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)

The present study examined the distribution in the human spinal cord of a unique carboxy terminus sequence contained within MOR-1C, one of the recently described splice variants of the cloned mu opioid receptor gene MOR-1. Although MOR-1-like immunoreactivity (LI) and delta opioid receptor-like immunoreactivity were observed only in the superficial laminae, MOR-1C-LI was abundant in the superficial laminae of the dorsal horn and around the central canal. In the substantia gelatinosa, MOR-1C-LI was found in small diameter axonal elements, the cytoplasm and the plasmalemma of small spinal neurons and dendrites in inner lamina II and in some fibers within Lissauer's tract. These studies imply the presence of MOR-1C in human spinal cord and its distribution suggests that it plays a role in the control of pain processing.
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PMID:Immunohistochemical localization of the carboxy terminus of the novel mu opioid receptor splice variant MOR-1C within the human spinal cord. 1088 50

The present studies assessed the role of G(zalpha) and G(oalpha) in spinal alpha(2) adrenergic receptor agonist-induced antinociception, as well as in antinociceptive synergism between spinal morphine and clonidine. Mice were pretreated with a single intrathecal (i.t.) injection of artificial cerebrospinal fluid (ACSF), antisense oligodeoxynucleotide(s) (ODN) directed against G(zalpha) or G(oalpha), or nonsense ODN. After 48 h, the antinociceptive effects expressed as per cent maximal possible effect (% MPE) of either i.t. morphine alone, clonidine alone or coadministered morphine plus clonidine, were evaluated in the tail flick test. Antisense ODN to G(zalpha) attenuated clonidine- but not morphine-induced antinociception. The ED(50) (95% confidence interval) value for clonidine in ACSF pretreated mice was 6.3 (4.9-8.1) nmol, and in nonsense ODN pretreated mice, it was 4.2 (2.8-6.3) nmol. However, in the G(zalpha) antisense ODN pretreated mice, the highest dose clonidine tested (50 nmol) produced only 41+/-8.5% MPE. Antisense ODN to G(zalpha) also blocked antinociception produced by i.t. UK14, 304 (alpha(2) adrenergic receptor agonist) and [D-Pen(2), D-Pen(5)] enkephalin (DPDPE) (delta opioid receptor agonist), whereas it failed to attenuate i.t. Tyr-D-Ala-Gly-N-Me-Phe-Gly-ol (DAMGO)- (mu opioid receptor agonist) and U50-488 (kappa opioid receptor agonist) -induced antinociception. Pretreatment with antisense ODN to G(oalpha) attenuated both morphine and clonidine induced antinociception and did not affect synergism between the agonists. These results suggest that spinal G(o)alpha mediates antinociception produced by both clonidine and morphine while G(zalpha) mediates alpha(2) adrenergic and delta opioid receptor mediated antinociception, but not antinociception produced by mu or kappa opioid agonists.
Pain 2000 Aug
PMID:Differential effects of antisense oligodeoxynucleotides directed against g(zalpha) and g(oalpha) on antinociception produced by spinal opioid and alpha(2) adrenergic receptor agonists. 1092 11

This study examined a mechanism responsible for the enhanced antihyperalgesic and antinociceptive effects of the mu opioid receptor agonist (ORA) [D-Ala(2), NMePhe(4), Gly(5)-ol]enkephalin (DAMGO) microinjected in the rostroventromedial medulla (RVM) of rats with inflammatory injury induced by injection of complete Freund's adjuvant (CFA) in one hindpaw. In rats injected with CFA 4 hr earlier, microinjection of the mu opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH(2) (CTAP) in the RVM antagonized both the marginal enhancement of the potency of DAMGO and its antinociceptive effect. The delta opioid receptor antagonist naltriben (NTB) was without effect. In rats injected with CFA 2 weeks earlier, CTAP antagonized the effects of DAMGO to a lesser extent. However, NTB completely prevented the enhancement of the potency of DAMGO, whereas it did not antagonize DAMGO's antinociceptive effects. Microinjection of NTB alone, but not CTAP in the RVM of CFA-treated rats, enhanced the hyperalgesia present in the ipsilateral hindpaw and induced hyperalgesia in the contralateral, uninjured hindpaw. These results suggest that persistent inflammatory injury increased the release in the RVM of opioid peptides with preferential affinity for the delta opioid receptor, which can interact in a synergistic or additive manner with an exogenously administered mu opioid receptor agonist. Indeed, the levels of [Met(5)]enkephalin and [Leu(5)]enkephalin were increased in the RVM and in other brainstem nuclei in CFA-treated rats. This increase most likely presents a compensatory neuronal response of the CNS of the injured animal to mitigate the full expression of inflammatory pain and to enhance the antinociceptive and antihyperalgesic effects of exogenously administered mu opioid receptor analgesics.
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PMID:Contribution of endogenous enkephalins to the enhanced analgesic effects of supraspinal mu opioid receptor agonists after inflammatory injury. 1126 27

