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)

Opioid peptides and their G-protein-coupled receptors (delta, kappa, mu) are located in the central nervous system and peripheral tissues. The opioid system has been studied to determine the intrinsic mechanism of modulation of pain and to develop uniquely effective pain-control substances with minimal abuse potential and side effects. Two types of endogenous opioid peptides exist, one containing Try-Gly-Gly-Phe as the message domain (enkephalins, endorphins, dynorphins) and the other containing the Tyr-Pro-Phe/Trp sequence (endomorphins-1 and -2). Endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), which has high mu receptor affinity (Ki = 0.36 nM) and remarkable selectivity (4000- and 15,000-fold preference over the delta and kappa receptors, respectively), was isolated from bovine and human brain. In addition, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), isolated from the same sources, exhibited high mu receptor affinity (Ki = 0.69 nM) and very high selectivity (13,000- and 7500-fold preference relative to delta and kappa receptors, respectively). Both opioids bind to mu-opioid receptors, thereby activating G-proteins, resulting in regulation of gastrointestinal motility, manifestation of antinociception, and effects on the vascular systems and memory. To develop novel analgesics with less addictive properties, evaluation of the structure-activity relationships of the endomorphins led to the design of more potent and stable analgesics. Opioidmimetics and opioid peptides containing the amino acid sequence of the message domain of endomorphins, Tyr-Pro-Phe/Trp, could exhibit unique binding activity and lead to the development of new therapeutic drugs for controlling pain.
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PMID:Endomorphins and related opioid peptides. 1248 50

Several neuropeptide FF (NPFF)-related peptides, known as modulators of the opioid system, have been previously characterized in bovine and rodent brain. Reverse-phase high pressure liquid chromatography (HPLC) fractions of a human with normal pressure hydrocephalus cerebrospinal fluid (CSF), co-migrating with NPFF-related synthetic peptides, were characterized by capillary HPLC coupled on-line to nanospray ion trap tandem mass spectrometry. Two peptides present in the pro-NPFF(A) precursor, NPAF (AGEGLNSQFWSLAAPQRF-NH2) and NPSF (SLAAPQRF-NH2), were identified. The monitoring of NPFF-related peptides in human CSF can be helpful to understand their roles in pain sensitivity.
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PMID:Identification of neuropeptide FF-related peptides in human cerebrospinal fluid by mass spectrometry. 1248 85

RFamide related peptides (RFRP)-1 and RFRP-3 are neuropeptides derived from the same preproprotein. We have examined the distribution of RFRP-1 and RFRP-3 immunoreactivities (irs) in the rat central nervous system using specific antibodies. Neuronal cell bodies containing both RFRP-1 and RFRP-3 were detected within the caudal portion of the hypothalamus, the periventricular nucleus (PerVN), and the portion around or above the ventromedial nucleus of the hypothalamus. Both immunohistochemical and in situ hybridization analyses showed that neurons containing RFRP immunoreactivity and mRNA were distinct from those of neuropeptide FF, which contains the same structure at the C-terminus, Pro-Glu-Arg-Phe-NH2, as RFRP-3. Fibers containing both RFRP-1 and RFRP-3 were widely distributed in the brain: the lateral septal nucleus in the telencephalon, the paraventricular thalamic nucleus, various hypothalamic nuclei, the periaqueductal gray in the midbrain, the parabrachial nucleus in the pons, and the nucleus tractus solitarius (NTS) in the medulla oblongata. Only RFRP-1-ir was detected within the posterior gray horn in the spinal cord. Only RFRP-3-ir was detected in several thalamic nuclei and the spinal cord, especially at the posterior intermediate sulcus and within the anterior gray horn. Intracerebroventricular administration of RFRPs induced c-Fos expression in the anterior portion of the NTS, locus coeruleus, the nucleus of incertus, supraoptic nucleus, PerVN and the arcuate nucleus of the hypothalamus. These results show that RFRP-1 and RFRP-3 are widely distributed in the rat central nervous system and might be involved in various functions such as the neuroendocrine system or pain modulation.
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PMID:Localization and neuronal response of RFamide related peptides in the rat central nervous system. 1291 51

