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Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mu-Opioid receptors have been shown to contribute to orphanin FQ/nociceptin (OFQ/N)-mediated analgesia and hyperalgesia, indicating that both pro- and antinociceptive actions of OFQ/N are influenced by mu-opioid receptors. A 60-min activation of mu-or opioid receptor-like 1 (ORL1) opioid receptors natively expressed in BE(2)-C human neuroblastoma cells desensitized both mu- and ORL1 receptor-mediated inhibition of cAMP accumulation. The mechanism(s) of OFQ/N-mediated mu and ORL1 cross talk involves the conventional protein kinase C isozyme, PKC-alpha, and G protein-coupled receptor kinases (GRKs) 2 and 3. Unlike OFQ/N-mediated desensitization of ORL1 and mu-opioid receptors, [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO)-mediated ORL1 desensitization in BE(2)-C cells is PKC-independent. However, DAMGO (1 microM) pretreatment increased membrane levels of GRK2 and GRK3, indicating their translocation to the membrane upon activation. This suggests that DAMGO activation of mu-opioid receptors results in GRK2 and GRK3 inactivation of ORL1 upon challenge with OFQ/N. Antisense, but not sense, DNA selectively targeting GRK2 or GRK3 blocks DAMGO-mediated mu- and ORL1 desensitization, respectively. However, in SH-SY5Y neuroblastoma cells, DAMGO failed to desensitize ORL1 or alter membrane PKC-alpha or GRK levels. Instead, DAMGO stimulated PKC-epsilon translocation to the cell membrane and produced micro-receptor desensitization. These results indicate that acute exposure to mu-receptor agonists can regulate ORL1 function, but the ability to do so varies from cell type to cell type. These results also confirm the existence of multiple signaling mechanisms for mu-opioid receptors and the importance of these mechanisms for mu-receptor-mediated-heterologous effects.
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PMID:Mu-opioid-induced desensitization of opioid receptor-like 1 and mu-opioid receptors: differential intracellular signaling determines receptor sensitivity. 1275 Apr 34

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

Orphanin FQ/nociceptin (OFQ/N), the endogenous ligand for the "orphan" opioid receptor ORL-1 (NOP(1)) was first identified in 1995. In the years since its discovery, a large body of evidence has accumulated showing that OFQ/N and its receptor are widely distributed in the nervous system, and showing that OFQ/N has potent and indiscriminate inhibitory actions on neurons in many regions. However, numerous studies investigating the functional role of OFQ/N in physiology or behavior have failed to provide a coherent view. Pain and analgesia have been the best studied, and administration of OFQ/N is reported to have no effect, to produce hyperalgesia, analgesia or anti-hyperalgesia. Effects of OFQ/N receptor antagonists have proved similarly contentious. In an attempt to resolve this controversy, we investigated the actions of OFQ/N on the activity of physiologically characterized neurons in the rostral ventromedial medulla, a region with a well-documented role in pain modulation(Heinricher et al., 1997). The results of those experiments demonstrate that this peptide is neither "anti-opioid" or "anti-hyperalgesic". It is simply inhibitory. For this reason, the effects seen in functional studies will only be fully understood when examined in the context of identified neural circuits.
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PMID:Orphanin FQ/nociceptin: from neural circuitry to behavior. 1280 1

There are now four types of opioid receptors. The new designations OP(1), OP(2) and OP(3) correspond, respectively, to the classic delta-, kappa- and micro-nomenclature. OP(4) was previously known as ORL(1), the receptor for the endogenous heptadecapeptide nociceptin/orphanin FQ. Although the cellular effects of nociceptin resemble those of conventional OP(1), OP(2), and OP(3) opioid agonists, its effects on nociceptive processes are quite different. Nociceptin produces spinal analgesia but appears to antagonize the effects of opioids. Following the recent synthesis of the nonpeptide OP(4) agonist Ro-64-6198 by Hoffmann-La Roche and the nonpeptide OP(4) antagonist J-113397 by Banyu, the nociceptin-OP(4) system now represents a viable and intriguing new target for drug design. OP(4) agonists may be of use in the management of neuropathic pain, anxiety, anorexia, epilepsy, drug dependence, male impotence, hypertension, cerebral ischemia and neurogenic bladder. They may also serve as novel diuretics and to help to reduce gastrointestinal motility. OP(4) antagonists may be of use as general analgesics and in the improvement of memory function. This review covers the recent exciting progress in this field, compares the actions of OP(4) agonists and antagonists with those of classic opioids, and seeks to predict some of the untoward effects that may be seen with such drugs.
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PMID:The nociceptin receptor as a potential target in drug design. 1281 96