We designed the nonpeptidic highly selective delta opioid receptor agonist on the basis of message address concept and the accessory site theory and synthesized (+/-) TAN-67. In spite of highly potent agonistic activity in in vitro assay, (+/-) TAN-67 (racemate) afforded a weak antinociceptive effect in the mouse tail-flick test. This result led us to separate (+/-) TAN-67 to optical pure compounds, (+) and (-) TAN-67. An i.t.-treatment with (-) TAN-67 produced profound antinociceptive effects through specifically acting on delta1 receptors. Unlike (-) TAN-67, i.t.-administered (+) TAN-67 displayed dose-related nociceptive behaviors such as scratching, biting and licking. The effect of (+) TAN-67 was blocked by i.t.-treatment with NTI (delta receptor antagonist) and (-) TAN-67 (delta1 receptor agonist), but not by morphine (mu receptor agonist). The mechanisms involved in spinal pain modulation induced by (+) and (-) TAN-67 were also described.
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PMID:The pharmacological profile of delta opioid receptor ligands, (+) and (-) TAN-67 on pain modulation. 1135 31

Pharmacological and physiological evidence supports a role for delta (delta) opioid receptors in the nociceptive mechanisms of inflammation. However, few data exist regarding delta opioid receptor expression and localization in such conditions. In this study, we have assessed the distribution and function of delta opioid receptors in the rat spinal cord following induction of chronic inflammation by intraplantar injection of complete Freund's adjuvant (CFA). Intrathecal administration of the selective delta opioid receptor agonist, D-[Ala(2), Glu(4)] deltorphin, dose-dependently reversed thermal hyperalgesia induced by CFA. In situ hybridization and Western blotting experiments revealed an increase in delta opioid receptor mRNA and protein levels, respectively, in the dorsal lumbar spinal cord ipsilateral to the CFA injection site compared to the contralateral side and sham-injected controls. By electron microscopy, immunopositive delta opioid receptors were evident in neuronal perikarya, dendrites, unmyelinated axons and axon terminals. Quantification of immunopositive signal in dendrites revealed a twofold increase in the number of immunogold particles in the ipsilateral dorsal spinal cord of CFA-injected rats compared to the contralateral side and to sham-injected rats. Moreover, the relative frequency of immunogold particles associated with or in close proximity to the plasma membrane was increased in the ipsilateral dorsal spinal cord, indicating a more efficient targeting of delta opioid receptors to neuronal plasma membranes. These data demonstrate that CFA induces an up-regulation and increased membrane targeting of delta opioid receptors in the dorsal spinal cord which may account for the enhanced antinociceptive effects of delta opioid receptor agonists in chronic inflammatory pain models.
Pain 2003 Jan
PMID:Up-regulation and trafficking of delta opioid receptor in a model of chronic inflammation: implications for pain control. 1250 15

Here we describe a novel mechanism for plasma membrane insertion of the delta opioid receptor (DOR). In small dorsal root ganglion neurons, only low levels of DORs are present on the cell surface, in contrast to high levels of intracellular DORs mainly associated with vesicles containing calcitonin gene-related peptide (CGRP). Activation of surface DORs caused Ca(2+) release from IP(3)-sensitive stores and Ca(2+) entry, resulting in a slow and long-lasting exocytosis, DOR insertion, and CGRP release. In contrast, membrane depolarization or activation of vanilloid and P2Y(1) receptors induced a rapid DOR insertion. Thus, DOR activation induces a Ca(2+)-dependent insertion of DORs that is coupled to a release of excitatory neuropeptides, suggesting that treatment of inflammatory pain should include blockade of DORs.
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PMID:Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion. 1252 78

