Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although intrathecal administration of nociceptin, an endogenous ligand of the opioid receptor-like1 receptor, exhibits an antinociceptive effect in various pain models, cellular mechanisms underlying this action are still unknown. Here, we investigated the effects of nociceptin on excitatory and inhibitory synaptic transmission to substantia gelatinosa neurones of an adult rat spinal cord slice with an attached dorsal root by use of the blind whole-cell patch-clamp technique; this was done under the condition of a blockade of a hyperpolarising effect of nociceptin. In about 70% of the neurones examined, nociceptin (1 microM) reduced the amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) which were monosynaptically evoked by stimulating Adelta- or C-afferent fibres; the inhibition of C-fibre EPSCs (50+/-6%, n=11) was larger than that of Adelta-fibre EPSCs (30+/-5%, n=23; P<0.05). Each of the nociceptin actions was dose-dependent in a concentration range of 0.1 to 1 microM, and was largely suppressed by a selective opioid receptor-like1 receptor antagonist, 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (3 microM). Nociceptin (1 microM) also decreased miniature EPSCs frequency by 22+/-6% (n=7) while not affecting their amplitude. Responses of substantia gelatinosa neurones to bath-applied alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (10 microM) were not changed by nociceptin. Both electrically evoked and miniature inhibitory postsynaptic currents, mediated by either the GABA(A) or glycine receptor, were unaffected by nociceptin. These results indicate that nociceptin suppresses excitatory but not inhibitory synaptic transmission to substantia gelatinosa neurones through the activation of the opioid receptor-like1 receptor; this action is pre-synaptic in origin. Considering that the substantia gelatinosa is the main part of termination of Adelta- and C-fibres transmitting nociceptive information, the present finding would account for at least a part of the inhibitory action of nociceptin on pain transmission. Nociceptin could inhibit more potently slow-conducting than fast-conducting pain transmission.
 ...
PMID:Nociceptin inhibits excitatory but not inhibitory transmission to substantia gelatinosa neurones of adult rat spinal cord. 1180 70

A novel member of the opioid related receptor family, the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor was identified and demonstrated to be involved in many physiological functions including pain regulation. [Nphe(1)]N/OFQ-(1-13)-NH(2) (Nphe) is a novel peptide antagonist of NOP receptors, developed using peripheral preparations. We have quantitatively investigated the interaction of Nphe with N/OFQ, the endogenous ligand of NOP receptors, in the midbrain ventrolateral periaqueductal gray (PAG), a crucial brain region for N/OFQ-induced reversal of opioid analgesia, using the patch-clamp recording technique in brain slices. N/OFQ concentration-dependently activated an inwardly rectifying K(+) current in response to hyperpolarization ramps from -60 to -140 mV. Nphe concentration-dependently attenuated the K(+) current activated by N/OFQ without changing its reversal potential. The presence of Nphe right-shifted the concentration-response curve to N/OFQ in a parallel manner. The Schild plot analysis yielded a slope of 1.16 and a pA(2) value of 6.64 that is similar to those obtained in peripheral preparations. At concentrations up to 3 microM, Nphe affected neither the membrane current per se, nor the inwardly rectifying K(+) current activated by [D-Ala(2), N-Me-Phe(4),Gly-ol(5)]-enkephalin or baclofen, a mu-opioid and GABA(B) receptor agonist, respectively. It is concluded that Nphe acts as a pure, selective and competitive antagonist at native NOP receptors of ventrolateral PAG neurons.
 ...
PMID:[Nphe(1)]N/OFQ-(1-13)-NH(2) is a competitive and selective antagonist at nociceptin/orphanin FQ receptors mediating K(+) channel activation in rat periaqueductal gray slices. 1180 21

