Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated the role of protein kinase C (PKC) in cell mu-opioid receptor (MOR) internalization and MOR-mediated acute tolerance in vivo. When Chinese hamster ovary cells expressing MOR were exposed to [D-Ala(2),MePhe(4),Gly-ol(5)]-enkephalin (DAMGO), receptor internalization was observed at 30 min. Incubation with morphine failed to induce receptor internalization. When calphostin C, a PKC inhibitor, was added, receptor internalization was observed as early as 10 min after morphine stimulation. The MOR internalization induced by DAMGO or morphine in the presence of calphostin C was dynamin dependent, because it was abolished 2 d after pretreatment with recombinant adenovirus to express a dominant interfering dynamin mutant (K44A/dynamin adenovirus). On the other hand, in a peripheral nociception test in mice, the nociceptive flexor response after intraplantar injection (i.pl.) of bradykinin was markedly inhibited by DAMGO (i.pl.). DAMGO analgesia was not affected by 2 hr prior injection (i.pl.) of DAMGO. Marked acute tolerance was observed after pretreatment with dynamin antisense oligodeoxynucleotide or K44A/dynamin adenovirus. The DAMGO-induced acute tolerance under such pretreatments was inhibited by calphostin C. Together, these findings suggest that PKC desensitizes MOR or has a role in the development of acute tolerance through MOR by inhibiting internalization mechanisms as a resensitization process.
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PMID:Protein kinase C-mediated inhibition of mu-opioid receptor internalization and its involvement in the development of acute tolerance to peripheral mu-agonist analgesia. 1131 80

Chronic opioid agonist treatment produces tolerance and in some cases opioid receptor internalization and down-regulation. Both morphine and etorphine induce tolerance; however, only etorphine produces mu-opioid receptor (muOR) down-regulation. In vitro studies implicate dynamin-2 (DYN-2) and G-protein receptor kinase-2 (GRK-2) in these processes. Therefore, we examined etorphine and morphine effects on regulation of GRK-2 and DYN-2 in mouse spinal cord. Mice were treated for 7 days with etorphine (200 microg/kg/day infusion) or morphine (40 mg/kg/day infusion + one 25-mg implant pellet). Controls were implanted with a placebo pellet. On the 7th day after implantation mice were tested for i.t. [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO) analgesia. In other mice, spinal cord was removed for [(3)H]DAMGO binding studies or GRK-2 and DYN-2 protein and mRNA abundance were determined. Both etorphine and morphine produced significant tolerance (ED(50) shift = 7.6- and 7.3-fold for morphine and etorphine, respectively). Etorphine decreased spinal muOR density by approximately 30%, whereas morphine did not change muOR density. Etorphine increased ( approximately 70%) DYN-2 protein abundance and decreased its mRNA (31%), whereas it had no effect on GRK-2 protein and mRNA abundance. Morphine had no effect on either DYN-2 or GRK-2 protein or mRNA abundance. These data raise the possibility that unequal receptor regulation by etorphine and morphine might be due to differential regulation of trafficking proteins. Overall, receptor down-regulation associated with chronic etorphine treatment may accelerate dynamin-related activity. Finally, the decrease in DYN-2 mRNA may be related to stabilization of DYN-2 protein abundance, which might inhibit transcription.
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PMID:Opioid agonists differentially regulate mu-opioid receptors and trafficking proteins in vivo. 1243 15

Chronic opioid antagonist treatment produces functional supersensitivity and mu-opioid receptor (muOR) upregulation. Studies suggest a role for G-protein receptor kinases (GRKs) and dynamin (DYN), but not signaling proteins (e.g., G(ialpha2)), in regulation of muOR density following opioid treatment. Therefore, this study examined muOR density, agonist potency, and the abundance and gene expression of GRK-2, DYN-2, and G(ialpha2) in mouse spinal cord after opioid antagonist treatment. Mice were implanted with a 15 mg naltrexone (NTX) or placebo pellet and 8 days later pellets were removed. At 24 and 192 h following NTX treatment, mice were tested for spinal DAMGO analgesia. Other mice were sacrificed at 0 or 192 h following NTX treatment and G(ialpha2), GRK-2, and DYN-2 protein and mRNA levels determined. [(3)H] DAMGO binding studies were also conducted. Immediately following NTX treatment (0 h), muOR density was increased (+ approximately 135%), while 192 h following NTX treatment muOR density was unchanged. NTX increased DAMGO analgesic potency (3.1-fold) 24 h following NTX treatment, while there was no effect at 192 h. NTX decreased protein and mRNA abundance of GRK-2 (-32%; -48%) and DYN-2 (-25%; -29%) in spinal cord at 0 h. At 192 h following 8-day NTX treatment, GRK-2 protein and mRNA were at control levels, while DYN-2 protein remained decreased (-31%) even though DYN-2 mRNA had returned to control levels. G(ialpha2) was unaffected by NTX treatment. These data suggest that opioid antagonist-induced mu-receptor upregulation is mediated by changes in abundance and gene expression of proteins implicated in receptor trafficking, which may decrease constitutive receptor cycling.
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PMID:Chronic opioid antagonist treatment selectively regulates trafficking and signaling proteins in mouse spinal cord. 1287 95