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

Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.
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PMID:3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides: potent, non-peptidic agonists of both the micro and delta opioid receptors. 1257 Mar 83

The role of peripheral potassium channels on the antinociceptive effect of Crotalus durissus terrificus venom, a mixed delta- and kappa-opioid receptor agonist, was investigated in hyperalgesia induced by carrageenin or prostaglandin E(2). Rat paw pressure test was applied before and 3 h after the intraplantar (i.pl.) injection of the nociceptive stimuli. Oral administration of venom 2 h after carrageenin or prostaglandin E(2) induces antinociception. Local pretreatment with 4-aminopyridine and tetraethylammonium (blockers of voltage-dependent K(+) channel) or charybdotoxin and apamin (inhibitors of large- and small-conductance Ca(2+)-activated K(+) channel, respectively) did not modify venom effect. On the other hand, glybenclamide, an inhibitor of ATP-sensitive K(+) channel abolished antinociception induced by the venom. Glybenclamide also inhibited the antinociceptive effect of [D-Pen(2.5)] enkephalin (DPDPE), a delta opioid receptor agonist, but did not modify the effect of (+)-trans-(1R,2R)-U-50488 (U50488), a kappa opioid receptor agonist. Diazoxide and pinacidil, two ATP-sensitive K(+) channel openers, injected by intraplantar route, induced a long-lasting increment of pain threshold of the animals and produced antinociception in both models of hyperalgesia. These results suggest that the antinociceptive effect of crotalid venom is mediated by activation of ATP-sensitive K(+) channels at peripheral afferent neurons.
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PMID:Activation of peripheral ATP-sensitive K+ channels mediates the antinociceptive effect of Crotalus durissus terrificus snake venom. 1278 85

When agonists to alpha(2)adrenergic receptor (AR) and delta opioid receptor (DOR) are co-administered, they act synergistically to inhibit nociceptive elicited behavior. Some previous studies of synergism have used the DOR-selective agonist [D-Pen(2),D-Pen(5)]-enkehphalin (DPDPE), however, DPDPE has been shown to be less potent in mu opioid receptor-knockout (MOR-KO) mice. It is possible, therefore, that MOR contributes to the synergism of DPDPE with the alpha(2)AR agonists. We compared the interactions of spinally administered DPDPE with an alpha(2)AR-adrenergic agonist in MOR-KO and MOR-wildtype (WT) mice. In these mice, morphine is ineffective and the potency of spinally administered DOR agonists, deltorphin II (DELT II) and DPDPE decreased 16- and 250-fold, respectively. Antagonism studies using the MOR-selective antagonist, D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH(2) (CTOP) and the DOR-selective antagonist, naltrindole HCl (naltrindole) demonstrated that while DOR mediates DPDPE-induced antinociception in MOR-KO, both MOR and DOR participate in DPDPE antinociception in WT mice, suggesting that DPDPE is less selective for DOR than previously observed in binding studies when given in vivo. The potency of the alpha(2)AR agonist UK14,304 was equivalent in WT and MOR-KO, demonstrating that the loss of opioid-mediated antinociception in the MOR-KO was not due to generalized impairment of antinociceptive processing. Interestingly, isobolographic analysis showed that, despite substantial loss of DPDPE potency in MOR-KO, DPDPE-UK14,304 synergism is fully retained. Collectively, these experiments demonstrate that although MOR participates in DELT II- and DPDPE-mediated spinal antinociception, DOR independently participates in synergistic antinociception with alpha(2)AR. Resolution of the roles of the opioid receptor subtypes in opioid agonist-induced effects may require comparison of the effects of multiple selective agonists in knockout animals.
Pain 2003 Jul
PMID:DPDPE-UK14,304 synergy is retained in mu opioid receptor knockout mice. 1285 31


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