Neurogenic inflammation is an inflammatory response of peripheral tissue to vasoactive substances released from sensory afferent terminals. It can be triggered via a local axon reflex and by dorsal root reflex (DRR) activity involving the spinal cord. Nociceptin, an endogenous ligand for the opioid receptor-like (ORL-1) G-protein coupled receptor, has been found to inhibit the local axon reflex-mediated neurogenic inflammation by suppressing the release of vasoactive neuropeptides from sensory afferent terminals. The present study was to explore the role of spinal ORL-1 receptors in the modulation of DRR-induced neurogenic inflammation. We first examined the effect of nociceptin on DRR by recording dorsal root potentials (DRPs) and the associated antidromic discharges, evoked by electrical stimulation of an adjacent dorsal root in an in vitro neonatal rat spinal cord preparation. Nociceptin reversibly inhibited the DRP in a concentration-dependent manner (IC50: approximately 45 nM, maximal inhibition: approximately 50%), an effect that was antagonized by the ORL-1 receptor antagonist, J-113397. Neurochemical studies demonstrated that nociceptin (10 microM) also produced an approximately 40% reduction in gamma amino butyric acid (GABA) release evoked by electrical stimulation of neonatal rat spinal cord slices. On the other hand, nociceptin had no effect on exogenous GABA-evoked DRP. These findings suggest that the nociceptin-induced inhibition of the DRP is most likely due to the suppression of GABA release, the principle transmitter mediating DRP, from GABAergic neurons that are pre-synaptic to primary afferent terminals. Finally, in order to explore the physiological significance of such modulation in a fully integrated system, we evaluated the effect of intrathecally administered nociceptin on capsaicin-induced acute cutaneous neurogenic inflammation in rat hind paw, quantified by examining the degree of paw edema in anesthetized rats. The magnitude of capsaicin-induced increase of paw thickness was reduced by approximately 50% from 31+/-1.34% (n=6) to 15+/-1.63% (n=8; P<0.05) by nociceptin (10 micromol). We conclude that spinal ORL-1 receptors can modulate neurogenic inflammation by suppressing the GABAergic neuronal activity in the dorsal horn that is responsible for generating DRRs.
Pain 2002 Apr
PMID:Activation of spinal ORL-1 receptors prevents acute cutaneous neurogenic inflammation: role of nociceptin-induced suppression of primary afferent depolarization. 1197 3

A novel opioid receptor family, the nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptors, has been identified to be involved in many physiological functions including pain regulation. CompB (also known as J-113397) is the first non-peptide antagonist of NOP receptors. Using the patch-clamp recording technique in brain slices, we have quantitatively studied the interactions of CompB with N/OFQ at native NOP receptors of ventrolateral neurons of the midbrain periaqueductal gray (PAG), a crucial region for N/OFQ-induced reversal of opioid analgesia. N/OFQ concentration-dependently activated inwardly rectifying K(+) channels in response to hyperpolarization ramps from -60 to -140 mV. CompB attenuated the magnitude but not the reversal potential of the K(+) current activated by N/OFQ in a concentration-dependent manner. The presence of CompB produced a parallel right-shift of the concentration-response curve to N/OFQ. The Schild plot analysis yielded a pA(2) value of 8.37. At concentrations up to 1 microM, CompB affected neither the membrane current per se nor the inwardly rectifying K(+) current activated by [D-Ala(2), N-Me-Phe(4),Gly-ol(5)]-enkephalin or baclofen, a mu-opioid and GABA(B) receptor agonist, respectively. It appears that CompB, at nanomolar concentrations, is a pure, selective and competitive antagonist of postsynaptic NOP receptors that mediate inwardly rectifying K(+) channel activation in ventrolateral PAG neurons.
 ...
PMID:CompB (J-113397), selectively and competitively antagonizes nociceptin activation of inwardly rectifying K(+) channels in rat periaqueductal gray slices. 1206 9

