Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We examined the effects of amlodipine, a selective L-type voltage dependent Ca(2+) channel (VDCC) blocker, and mibefradil, a selective T-type VDCC blocker on the antinociceptive effects of morphine, and mu, delta and kappa opioid receptor selective agonist-induced antinociception at the spinal level. Intrathecally administered amlodipine and mibefradil potentiated morphine and [D-Ala(2), N mePhe(4), Gly-ol(5)] enkephalin (DAMGO)-induced antinociception by shifting their dose response curves to the left. However, intrathecally administered amlodipine and mibefradil did not affect [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) and [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrolidinyl)cyclohexyl] benzene acetamide (U-50, 488H)-induced antinociception. These data indicate that L-type and T-type VDCC blockers synergistically potentiate the analgesic effects of mu opioid receptor agonists, but not delta and kappa opioid receptor agonists, at the spinal level. Additionally, these data suggest that there is an important functional interaction between L-type and/ or T-type VDCC and mu opioid receptors in the process of analgesia.
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PMID:L-type and T-type calcium channel blockade potentiate the analgesic effects of morphine and selective mu opioid agonist, but not to selective delta and kappa agonist at the level of the spinal cord in mice. 1140 39

As was the case in the era before us, in the new millennium we will continue to see an abundance of patients experiencing cancer-related pain for different reasons. Although much needless pain and suffering still affects many of those with cancer, we are presented with a medical dichotomy. With the analgesic drugs available today, and the relatively simple and effective guidelines to treat cancer pain published and disseminated by the World Health Organization, why do people with cancer continue to experience pain? As we search for the answer, the horizon may hold promising new drugs, 'old drugs' with new interest and applications, and new strategies for the field of pain therapy. Possibilities include the isolation and development of analgesics or analgesic combinations that may minimise the adverse effects which are often associated with the current therapeutic class of opioid analgesics. In addition, current research points to promising results identifying the N-methyl D-aspartate non-opioid receptor as a likely component of neuropathic pain. Drugs such as gabapentin, the mechanism of action of which is not well known, have found favour within the clinical community for their analgesic properties and good tolerability. Methadone, in a phase of resurgence, has garnered the attention of the clinical community because of its unique receptor activity and pharmacoeconomic benefits. A number of clinical studies have demonstrated that methadone has a valuable role in treating cancer pain. Perhaps, an unbalanced focus on the risks of inappropriate use, rather than the benefits, should not compromise or distract from the use of methadone as an alternative to morphine. Studies are on going to assess the potential role of methadone in treating neuropathic pain. Drugs such as cannabinoids, although currently applicable for patients with anorexia, nausea and/or vomiting, may offer benefits to patients experiencing pain. Other opportunities exist with such compounds as alpha2-adrenergic agonists, nicotine, lidocaine and ketamine. New strategies such as the switching opioids and/or their route of administration may offer improved analgesia with fewer adverse effects, thus providing therapeutic alternatives for the clinical community. In addition, there is interest in the co-administration of opioids that act on different receptors. For instance, oxycodone appears to be a kappa opioid receptor agonist and may offer enhanced analgesia when combined with morphine.
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PMID:Strategies for the treatment of cancer pain in the new millennium. 1143 51

Morphine injected locally to the paw of an adult or an infant rat is analgesic. Opiates specific to micro and kappa opioid receptors, and less consistently to delta opioid receptors, given locally to the site of injury in adult animals are also analgesic in a variety of models of inflammatory pain. To determine which opioid receptor(s) are involved in local analgesia in the immature animal, agonists specific for micro, kappa, and delta opioid receptors were injected into the intraplantar pad in infant rats and the resultant nociceptive behavior and Fos expression assayed in the formalin test. The kappa opioid receptor agonist U50,488 reduced nociceptive behavior in both phases of the formalin test and reduced Fos expression in the dorsal horn of the lumbar spinal cord, at 3 and 21 days of age. Morphiceptin (micro opioid agonist) was analgesic in the 21-day-old pups, but not the 3-day-old pups, measured behaviorally or by Fos expression. DPDPE (delta opioid agonist) was not analgesic at either age. We also tested the effects of opioid receptor antagonists on morphine's local analgesic action. Naltrexone, and to a lesser extent the micro opioid antagonist CTOP, antagonized morphine's analgesic effect. Kappa and delta opioid receptor blockers were inactive. The results demonstrate the ability of the kappa opioid system to mediate analgesia in the neonate at the site of injury in acute and chronic pain models, that the micro opioid agonists are active later in development, but that morphine is analgesic in part through micro opioid receptors.
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PMID:Analgesia induced by local plantar injections of opiates in the formalin test in infant rats. 1255 76

