy-induced decrease in 5-HT receptor expression in the spinal cord, although the effects of calcitonin were observed regardless of the timing of calcitonin injection. These results suggest that the estrogen receptor is downregulated gradually after ovariectomy. Disappearance of the estrogen receptor may be one of the reasons that estrogen is not recommended for the treatment for chronic pain associated with osteoporosis.
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PMID:Administration of estrogen shortly after ovariectomy mimics the anti-nociceptive action and change in 5-HT1A-like receptor expression induced by calcitonin in ovariectomized rats. 1533 6

Sensory innervation of the skin influences wound healing through the release of neuropeptides from the nerve endings. The purpose of this study was to investigate the differences in the sensory innervation of the normal and the hypospadiac prepuce. The prepuce from 10 healthy children undergoing routine circumcision and 10 age-matched children undergoing hypospadias repair were submitted for immunohistochemistry, using antibodies against protein gene product (PGP) 9.5, calcitonin gene-related peptide (CGRP), and substance P (SP). The hypospadiac prepuce was found to be hypo-innervated for PGP 9.5 and CGRP positive nerves when compared with the normal prepuce ( p<0.05). The number of SP-positive nerves were increased in the hypospadiac prepuce, but not to statistical significance ( p=0.06, confidence interval >95%). There may be differences in the sensory innervation of the normal and hypospadiac prepuce. These differences in tissue environment may partly explain the postoperative edema, poor wound healing leading to urethrocutaneous fistula (UF), and increased analgesia requirements in patients undergoing hypospadias surgery.
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PMID:Sensory innervation of normal and hypospadiac prepuce: possible implications in hypospadiology. 1544 86

Although radiotherapy is highly effective in relieving bone pain from cancer invasion, the mechanism of pain relief remains unclear. To explore the mechanism of radiotherapy-induced analgesia, we have developed an animal model of bone pain resulting from cancer invasion. Using this animal model system, radiation-induced pain response and pain-related signals in the spinal cord were analyzed. The hind paw model of bone pain from cancer invasion was developed by injecting transplantable hepatocellular carcinoma, HCa-1, into the periosteal membrane of the foot dorsum in C3H/HeJ mice. Bony invasion from HCa-1 cells was confirmed by histopathological examinations. We also measured the development of pain-associated behaviors. In this model, changes in the objective level of pain response after irradiation of the tumor were analyzed. Expression of pain-related host signals in the spinal cord, such as calcitonin gene-related peptide (CGRP), substance P, and c-fos, was investigated with immunohistochemical staining. In the histopathological examinations, bone invasion from HCa-1 cells was seen from day 7 and was evident at day 14 after injection. Measurable pain-associated behaviors were developed from day 7. In this model, mice treated with radiotherapy showed decreased objective levels of pain with a higher threshold to graded mechanical stimulation than did control mice from day 3 after irradiation. After irradiation of tumors, significant decreases in the expression of CGRP were shown in the spinal cord, whereas neither substance P nor c-fos showed any alteration. We developed a novel hind paw model of bone pain from cancer invasion that was confirmed by histopathological examination and measurable pain-associated behaviors. Radiotherapy decreased the objective level of pain and the underlying mechanism involved in the alteration of pain-related host signal, CGRP, in the spinal cord.
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PMID:Radiation-induced alteration of pain-related signals in an animal model with bone invasion from cancer. 1565 96

Nerve injury resulting in chronic pain is associated with novel excitatory effects of norepinephrine on injured peripheral nerve terminals and their cell bodies, due to actions on alpha2-adrenoceptors. Paradoxically, alpha2-adrenoceptor agonists administered near peripheral terminals or their cell bodies results in analgesia, not pain. This study tested, using intracellular Ca2+ response to stimulation, the effects of alpha2-adrenoceptor agonists on injured sensory neurons and classified their neuronal phenotype. Dorsal root ganglion cells from normal and spinal nerve-ligated rats were dissociated and activated twice with electrical field stimulation, while measuring Fura-2 fluorescence. Cells were perfused between stimulations with vehicle or alpha2-adrenoceptor agonists alone or with antagonists. Cells were considered inhibited if the ratio of their peak Ca2+ response to the second stimulus divided by the first was less than the 2.5th percentile for vehicle controls. alpha2-, But not alpha1-adrenoceptor agonists inhibited the Ca2+ response in a concentration related fashion, and this inhibition was blocked by alpha2-adrenoceptor antagonists. Clonidine inhibited a similar percentage of cells in the normal and spinal nerve-ligated group. In both groups, the large majority of clonidine-inhibited cells stained for isolectin B4. Spinal nerve ligation resulted in a 4-10-fold increase in the percentage of clonidine inhibited cells which immunostained for calcitonin gene-related peptide. These data are consistent with the known inhibition of Ca2+ currents by alpha2-adrenoceptors and suggest that, at the level of intracellular Ca2+, the key determinant of neurotransmitter release, alpha2-adrenoceptors are inhibitory after nerve injury, not excitatory. There is a shift in phenotype of sensory neurons which are inhibited by clonidine after nerve injury, which may explain clonidine's increased potency in the treatment of neuropathic compared with acute pain.
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PMID:alpha2-adrenoceptors inhibit the intracellular Ca2+ response to electrical stimulation in normal and injured sensory neurons, with increased inhibition of calcitonin gene-related peptide expressing neurons after injury. 1568 Jul 2