TRPV1 ion channels mediate the response to painful heat, extracellular acidosis, and capsaicin, the pungent extract from plants in the Capsicum family (hot chili peppers) (Szallasi, A., and P.M. Blumberg. 1999. Pharmacol. Rev. 51:159-212; Caterina, M.J., and D. Julius. 2001. Annu. Rev. Neurosci. 24:487-517). The convergence of these stimuli on TRPV1 channels expressed in peripheral sensory nerves underlies the common perceptual experience of pain due to hot temperatures, tissue damage and exposure to capsaicin. TRPV1 channels are nonselective cation channels (Caterina, M.J., M.A. Schumacher, M. Tominaga, T.A. Rosen, J.D. Levine, and D. Julius. 1997. Nature. 389:816-824). When activated, they produce depolarization through the influx of Na+, but their high Ca2+ permeability is also important for mediating the response to pain. In particular, Ca2+ influx is thought to be required for the desensitization to painful sensations over time (Cholewinski, A., G.M. Burgess, and S. Bevan. 1993. Neuroscience. 55:1015-1023; Koplas, P.A., R.L. Rosenberg, and G.S. Oxford. 1997. J. Neurosci. 17:3525-3537). Here we show that in inside-out excised patches from TRPV1 expressed in Xenopus oocytes and HEK 293 cells, Ca2+/calmodulin decreased the capsaicin-activated current. This inhibition was not mimicked by Mg2+, reflected a decrease in open probability, and was slowly reversible. Furthermore, increasing the calmodulin concentration in our patches by coexpression of wild-type calmodulin with TRPV1 produced inhibition by Ca2+ alone. In contrast, patches excised from cells coexpressing TRPV1 with a mutant calmodulin did not respond to Ca2+. Using an in vitro calmodulin-binding assay, we found that TRPV1 in oocyte lysates bound calmodulin, although in a Ca2+-independent manner. Experiments with GST-fusion proteins corresponding to regions of the channel NH2-terminal domain demonstrated that a stretch of approximately 30 amino acids adjacent to the first ankyrin repeat bound calmodulin in a Ca2+-dependent manner. The physiological response to pain involves an influx of Ca2+ through TRPV1. Our results indicate that this Ca2+ influx may feed back on the channels, inhibiting their gating. This type of feedback inhibition could play a role in the desensitization produced by capsaicin.
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PMID:Ca2+/calmodulin modulates TRPV1 activation by capsaicin. 1469 77

The endogenous peptide nociceptin (orphanin FQ) plays a role in several important physiological functions in the CNS such as pain, anxiety and locomotion. It has previously been found that injection of 10 nmol nociceptin into the CA3 region of the hippocampus markedly impairs spatial learning and memory in the rat. The present study examined the effects of lower doses of nociceptin (3.3, 1, 0.33 and 0.1 nmol/rat) on spatial learning. The 3.3 nmol dose impaired spatial learning over the 5 days of training although the effect was not as strong as with 10 nmol. In contrast, the two lower doses, 1 and 0.33 nmol/rat, improved spatial learning whereas the lowest dose, 0.1 nmol/rat, had no significant effect. Both the impairing and facilitating effect of nociceptin could be blocked by an ORL-1 receptor antagonist, [Phe1Psi(CH(2)-NH)Gly2]NC(1-13)NH2 (10 nmol/rat), indicating that both effects are ORL-1 receptor-mediated. The 3.3 nmol dose of nociceptin did not impair the performance in the visual platform task and did not alter swim speed or motor activity indicating no effects on motivation or motor performance. Taken together, these results show that nociceptin has a biphasic dose-effect curve and provide further evidence for a role of this neuropeptide in cognitive processes in the hippocampus.
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PMID:Nociceptin/orphanin FQ modulates spatial learning via ORL-1 receptors in the dorsal hippocampus of the rat. 1470 74

The side effects typically associated with the clinical profiles of opioid mu-receptor agonists have driven continuing efforts to identify novel efficacious analgesics, including agonists acting at opioid kappa receptors. Unfortunately, the therapeutic potential of kappa agonists seems limited by significant central nervous system side effects. Kappa opioid agonists, however, exhibit potent peripherally mediated antihyperalgesic and antinociceptive effects, suggesting that a peripherally acting kappa agonist may be efficacious in pain control with a more desirable safety profile than that associated with currently available opioids. Here, we report an all D-amino acid tetrapeptide characterized as a novel, highly selective kappa opioid receptor agonist. FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2) showed selectivity for the human kappa opioid receptor of greater than 30,000- and 68,000-fold versus human mu opioid receptor and human delta-opioid receptor receptors, respectively, and efficacious agonist activity using in vitro tissue assays. FE200041 produced local, peripheral antinociception in the hindpaw ipsilateral, but not contralateral, to injection. Antinociceptive effects of FE200041 in the mouse acetic acid writhing assay lasted over 60 min and were antagonized by naloxone and by selective kappa, but not mu, opioid receptor antagonists. FE200041 significantly inhibited acetic acid writhing and inhibited formalin-induced flinching in rats. FE200041 did not elicit sedation or motor impairment after systemic administration at a dose 10-fold higher than that needed to achieve antinociception. FE200041 is thus a potent peripherally restricted opioid kappa agonist with no demonstrable side effects typical of kappa agonists with central nervous system activity and with unprecedented selectivity for the opioid kappa receptor. The pharmacology of this compound suggests the possibility of therapeutic application.
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PMID:FE200041 (D-Phe-D-Phe-D-Nle-D-Arg-NH2): A peripheral efficacious kappa opioid agonist with unprecedented selectivity. 1499 60