The 17-amino acid neuropeptide nociceptin/Orphanin FQ (N/OFQ) was recently identified as the endogenous ligand for the opioid receptor-like (ORL1) receptor, a fourth member of the classical mu, delta, and kappa opioid receptor family. Although ORL1 clearly belongs to the opioid receptor family, it does not bind classical opiates and the ORL1-N/OFQ system has pharmacological actions distinct from the opioid receptor system. This new ligand-receptor system has generated active interest in the opioid community because of its wide distribution and involvement in a myriad of neurological pathways. The past two years have witnessed tremendous advances in the design and discovery of very potent and selective peptide and nonpeptide agonist and antagonist ligands at ORL1. These discoveries have facilitated the understanding of the role of the ORL1-N/OFQ system in a variety of processes such as pain modulation, anxiety, food intake, learning, memory, neurotransmitter release, reward pathways, and tolerance development. The ORL1 receptor therefore represents a new molecular target for the design of novel agents for anxiety, analgesia, and drug addiction. Indeed, there is tremendous interest in the pharmaceutical industry in the development of nonpeptide ligands such as the potent ORL1 agonist, Ro 64-6198, as anxiolytics and the ORL1 antagonist JTC-801 as novel analgesics. This review presents an overview of the various peptide and nonpeptide ORL1 ligands with an emphasis on their potential therapeutic utility in various human disorders.
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PMID:Peptide and nonpeptide ligands for the nociceptin/orphanin FQ receptor ORL1: research tools and potential therapeutic agents. 1280 88

Previous studies have demonstrated that stress may increase prodynorphin gene expression, and kappa opioid agonists suppress drug reward. Therefore, we tested the hypothesis that stress-induced release of endogenous dynorphin may mediate behavioral responses to stress and oppose the rewarding effects of cocaine. C57Bl/6 mice subjected to repeated forced swim testing (FST) using a modified Porsolt procedure at 30 degrees C showed a characteristic stress-induced immobility response and a stress-induced analgesia observed with a tail withdrawal latency assay. Pretreatment with the kappa opioid receptor antagonist nor-binaltorphimine (nor-BNI; 10 mg/kg, i.p.) blocked the stress-induced analgesia and significantly reduced the stress-induced immobility. The nor-BNI sensitivity of the behavioral responses suggests an activation of the kappa opioid receptor by a stress-induced release of dynorphin peptides. Supporting this hypothesis, transgenic mice possessing a disrupted prodynorphin gene showed no increase in immobility or stress-induced analgesia after exposure to repeated FST. Because both stress and the kappa opioid system can modulate the response to drugs of abuse, we tested the effects of forced swim stress on cocaine-conditioned place preference (CPP). FST-exposed mice conditioned with cocaine (15 mg/kg, s.c.) showed significant potentiation of place preference for the drug-paired chamber over the responses of unstressed mice. Surprisingly, nor-BNI pretreatment blocked stress-induced potentiation of cocaine CPP. Consistent with this result, mice lacking the prodynorphin gene did not show a stress-induced potentiation of cocaine CPP, whereas wild-type littermates did. The findings suggest that chronic swim stress may activate the kappa opioid system to produce analgesia, immobility, and potentiation of the acute rewarding properties of cocaine in C57Bl/6 mice.
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PMID:Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral responses. 1284 70