Peripheral opioid analgesia is increased substantially after inflammation. We evaluated the hypothesis that an inflammatory mediator, bradykinin (BK), evokes functional competence of the delta-opioid receptor (DOR) for inhibiting trigeminal ganglia (TG) sensory neurons. We also evaluated whether BK evokes trafficking of the DOR to the plasma membrane. Rat TG cultures were pretreated with BK (10 microm) or vehicle, and the effects of DOR agonists ([D-Pen2,5]-enkephalin or [D-Ala2, D-Leu5]-enkephalin) on BK (10 microm)/prostagladin E2 (PGE2; 1 microm)-stimulated immunoreactive calcitonin gene-related peptide (iCGRP) release or PGE2 (1 microm)-stimulated cAMP accumulation were measured. The effect of BK treatment on opioid receptor trafficking was evaluated by DOR immunohistochemistry, cell-surface DOR biotinylation, and live imaging of neurons transfected with mDOR-green fluorescent protein. BK pretreatment rapidly and significantly increased DOR agonist inhibition of evoked iCGRP release and cAMP accumulation. These effects of BK pretreatment were blocked by a B2 receptor antagonist (HOE-140; 10 microm) or a protein kinase C (PKC) inhibitor [bisindolymaleimide (BIS); 1 microm]. Moreover, BK treatment rapidly and significantly increased the accumulation of DOR in the plasma membrane. However, BK-induced trafficking of DOR was not reversed by pretreatment with BIS, nor was trafficking evoked by application of a PKC activator PMA (200 nm). These data suggest that BK, in a PKC-dependent manner, induces rapid functional competence of DOR for inhibiting TG nociceptors and in a PKC-independent manner rapidly induces trafficking of DOR to the plasma membrane. These findings indicate that exposure to certain inflammatory mediators rapidly alters the signaling properties and neuronal localization of DOR, possibly contributing to peripheral opioid analgesia.
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PMID:Bradykinin-induced functional competence and trafficking of the delta-opioid receptor in trigeminal nociceptors. 1619 72

Opiates are the primary treatment for pain management in cancer patients reporting moderate to severe pain, and are being increasingly used for non-cancer chronic pain. However, prolonged administration of opiates is associated with significant problems including the development of antinociceptive tolerance, wherein higher doses of the drug are required over time to elicit the same amount of analgesia. High doses of opiates result in serious side effects such as constipation, nausea, vomiting, dizziness, somnolence, and impairment of mental alertness. In addition, sustained exposure to morphine has been shown to result in paradoxical pain in regions unaffected by the initial pain complaint, and which may also result in dose escalation, i.e. 'analgesic tolerance'. A concept that has been gaining considerable experimental validation is that prolonged use of opioids elicits paradoxical, abnormal pain. This enhanced pain state requires additional opioids to maintain a constant level of antinociception, and consequently may be interpreted as antinociceptive tolerance. Many substances have been shown to block or reverse antinociceptive tolerance. A non-inclusive list of examples of substances reported to block or reverse opioid antinociceptive tolerance include: substance P receptor (NK-1) antagonists, calcitonin gene-related peptide (CGRP) receptor antagonists, nitric oxide (NO) synthase inhibitors, calcium channel blockers, cyclooxygenase (COX) inhibitors, protein kinase C inhibitors, competitive and non-competitive antagonists of the NMDA (N-methyl-D-aspartate) receptor, AMPA (alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid) antagonists, anti-dynorphin antiserum, and cholecystokinin (CCK) receptor antagonists. Without exception, these substances are also antagonists of pain-enhancing agents. Prolonged opiate administration indeed induces upregulation of substance P (SP) and calcitonin gene-related peptide (CGRP) within sensory fibers in vivo, and this is accompanied by an enhanced release of excitatory neurotransmitters and neuropeptides from primary afferent fibers upon stimulation. The enhanced evoked release of neuropeptides is correlated with the onset of abnormal pain states and opioid antinociceptive tolerance. Importantly, the descending pain modulatory pathway from the brainstem rostral ventromedial medulla (RVM) via the dorsolateral funiculus (DLF) is critical for maintaining the changes observed in the spinal cord, abnormal pain states and antinociceptive tolerance, because animals with lesion of the DLF did not show enhanced evoked neuropeptide release, or develop abnormal pain or antinociceptive tolerance upon sustained exposure to opiates. Microinjection of either lidocaine or a CCK antagonist into the RVM blocked both thermal and touch hypersensitivity as well as antinociceptive tolerance. Thus, prolonged opioid exposure enhances a descending pain facilitatory pathway from the RVM that is mediated at least in part by CCK activity and is essential for the maintenance of antinociceptive tolerance.
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PMID:Is paradoxical pain induced by sustained opioid exposure an underlying mechanism of opioid antinociceptive tolerance? 1621 2

The pineal gland and its secretory product, melatonin, have been implicated in the pathophysiology of migraine, as well as some of its comorbid disorders. Supporting this view, many migraineurs are susceptible to various environmental triggers that influence the secretion of melatonin from the pineal gland, and many prodromal symptoms are probably generated in the hypothalamus, a brain region that provides input into the pineal gland to modulate the secretion of melatonin. In addition, studies have shown abnormalities in melatonin secretion in patients who experience migraine and an improvement in migraine following administration of melatonin. However, the dysfunction in melatonin secretion in migraineurs may simply be a marker of hypothalamic dysfunction or neuronal hyperexcitability, leading to migraine susceptibility. It is also possible that abnormal melatonin secretion leads to decreased inhibitory neurotransmitter activity, decreased inhibition of the release of calcitonin gene-related peptide (CGRP) from activation of the trigeminal system, or less analgesia. Whatever its role in the pathogenesis of migraine, melatonin may prove to be a useful therapy. Future studies are necessary to further elucidate whether melatonin is a well tolerated, beneficial therapy, and to determine the optimal dose and formulation of melatonin for use in migraine therapy.
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PMID:Role of melatonin in the pathophysiology of migraine: implications for treatment. 1669 76


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