G protein-coupled delta-opioid receptors (DORs) participate in opioid-mediated analgesia, and chronic opioid application is well known to produce tolerance, limiting the therapeutic use of these drugs. To control and eventually avoid the underlying adaptive mechanisms, several cellular functions were examined with regard to their roles in tolerance development. Specific interest focused on DOR internalization, and the relevant findings are reviewed here. In general, DOR endocytosis is accomplished by complex interactions of various determinants, each having distinct roles in this process. For instance, DOR activation by certain opioids has been shown to turn on the machinery of endocytosis, whereas other opioids stimulate the receptors but fail to bring about internalization. In addition, receptor phosphorylation by different kinases was commonly found to promote DOR sequestration, but receptor internalization also occurs without their phosphorylation. A central role in DOR endocytosis is referred to the adaptor proteins arrestin-2 and arrestin-3, which bind to receptors and subsequently cause the formation of clathrin-coated pits to trigger dynamin-controlled endocytosis. Distinct sorting proteins, kinases, and phosphatases determine whether internalized DORs are delivered either for proteolytic degradation or for recycling, although the underlying mechanisms are hence not clear. Despite intensive studies, understanding of DOR sequestration, degradation, and recycling becomes increasingly difficult. However, the phenomenon of cellular desensitization is recognized to correspond to the loss of responsiveness as consequence of DOR internalization and degradation. In contrast, DOR endocytosis is also discussed to promote resensitization of cells to opioids by recycling of internalized DORs. Even stimulation of extracellular signal-regulated protein kinases (ERK 1/2) may be accomplished by DOR sequestration. However, opposite findings, as well as the fact that multiple cellular mechanisms underly receptor desensitization, resensitization, and ERK activation, questions whether DOR internalization is essential for these processes. Further investigations in both the cellular mechanism and the consequences of DOR endocytosis might thus reveal new aspects of opioid-controlled functions.
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PMID:Mechanism and consequences of delta-opioid receptor internalization. 1630 25

To account for benzodiazepine-induced spinal analgesia observed in association with an inflammation-induced shift in the influence of the GABA(A) receptor antagonist gabazine on nociceptive threshold, the present study was designed to determine whether persistent inflammation is associated with the upregulation of high-affinity GABA(A) receptors in primary afferents. The cell bodies of afferents innervating the glabrous skin of the rat hind paw were retrogradely labeled, acutely dissociated, and studied before and after the induction of persistent inflammation. A time-dependent increase in GABA(A) current density was observed that was more than twofold by 72 h after the initiation of inflammation. This increase in current density included both high- and low-affinity currents and was restricted to neurons in which GABA increased intracellular Ca(2+). No increases in GABA(A) receptor subunit mRNA or protein were detected in whole ganglia. In contrast, the increased current density was completely reversed by 20-min preincubation with the tyrosine kinase inhibitor genistein and partially reversed with the Src kinase inhibitor PP2. Genistein reversal was partially blocked by the dynamin inhibitor peptide P4. Changes in nociceptive threshold following spinal administration of genistein and muscimol to inflamed rats indicated that the pronociceptive actions of muscimol observed in the presence of inflammation were reversed by genistein. These results suggest that persistent changes in relative levels of tyrosine kinase activity following inflammation provide not only a sensitive way to dynamically regulate spinal nociceptive signaling but a viable target for the development of novel therapeutic interventions for the treatment of inflammatory pain.
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PMID:Inflammation-induced shift in spinal GABA(A) signaling is associated with a tyrosine kinase-dependent increase in GABA(A) current density in nociceptive afferents. 2291 54