Activation of kappa opioid receptors (KORs) in the spinal cord can diminish nociception. Humans and rodents show sex differences in the analgesia produced by KOR agonists, and female rats show fluctuations in KOR density and sensitivity across the estrous cycle. However, it is unclear whether there are sex differences in the amount and/or distribution of spinal KORs. In the present study, immunocytochemically labeled KORs were examined in laminae I and II of the lumbosacral spinal dorsal horn of male and normally cycling female Sprague-Dawley rats. The basic pattern of KOR labeling was determined in both sexes using qualitative electron microscopy (EM), and sex-linked differences in the density and subcellular distribution of KOR immunoreactivity were determined with quantitative EM and light microscopy. KOR labeling was visualized with immunoperoxidase for optimally sensitive detection, or with immunogold for precise subcellular localization. By EM, the general pattern of KOR immunoreactivity was similar in males and females. KOR immunoreactivity was common in dendrites, axons, and axon terminals, and was in a few glia and neuronal somata. Most KOR-immunoreactive (-ir) axons were fine-diameter and unmyelinated. Most KOR-ir terminals were small or medium-sized, and a minority formed asymmetric or symmetric synapses with unlabeled dendrites. KOR immunoreactivity was associated both with the plasma membrane and with cytoplasmic organelles, notably including dense core vesicles in terminals. Light microscopic densitometry revealed that KOR immunoreactivity was significantly denser in estrus and proestrus females than in males. By EM, the distribution of KOR-immunogold labeling within axon terminals differed, with a greater proportion of cytoplasmic KOR labeling in estrus females compared with males. In contrast, the abundance and types of KOR-immunoperoxidase-labeled profiles did not show sex-linked differences. We conclude that in both sexes, KORs are positioned to influence both pre- and postsynaptic neurotransmission and are present in morphologically heterogeneous neuron populations. These findings are consistent with complex consequences of KOR activation in the spinal cord. In addition, the presence of increased KOR density and proportionally elevated intracellular KORs in proestrus/estrus females suggests a basis for sex-linked differences in KOR-mediated antinociception.
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PMID:Kappa opioid receptors in rat spinal cord: sex-linked distribution differences. 1502 28

Our previous study showed that electroacupuncture (EA) significantly attenuated inflammatory hyperalgesia. It has also been reported that EA analgesia in uninjured animals is mediated by mu and delta opioid receptors at 2-15 Hz and by kappa opioid receptor at 100 Hz. Because persistent pain changes neural response to external stimulation, we hypothesized that (1) the mechanisms of EA anti-hyperalgesia may be different under conditions of persistent pain and that (2) combining EA with a sub-effective dose of morphine could enhance EA anti-hyperalgesia. Hyperalgesia, decreased paw withdrawal latency (PWL) to a noxious thermal stimulus, was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the hind paws of rats. Selective antagonists against mu (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-ThrNH2, CTOP), delta (naltrinodole, NTI) and kappa (nor-binaltorphimine, BNI) opioid receptors were administered intrathecally 10 min before each of two EA treatments at acupoint Huantiao (GB30), one immediately post and the other 2 h post-CFA. Morphine was given (i.p.) 40 min before the second EA treatment. PWL was measured before and 2.5 and 5 h post-CFA. Both 10 and 100 Hz EA-produced anti-hyperalgesia were blocked spinally by mu- and delta- but not kappa-receptor antagonists. EA combined with a sub-threshold dose of morphine (2.5 mg/kg) enhanced anti-hyperalgesia additively (10 Hz EA) or synergistically (100 Hz EA) compared to that produced by each component alone. These results suggest selective involvement of mu and delta, but not kappa, receptors in EA-produced anti-hyperalgesia in rats. A combined EA and opioid drug protocol may provide an improved treatment strategy for inflammatory pain.
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PMID:Involvement of opioid receptors in electroacupuncture-produced anti-hyperalgesia in rats with peripheral inflammation. 1531 82