Nociceptin, acting through the opioid receptor-like 1 (ORL1) receptor, produces anti-nociception in several models of neuropathy. We examined the involvement of the ORL1 receptor system in the allodynia developed after sciatic nerve ligation. Allodynic rats were selected by the von Frey hair and treated intrathecally with nociceptin or morphine. The peptide induced dose-dependent anti-allodynic activities, while morphine was effective at the higher dose only. By the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay, the two described ORL1 receptor isoforms were up-regulated in the allodynic animals, but unmodified in non-allodynic rats. Both short and long ORL1 receptor mRNA isoforms increased in the ipsilateral lumbar enlargement (by 50% and 100%, respectively), while 50% and 60% increases were found in the ipsilateral L5-L6 dorsal root ganglia, respectively. No significant changes were observed for either the nociceptin precursor or mu-opioid receptor expression. Thus, the ORL1 receptor system seems to regulate the mechano-allodynia that developed after nerve damage, suggesting its potential role in the treatment of neuropathic pain.
 ...
PMID:Up-regulation of ORL-1 receptors in spinal tissue of allodynic rats after sciatic nerve injury. 1210 3

Expression of the neuropeptide orphanin FQ/nociceptin (OFQ/N) and its receptor, the opioid receptor-like receptor (ORL1), have been found to have a wide distribution in the central nervous system, and in brain areas involved in sensory perception in particular. The effects of OFQ/N on, e.g., sensory transmission are very complex, and a modulatory effect on pain perception has been suggested. We therefore wanted to investigate the distribution of OFQ/N and ORL1 in the spinal cord and DRG, and also in SCG and some other peripheral tissues. The methods used were in situ hybridization, immunohistochemistry and ligand binding. We found that OFQ/N and ORL1 mRNA are expressed in DRG; primarily in small and large neurons, respectively. In spinal cord, mRNA for OFQ/N and ORL1 is expressed in neurons in laminae I, II and X, and in ventral horn neurons. Further, immunoreactivity for OFQ/N is observed in fibers and neurons in the superficial laminae of the dorsal horn and around the central canal, and also in neurons in the ventral horn of the spinal cord. Receptor ligand binding to the spinal cord grey matter is demonstrated, primarily concentrated to the dorsal horn and around the central canal, and also to medium and large size DRG neurons. These findings on the morphological distribution pattern of OFQ/N and ORL1 at the cellular level may support the notion that OFQ/N is involved in modulating pain transmission. Further, expression of OFQ/N and ORL1 mRNA was also found in SCG, whereas expression was undetectable in skin.
 ...
PMID:Expression of orphanin FQ/nociceptin and its receptor in rat peripheral ganglia and spinal cord. 1212 89

Orphanin FQ/Nociceptin (OFQ/N), an endogenous peptide found throughout the central nervous system, has been attributed with a wide range of functions, including modulation of motivational and emotional behavior, but most prominently, facilitation of hyperalgesia. It has also been shown that brain OFQ/N is stimulated during locally-induced peripheral inflammation, a condition well known to increase pain sensitivity. However, few studies have addressed whether specific immunological challenge using T-cell dependent and independent stimuli alters OFQ/N gene activation in the brain. Consequently, male C57BL/6J mice were challenged with 5 microg of lipopolysaccharide (LPS) or a T-cell-activating bacterial superantigen, Staphyloccocal enterotoxin A (SEA), and levels of brain OFQ/N precursor, pNOC, mRNA were analyzed by semi-quantitative RT-PCR. In addition, nociceptive thresholds were examined in immunologically challenged mice using the hotplate test. Initial results on a combined region of the brain containing various limbic components, revealed increased levels of pNOC mRNA in response to SEA challenge, but not to LPS. Further analysis of more discrete brain regions revealed increased pNOC mRNA in the hypothalamus and amygdala in response to SEA. Interestingly, challenge with SEA, but not LPS, significantly reduced hindpaw-lick latency in the hot plate test, although this effect was observed only if the hotplate environment was unfamiliar, suggesting an interaction between immunological stimulation and novelty-induced stress. Since SEA induces various cytokines, including TNF-alpha, these results are consistent with a growing literature documenting the effects of cytokines on nociceptive functions, and a possible involvement of the OFQ/nociceptin system.
 ...
PMID:Immunological challenge modulates brain orphanin FQ/nociceptin and nociceptive behavior. 1221 1