Protease-activated receptors (PARs) 1 and 2 are expressed in capsaicin-sensitive sensory neurons, being anti- and pro-nociceptive, respectively. Given the possible cross talk between PAR-2 and capsaicin receptors, we investigated if PAR-2 activation could facilitate capsaicin-evoked visceral pain and referred hyperalgesia in the mouse and also examined the effect of PAR-1 activation in this model. Intracolonic (i.col.) administration of capsaicin triggered visceral pain-related nociceptive behavior, followed by referred hyperalgesia. The capsaicin-evoked visceral nociception was suppressed by intraperitoneal (i.p.) TFLLR-NH2, a PAR-1-activating peptide, but not FTLLR-NH2, a control peptide, and unaffected by i.col. TFLLR-NH2. SLIGRL-NH2, a PAR-2-activating peptide, but not LRGILS-NH2, a control peptide, administered i.col., facilitated the capsaicin-evoked visceral nociception 6-18 h after administration, while i.p. SLIGRL-NH2 had no effect. The capsaicin-evoked referred hyperalgesia was augmented by i.col. SLIGRL-NH2, but not LRGILS-NH2, 6-18 h after administration, and unaffected by i.p. SLIGRL-NH2, and i.p. or i.col. TFLLR-NH2. Our data suggest that PAR-1 is antinociceptive in processing of visceral pain, whereas PAR-2 expressed in the colonic luminal surface, upon activation, produces delayed sensitization of capsaicin receptors, resulting in facilitation of visceral pain and referred hyperalgesia.
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PMID:Modulation of capsaicin-evoked visceral pain and referred hyperalgesia by protease-activated receptors 1 and 2. 1503 13

The brain substrates involved in the pharmacological effects of neuropeptide FF (NPFF, Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2) including interactions with opioid systems, were investigated with the [14C]-2-deoxyglucose ([14C]-2-DG) autoradiography technique in mouse. The changes in cerebral activity were mapped after i.p. administration of 1DMe ([D-Tyr1,(NMe)Phe3]NPFF; 70 mg/kg), a neuropeptide FF analogue partially resistant to peptidases, alone or in combination with morphine (15 mg/kg). 1DMe induced a rapid decrease in the cerebral activity in the thalamus, the pontine reticular nuclei and the cerebellar cortex, brain regions involved in the control of motor activity and/or the processing of sensory data. This decrease, observed when 1DMe was administered 5 min before [14C]-2-DG, was reversed by morphine, which was devoid of significant effect at this time. When administered 30 min before the radioisotope, 1DMe was without effect, whereas morphine induced a significant increase in cerebral glucose utilization in the caudate putamen, the primary somatosensory cortex, the thalamus, the superior colliculus, the pontine reticular nuclei and the spinal cord. The association of morphine and 1DMe significantly increased cerebral glucose utilization in the same regions as morphine alone and also in three additional regions: the auditory cortex, the inferior colliculus and the dorsomedial periaqueductal gray. Following systemic administration, 1DMe and morphine modulated cerebral activity in brain regions involved in pain transmission and motor control, but their effects were temporally shifted, as were their effects on horizontal locomotor activity. However, neuropeptide FF-induced changes in brain activity were modulated in part by opioid receptors activation.
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PMID:Functional consequences of neuropeptide FF receptors stimulation in mouse: a cerebral glucose uptake study. 1520 62

To clarify involvement of protease-activated receptor-2 (PAR-2) in parotid pain, we examined whether PAR-2 activation in the parotid gland could activate trigeminal nociceptive neurons in anesthetized rats, by analyzing immunoreactive Fos as a nociceptive marker. Either the PAR-2 agonist SLIGRL-NH2 or capsaicin, injected into the parotid duct, caused expression of Fos in the trigeminal subnucleus caudalis, although the PAR-2-inactive reversed peptide had no such effect. The Fos expression caused by PAR-2 activation was inhibited by ablation of capsaicin-sensitive sensory neurons. Intraductal SLIGRL-NH2 did not increase vascular permeability in the parotid gland. Our data thus reveal that activation of PAR-2 in the parotid gland can cause activation of trigeminal nociceptive neurons via capsaicin-sensitive sensory nerves most probably by a non-inflammatory mechanism.
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PMID:Activation of trigeminal nociceptive neurons by parotid PAR-2 activation in rats. 1523 94

Tertiary amine local anesthetics (LAs) are clinically valuable agents for controlling pain and for treating some cardiac arrhythmias. These drugs inhibit conduction of electrical activity by blocking voltage-gated sodium channels. Interestingly, LAs can influence the conduction of electrical activity in heart muscle without markedly altering normal skeletal muscle activity. This review discusses the interactions between sodium channels and LAs, the methods used to investigate these interactions, and the mechanisms proposed to explain the greater LA sensitivity of cardiac sodium channels as compared with skeletal muscle sodium channels.
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PMID:Cardiotoxic and antiarrhythmic tertiary amine local anesthetics: sodium channel affinity vs. sodium channel gating. 1532 Apr 70


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