Microinjection of kappa opioid receptor (KOR) agonists into the rostral ventromedial medulla (RVM) attenuates mu-opioid receptor mediated antinociception and stress-induced analgesia, yet is also reported to have an analgesic effect. To determine how KOR agonists produce both antinociceptive and antianalgesic actions within the RVM, the KOR agonist U69593 was microinjected directly into the RVM while concurrently monitoring tail flick latencies and RVM neuronal activity. Among RVM neurons recorded in vivo, two types show robust changes in activity just prior to the nocifensive tail flick reflex: ON cells burst just prior to a tail flick and their activity is pronociceptive, whereas OFF cells pause just prior to the tail flick and their activity is antinociceptive. Although RVM microinjection of U69593 did not affect tail flick latencies on its own, it did attenuate the on cell burst, an effect blocked by co-injection of the KOR antagonist, nor-binaltorphimine (nor-BNI). Furthermore, U69593 inhibited ongoing activity in subsets of OFF cells (4/11) and NEUTRAL cells (3/9). Microinjection of U69593 into the RVM also attenuated morphine antinociception and suppressed the excitation of off cells. Together with previous in vivo and in vitro studies, these results are consistent with the idea that KOR agonists can be either pronociceptive through direct inhibition of OFF cells, or antianalgesic through both postsynaptic inhibition and presynaptic inhibition of glutamate inputs to RVM OFF cells.
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PMID:Kappa opioids inhibit physiologically identified medullary pain modulating neurons and reduce morphine antinociception. 1545 5

This review summarizes the work from our laboratory investigating mechanisms of opioid analgesia using the Northern grass frog, Rana pipiens. Over the last dozen years, we have accumulated data on the characterization of behavioral effects after opioid administration on radioligand binding by using opioid agonist and antagonist ligands in amphibian brain and spinal cord homogenates, and by cloning and sequencing opioid-like receptor cDNA from amphibian central nervous system (CNS) tissues. The relative analgesic potency of mu, delta, and kappa opioids is highly correlated between frogs and other mammals, including humans. Radioligand binding studies using selective opioid agonists show a similar selectivity profile in amphibians and mammals. In contrast, opioid antagonists that are highly selective for mammalian mu, delta, and kappa opioid receptors were not selective in behavioral and binding studies in amphibians. Three opioid-like receptor cDNAs were cloned and sequenced from amphibian brain tissues and are orthologs to mammalian mu, delta, and kappa opioid receptors. Bioinformatics analysis of the three types of opioid receptor cDNAs from all vertebrate species with full datasets gave a pattern of the molecular evolution of opioid receptors marked by the divergence of mu, delta, and kappa opioid receptor sequences during vertebrate evolution. This divergence in receptor amino acid sequence in later-evolved vertebrates underlies the hypothesis that opioid receptors are more type-selective in mammals than in nonmammalian vertebrates. The apparent order of receptor type evolution is kappa, then delta, and, most recently, the mu opioid receptor. Finally, novel bioinformatics analyses suggest that conserved extracellular receptor domains determine the type selectivity of vertebrate opioid receptors.
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PMID:Opioid research in amphibians: an alternative pain model yielding insights on the evolution of opioid receptors. 1546 8

Arylacetamide analgesics that stimulate kappa opioid receptors in the central nervous system mediate dysphoria and psychosis as well as analgesia. However, the naturally occurring peptide agonist, dynorphin A, is analgesic in the absence of dysphoria and psychosis, indicating that the therapeutic effects of kappa opioid agonists may be separated from their side effects. As part of our effort to discover kappa opioid receptor analgesics lacking side effects, we designed and constructed two mu/kappa chimeric receptors, composed primarily of amino acid residues derived from the mu opioid receptor, that were expected to bind dynorphin A with high affinity. In one, extracellular loop 2 and transmembrane domain 4 were derived from the kappa opioid receptor and in the other, only extracellular loop 2 was derived from the kappa opioid receptor. Most competitors of [(3)H]diprenorphine binding from a variety of structural classes bound to the chimeras with affinities similar to those with which they bound to the mu opioid receptor. In contrast, dynorphin A analogs bound to the chimeras with affinities similar to those with which they bound to the kappa opioid receptor. Pharmacological characterization of [(35)S]GTPgammaS binding mediated by the chimera with extracellular loop 2 derived from the kappa opioid receptor showed that it behaved as if it were mu opioid receptor with high affinity for dynorphin A analogs. These chimeras may be useful in identifying novel kappa receptor agonists that bind to the second extracellular loop of the receptor and share the desirable therapeutic profile of dynorphin A.
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PMID:Pharmacological characterization of human kappa/mu opioid receptor chimeras that retain high affinity for dynorphin A. 1585 13


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