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)

Peripheral axotomy-induced sprouting of thick myelinated afferents (A-fibers) from laminae III-IV into laminae I-II of the spinal cord is a well-established hypothesis for the structural basis of neuropathic pain. However, we show here that the cholera toxin B subunit (CTB), a neuronal tracer used to demonstrate the sprouting of A-fibers in several earlier studies, also labels unmyelinated afferents (C-fibers) in lamina II and thin myelinated afferents in lamina I, when applied after peripheral nerve transection. The lamina II afferents also contained vasoactive intestinal polypeptide and galanin, two neuropeptides mainly expressed in small dorsal root ganglion (DRG) neurons and C-fibers. In an attempt to label large DRG neurons and A-fibers selectively, CTB was applied four days before axotomy (pre-injury-labelling), and sprouting was monitored after axotomy. We found that only a small number of A-fibers sprouted into inner lamina II, a region normally innervated by C-fibers, but not into outer lamina II or lamina I. Such sprouts made synaptic contact with dendrites in inner lamina II. Neuropeptide Y (NPY) was found in these sprouts in inner lamina II, an area very rich in Y1 receptor-positive processes. These results suggest that axotomy-induced sprouting from deeper to superficial layers is much less pronounced than previously assumed, in fact it is only marginal. This limited reorganization involves large NPY immunoreactive DRG neurons sprouting into the Y1 receptor-rich inner lamina II. Even if quantitatively small, it cannot be excluded that this represents a functional circuitry involved in neuropathic pain.
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PMID:Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord. 1216

Neurotrophins (NTFs) are a family of polypeptide growth factors that control the apoptotic death or survival, growth, and differentiation of neurons. NTFs also regulate several other cell populations such as lymphoid, epithelial, oligoglia, and mast cells. Disregulation of the NTFs or their receptors plays a key role (etiological or upstream) in certain human pathologies. Hyperactivity may lead to inflammatory pain, or some forms of cancer by autocrine/paracrine growth. Loss of activity may lead to neurodegeneration, neuropathic pain, or some forms of cancer by absence of differentiation. Consequently the NTFs and their receptors are important therapeutic targets, and pharmacological modulation may have applications ranging from treatment of chronic or acute neurodegeneration, some forms of cancer, and chronic pain (with agonists); and some forms of cancer or acute pain (with antagonists).
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PMID:Small molecule peptidomimetic ligands of neurotrophin receptors, identifying binding sites, activation sites and regulatory sites. 1236 63

The effects of pituitary adenylate cyclase-activating polypeptide (PACAP) on pain sensitivity, on morphine analgesia, on morphine tolerance and withdrawal were investigated in mice. The heat-radiant tail-flick test was used to assess antinociceptive threshold. Intracerebroventricular (i.c.v.) administration of PACAP alone had no effect on pain sensitivity but in a dose of 500 ng, it significantly diminished the analgesic effect of a single dose of morphine (2.25 mg/kg, s.c.). PACAP (500 ng, i.c.v.) significantly increased the chronic tolerance to morphine and enhanced the naloxone (1 mg/kg, s.c.)-precipitated withdrawal jumping. Theophylline (1 mg/kg, i.p.) pretreatment significantly enhanced the effect of PACAP on morphine analgesia but the effects of PACAP on tolerance and withdrawal were unaffected upon theophylline administration. On the grounds of our previous studies with vasoactive intestinal polypeptide (VIP), it appears that different receptors are involved in the effects of PACAP in acute and chronic morphine actions. Our results indicate that PACAP-induced actions likely participate in acute and chronic effects of morphine and suggest a potential role of PACAP in opioid analgesia, tolerance and withdrawal.
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PMID:The effects of pituitary adenylate cyclase-activating polypeptide on acute and chronic morphine actions in mice. 1240 15