The opioid peptide, Orphanin FQ/nociceptin (OFQ/N(1-17))(,) its active fragments, and a related precursor peptide each produce analgesia following microinjection into the amygdala of rats. OFQ/N(1-17)-induced analgesia elicited from the amygdala is blocked by amygdala pretreatment of either general, mu, kappa, or delta-opioid antagonists even though OFQ/N(1-17) binds poorly to these receptor subtypes, and the antagonists bind poorly to the ORL-1/KOR-3 receptor. Agonists at mu and kappa opioid receptors as well as beta-endorphin each produce analgesia elicited from the amygdala that is blocked by opioid antagonist pretreatment in the ventrolateral periaqueductal gray (vlPAG) of rats. The present study examined whether pretreatment of general and selective opioid antagonists in the vlPAG blocked OFQ/N(1-17)-induced analgesia on the tail-flick test elicited from the amygdala, and whether pretreatment of general and selective opioid antagonists in the amygdala blocked OFQ/N(1-17)-induced analgesia elicited from the vlPAG of rats. OFQ/N(1-17)-induced analgesia elicited from the amygdala was significantly and markedly reduced following vlPAG pretreatment with a dose range of either naltrexone, beta-funaltrexamine (beta-FNA, mu), nor-binaltorphamine (NBNI, kappa) or naltrindole (NTI, delta). In contrast, opioid antagonists administered into misplaced mesencephalic control placements ventral and lateral to the vlPAG actually enhanced OFQ/N(1-17)-induced analgesia elicited from the amygdala. OFQ/N(1-17)-induced analgesia elicited from the vlPAG was significantly and markedly reduced following amygdala pretreatment with naltrexone and NBNI, to a lesser degree by NTI, and was unaffected by beta-FNA. Yet, opioid antagonists administered into misplaced amygdala control placements were generally ineffective in altering OFQ/N(1-17)-induced analgesia elicited from the vlPAG. Latencies were transiently increased by general, but not selective opioid antagonist treatment alone in the amygdala, but not the vlPAG. These data indicate reciprocal and regional interactions between the amygdala and vlPAG in the mediation of OFQ/N(1-17) by classic opioid receptor subtype antagonists in rats.
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PMID:Reciprocal interactions between the amygdala and ventrolateral periaqueductal gray in mediating of Q/N(1-17)-induced analgesia in the rat. 1286 59

Nocistatin (NST) and nociception/orphanin FQ (OFQ) are peptides derived from the same precursor that play opposing roles in pain modulation. OFQ antagonizes morphine analgesia and electroacupuncture (EA)-induced antinociceptive effect. The present study investigates whether NST potentiates EA-induced antinociceptive effect and reverses chronic tolerance to EA in mice. Injection of NST (0.5, 5.0 and 50.0 ng) intracerebroventricularly had no effect on basal thermal latency, but produced a dose-dependent potentiation of EA-induced antinociceptive effect in mice with the maximum response at 5.0 ng. NST (5.0 ng) partly reversed chronic tolerance to EA. These results suggest that NST in the brain might play roles in EA-induced antinociceptive effect and the development of chronic tolerance to EA in mice.
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PMID:Nocistatin potentiates electroacupuncture antinociceptive effects and reverses chronic tolerance to electroacupuncture in mice. 1297 61

Nocistatin and nociceptin/orphanin FQ (N/OFQ) are two neuropeptides derived from the same precursor protein, prepronociceptin (ppOFQ), and exhibit different effects on spinal neurotransmission. Nocistatin does not bind to nociceptin/orphanin FQ peptide receptor (NOP), but intrathecal (i.t.) nocistatin has been reported to block the analgesic effect of i.t. N/OFQ. In this study, we investigated the effect of i.t. nocistatin on N/OFQ analgesia to radiant thermal stimuli in chronic constriction injury (CCI) rat. Firstly, to investigate the analgesic effect of N/OFQ, different doses of N/OFQ (3, 10, 30 microg) were intrathecally injected and foot withdrawal latency (FWL) to radiant heat was recorded. It is observed that 3 microg N/OFQ had no effect on FWL, 10 and 30 microg N/OFQ significantly increased FWL of CCI rat. Then, 10 microg N/OFQ, 10 microg nocistatin and a drug cocktail including 10 microg N/OFQ and 10 microg nocistatin were intrathecally injected. The results showed that FWL significantly decreased after using N/OFQ and nocistatin compared with using only N/OFQ, and 10 microg nocistatin had no effect on FWL versus control, suggesting that this dose of nocistatin per se had no effect on the pain threshold of CCI rat, but could block the analgesic effect of N/OFQ. These results indicated that i.t. N/OFQ dose-relatedly depressed thermal hyperalgesia produced by CCI and nocistatin could block N/OFQ analgesia at spinal level in CCI rat.
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PMID:Effect of intrathecal nocistatin on nociceptin/orphanin FQ analgesia in chronic constriction injury rat. 1451 41

Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the G protein-coupled receptor (opioid receptor like 1, ORL1), a member of the opioid receptor family. Although it is clear that this receptor system is involved in a variety of physiological functions, including analgesia, the precise actions of N/OFQ remain largely uncharacterized. One reason for this has been limited high affinity ligands to ORL1, and particularly the lack of availability of useful specific antagonists. Herein we describe the pharmacological activity of a series of N-terminally modified hexapeptides with high affinity for ORL1. These compounds were tested for binding affinity using [3H]N/OFQ binding to human ORL1 in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS binding in CHO cell membranes. The N-terminal modifications have produced compounds that maintained very high receptor affinity, but led to significant changes in intrinsic activity. One compound, pentanoyl-RYYRWR-NH2, with barely measurable agonist activity was tested in vivo. It was found to possess modest analgesic activity, but it was unable to block the morphine modulatory activity of N/OFQ.
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PMID:N-terminal modifications leading to peptide ORL1 partial agonists and antagonists. 1453 42

Nociceptin/orphanin FQ (N/OFQ) is a neuropeptide discovered in the middle of the 1990. It possesses an amino acid sequence very similar to those of endogenous opioid peptides (particularly dynorphin A). However, N/OFQ lacks the N-terminal tyrosine necessary for activation of mu-, kappa- and delta- opioid receptors and therefore does not bind to opioid receptors but to its own nociceptin receptor (NOP). Opioid peptides also do not bind to the NOP receptor. In spite of structural similarities, the pharmacological profile of N/OFQ is different from and, in many cases, opposite to that of the opioids. Intracerebroventricular injection of N/OFQ induces hyperalgesia and decreases the analgesic actions of opioids, but induces analgesia when given intrathecally. N/OFQ blocks the rewarding effects of morphine, ethanol, and psychostimulants such as cocaine and amphetamine, but given alone it does not have rewarding effect. N/OFQ is metabolized to shorter fragments, such as N/OFQ(1-13), N/OFQ(1-11), N/OFQ(1-7) and N/OFQ(1-6). These fragments show biological activity. The effects of N/OFQ include regulation of the release of numerous neurotransmitters and hormones, as NOP receptors are located presynaptically in different brain structures. The aim of this review was to present current opinion on the role of N/OFQ in nociception, reward and drug dependence.
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PMID:[Nociceptin/orphanin FQ (N/OFQ)--the opioid, antiopioid or neuromodulator?]. 1511 56

Ro 64-6198 [(1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one] was developed as a nonpeptide agonist of nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors, using bioassays at cloned receptors expressed in cell cultures. We have investigated the actions of Ro 64-6198 at native NOP receptors of the ventrolateral periaqueductal gray (PAG), a crucial site for N/OFQ-induced reversal of opioid analgesia, using the patch-clamp recording technique in rat brain slices. Ro 64-6198, like N/OFQ, activated G protein-coupled inwardly rectifying K(+) channels (GIRK) in ventrolateral PAG neurons but displayed only 60% efficacy and 22% potency of N/OFQ. Unlike N/OFQ that activated GIRK through NOP receptors in almost all tested neurons, Ro 64-6198 affected only 62% (114/185) of the neurons recorded, among which 57% were sensitive to CompB (J-113397), a selective NOP receptor antagonist. The effect of Ro 64-6198 was not affected by naloxone (1 microM), sulpiride (10 microM), and [1-(2-methoxyphenyl)-4-[4-2-phthalimido)butyl]piperazine (NAN-190) (1 microM), respectively, the antagonist of opioid, dopamine D(2), and 5-HT(1A) receptors. In Ro 64-6198-unresponsive neurons, N/OFQ activated GIRK through NOP receptors. It is concluded that Ro 64-6198 is a weak agonist of NOP receptors both in terms of potency and efficacy in ventrolateral PAG neurons. Heterogeneity of NOP receptors has been proposed from binding studies and in vivo functional studies. The possibility was discussed that two subsets of NOP receptors exist in ventrolateral PAG neurons, and Ro 64-6198 activates only one subset but N/OFQ activates both of them.
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PMID:Ro 64-6198 [(1S,3aS)-8-(2,3,3a,4,5,6-Hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one] acts differently from nociceptin/orphanin FQ in rat periaqueductal gray slices. 1525 41


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