Nociceptin-immunoreactive cellbodies were detected in the human trigeminal ganglion, while no such fibers were identified in the temporal artery or in dermal tissue from the neck region. In four healthy subjects receiving nociceptin into the temporal muscle in an open labeled design no pain was detected. In 10 healthy subjects who received 200pmol of nociceptin into tender non-dominant trapezius muscles in a placebo-controlled, randomized, balanced, and double-blinded design local tenderness increased (P=0.025) while no pain was noted. Thus, the action of nociceptin should be searched for in the trigeminal ganglion and/or in the central nervous system (CNS).
 ...
PMID:Does nociceptin play a role in pain disorders in man? 1221 18

We analyzed spinal metabolic pathway of nociceptin/orphanin FQ related to pain-transmission or modulation in the both in vitro and in vivo experiments. Nociceptin was degraded by spinal synaptic membranes. Major metabolites of nociceptin were free phenylalanine, nociceptin (1-13) and nociceptin (14-17). Both the degradation of nociceptin and the accumulation of the major cleavage metabolites, nociceptin (1-13) and nociceptin (14-17), were strongly inhibited by a metal chelator and also by specific inhibitors of endopeptidase-24.11, thiorphan and phosphoramidon. Furthermore, purified endopeptidase-24.11 hydrolyzed nociceptin at the cleavage site (Lys(13)-Leu(14) bond) identical to that by spinal synaptic membranes. Recently, we have found that nociceptin, injected intrathecally at small doses (fmol order) elicits a behavioral response consisting of scratching, biting and licking in mice. In the present study, we have examined the effect of peptidase inhibitors on the behavioral response elicited by intrathecal injection of nociceptin in mice. Phosphoramidon simultaneously injected with nociceptin additively enhanced nociceptin-induced behavioral response, whereas the nociceptin-induced behavioral response was unaffected by either bestatin, an aminopeptidase inhibitor or captopril, an angiotensin-converting enzyme inhibitor. However, the nociceptin effect was potentiated by combined injection of phosphoramidon and bestatin, indicating that inhibition of aminopeptidase may also contribute to inducing the behavioral response to nociceptin. These data suggest that endopeptidase-24.11 plays a major role in initial stage of nociceptin metabolism at the spinal cord level in mice.
 ...
PMID:Degradation of nociceptin (orphanin FQ) by mouse spinal cord synaptic membranes is triggered by endopeptidase-24.11: an in vitro and in vivo study. 1223 9

At the spinal level, nociceptin/orphanin FQ (Noc/OFQ) produces pronociceptive and allodynic effects at low doses (picogram range), while causing antinociceptive effects at high doses (microgram range). The discrepancy of pain modulation by Noc/OFQ at low and high doses raised a question whether Noc/OFQ exerted actions through the same Noc/OFQ receptor. In the present study, we examined the involvement of the Noc/OFQ receptor in pain responses with the novel nonpeptide antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride (JTC-801). Allodynia and hyperalgesia evoked by intrathecal administration of Noc/OFQ (50 pg/mouse) were dose dependently blocked by simultaneous administration of JTC-801 with IC(50) values of 32.2 and 363 pg, respectively. JTC-801 did not induce allodynia by itself. Subcutaneous injection of formalin into a hindpaw evoked biphasic pain behaviors such as flinching and biting in mice. Noc/OFQ at 10 pg increased the second-phase pain behaviors evoked by 1% formalin, whereas it strongly inhibited both the first-phase and second-phase pain evoked by 2% formalin at 1 microg. Although the pronociceptive effect by 10 pg of Noc/OFQ was dose dependently blocked by JTC-801 with an IC(50) value of 4.58 pg, the antinociceptive effects by 1 microg of Noc/OFQ were not antagonized by JTC-801. Furthermore, both phases of 2% formalin-induced pain behaviors were relieved by JTC-801. These results demonstrate that pronociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/OFQ receptor in the spinal cord and that JTC-801 can be a useful antagonist to examine the involvement of endogenous Noc/OFQ and mediation of the Noc/OFQ receptor under physiological and pathophysiological conditions including pain.
 ...
PMID:Characterization of nociceptin/orphanin FQ-induced pain responses by the novel receptor antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride. 1223 79


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>