We tested the hypothesis that increases in the spinal levels of vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY) were related to the development of neuropathic pain. To this aim, we compared two groups of rats. One group showed well-developed neuropathic pain in the tail following unilateral transection of the inferior and superior caudal trunks between the S1 and S2 spinal nerves, and the other group showed poorly-developed neuropathic pain despite the same nerve injury. The increases in immunoreactivity of VIP and NPY in the S1 dorsal horn (injured segment) were not significantly different between the two groups. These results suggested that increases in the spinal levels of VIP and NPY after peripheral nerve injury were not sufficient for the development of neuropathic pain.
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PMID:Increases in spinal vasoactive intestinal polypeptide and neuropeptide Y are not sufficient for the genesis of neuropathic pain in rats. 1272 30

Bradykinin (BK) is an important mediator of hyperalgesia, inflammatory diseases, asthma and cancer. It is a pro-inflammatory polypeptide that can cause pain, inflammation, increased vascular permeability, vasodilation, contraction of various smooth muscles and cell proliferation by stimulating B(1)and B(2)receptors. B(1) receptors are formed in vitro during trauma, inflammatory reactions and injury. B(2) receptors are most commonly distributed in the vascular and non-vascular smooth muscle, and in the heart. Numerous BK antagonists have been developed in recent years with the prime aim of treating diseases resulting from excessive BK formation. Non-peptide B(2) receptor antagonists are now being synthesized and are under intense experimental investigation at various research centers. The most clinically useful peptide and non-peptide BK antagonists must be stable against all BK-inactivating enzymes, orally active, and have a long half-life with minimal side effects. These BK receptor antagonists may have future novel therapeutic applications in various pathological conditions associated with the abnormal kinin system.
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PMID:Bradykinin receptor antagonists: therapeutic implications. 1281 81

Proopiomelanocortin (POMC) is the polypeptide precursor of ACTH. First discovered in anterior pituitary corticotroph cells, it has more recently been revealed to have many other physiological aspects. The fine molecular mechanisms of ACTH biosynthesis show that ACTH is but one piece of a puzzle which contains many other peptides. Present in various tIssues, among which are pituitary, hypothalamus, central nervous system and skin, POMC undergoes extensive post-translational processing. This processing is tIssue-specific and generates, depending on the case, various sets of peptides involved in completely diverse biological functions. POMC expressed in corticotroph cells of the pituitary is necessary for adrenal function. Recent developments have shown that POMC-expressing neurons in the brain play a major role in the control of pain and energy homeostasis. Local production of POMC-derived peptides in skin may influence melanogenesis. A still unknown function in the placenta is likely.POMC has become a paradigmatic polypeptide precursor model illustrating the variable roles of a single gene and its various products in different localities.
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PMID:Proopiomelanocortin, a polypeptide precursor with multiple functions: from physiology to pathological conditions. 1288 83

Neurotomy is widely used as a model of chronic, intractable pain, the proverbial "crux medicorum". Immunohistochemical aspects of this chronic pain model are discussed in this paper, with the aim of shedding new light on the pathomechanism and possible therapeutical consequences. Central terminals of nociceptive neurons contain substance P, somatostatin and calcitonin generelated peptide or exhibit fluoride resistant acid phosphatase and thiamine monophosphatase enzyme reaction in the superficial dorsal horn of the spinal cord and in analogous structures of the brain stem. These neuropeptides and neuroproteins are expressed by the related dorsal root ganglion cells and transported via orthograde axoplasmic transport via dorsal roots to the central nervous system. Transection of the ipsilateral, segmentally related peripheral sensory nerve results in transganglionic degenerative atrophy of central terminals of primary nociceptive neurons. Transganglionic degenerative atrophy is characterized by marked ultrastructural alterations superficially similar to, but essentially differing from the signs of Wallerian degeneration which ensue after dorsal rhizotomy. Transganglionic degenerative atrophy is accompanied by depletion of marker neuropeptides and enzymes, and later by the expression of vicarious neuropeptides such as vasoactive intestinal polypeptide, neuropeptide Y and galanin and of the enzyme choline acetyl transferase. Consequences of blockade of retrograde axoplasmic transport of the nerve growth factor elicited either by perineural application of microtubule inhibitors or by perineural administration of anti-nerve growth factor are similar to peripheral neurotomy. According to recent studies described in this paper, the blockade of nerve growth factor supply to primary nociceptive neurons induces activation of c-jun in nuclei of primary nociceptive neurons probably responsible for the plasticity of the neuropeptide and neuroprotein synthesizing machinery. In contrast, invasion of and formation of pericellular baskets by noradrenergic axons can be elicited only by axotomy and not by blockade of retrograde axoplasmic transport. Involvement of nerve growth factor and the nerve growth factor-dependent immediate early genes in neuroplasticity of neuropeptidergic primary sensory neurons raise the possibility of a gene therapy of chronic intractable pain.
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PMID:Molecular plasticity of primary nociceptive neurons: relations of the NGF-c-jun system to neurotomy and chronic pain. 1292 68

Partially purified kinin, a polypeptide in wasp venom, has been found to be a potent smooth-muscle stimulating and hypotensive agent. Such a preparation was 10 to 100 times more effective than histamine in enhancing capillary permeability on intradermal injection, and 10 times more effective than acetylcholine in evoking pain on a cutaneous blister base. Some differences between the actions of salivary kallikrein and trypsin in releasing kallidin or bradykinin have been observed, and some modifications of previous methods of preparing crude kallidin and bradykinin are suggested. Kallidin and bradykinin are effective enhancers of capillary permeability in the guinea-pig and rabbit. Chemical and pharmacological tests failed to differentiate between kallidin and bradykinin which must be, therefore, closely similar compounds. The possible role of kallidin and bradykinin in physiological or pathological conditions is discussed.
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PMID:A comparative study of kinin, kallidin, and bradykinin. 1344 66

The antibody molecule consists of several polypeptide chains. Peptides, which appear to have been derived from the binding region of the rabbitantibody molecule directed against pazobenzenearsonate, have been isolated. The particular polypeptide chain from which these peptides are derived has now been identified as the B chain described by Fleischman, Pain, and Porter.
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PMID:Antibody combining site: the B polypeptide chain. 1398 68

Certain serine proteases signal to cells by cleaving protease-activated receptors (PARs) and thereby regulate hemostasis, inflammation, pain and healing. However, in many tissues the proteases that activate PARs are unknown. Although pancreatic trypsin may be a physiological agonist of PAR(2) and PAR(4) in the small intestine and pancreas, these receptors are expressed by cells not normally exposed pancreatic trypsin. We investigated whether extrapancreatic forms of trypsin are PAR agonists. Epithelial cells lines from prostate, colon, and airway and human colonic mucosa expressed mRNA encoding PAR(2), trypsinogen IV, and enteropeptidase, which activates the zymogen. Immunoreactive trypsinogen IV was detected in vesicles in these cells. Trypsinogen IV was cloned from PC-3 cells and expressed in CHO cells, where it was also localized to cytoplasmic vesicles. We expressed trypsinogen IV with an N-terminal Igkappa signal peptide to direct constitutive secretion and allow enzymatic characterization. Treatment of conditioned medium with enteropeptidase reduced the apparent molecular mass of trypsinogen IV from 36 to 30 kDa and generated enzymatic activity, consistent with formation of trypsin IV. In contrast to pancreatic trypsin, trypsin IV was completely resistant to inhibition by polypeptide inhibitors. Exposure of cell lines expressing PAR(2) and PAR(4) to trypsin IV increased [Ca(2+)](i) and strongly desensitized cells to PAR agonists, whereas there were no responses in cells lacking these receptors. Thus, trypsin IV is a potential agonist of PAR(2) and PAR(4) in epithelial tissues where its resistance to endogenous trypsin inhibitors may permit prolonged signaling.
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PMID:Trypsin IV, a novel agonist of protease-activated receptors 2 and 4. 1472 24


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