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)

Protein kinase C (PKC) has been shown to be an important substrate in intracellular signal transduction. Very little is known concerning its possible role in mediating opiate-induced analgesia. In the present study, 12-O-tetradecanoylphorbol 13-acetate (TPA), a selective activator of PKC, was injected intrathecally (ith) to assess its influence on the analgesia induced by intrathecal injection of the mu opioid agonist PL017, the delta agonist DPDPE and the kappa agonist 66A-078. Radiant heat-induced tail flick latency (TFL) was taken as an index of nociception. TPA in the dose of 25-50 ng, which did not affect the baseline TFL, produced a marked suppression of opioid antinociception, with a higher potency in blocking mu and delta than the kappa effect. In addition, mu and delta agonists induced remarkable decreases in spinal cyclic AMP (cAMP) content whereas the kappa effect was weak. The results suggest a cross-talk between the PKC system and the signal transduction pathway subserving opioid analgesia.
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PMID:Phorbol ester suppression of opioid analgesia in rats. 197 38

Protein kinase C isoforms including the alpha isozyme have been implicated in morphine tolerance. In the present study, we examined the effect of intrathecal delivery of an antisense oligonucleotide targeting rat protein kinase Calpha mRNA on the expression of spinal protein kinase Calpha isozyme and spinal morphine tolerance. Continuous intrathecal infusion of rats with morphine produced an increase in paw withdrawal threshold to thermal stimulation on day 1, which disappeared by day 5. On day 6, a bolus intrathecal injection of morphine (a probe dose) produced significantly less analgesia in morphine-infused rats than in saline-infused rats, suggesting tolerance. Intrathecal treatment with the protein kinase Calpha antisense concurrent with spinal morphine infusion not only maintained the analgesic effect of morphine during the 5-day infusion, it also significantly increased responsiveness to the probe morphine dose on day 6. In comparison, the missense used in the same treatment paradigm had no effect. The inhibitory effect of protein kinase Calpha antisense on spinal morphine tolerance was dose-dependent, and reversible. Intrathecal treatment with the antisense, but not the missense, in rats decreased expression of spinal protein kinase Calpha mRNA and protein, as revealed by real-time quantitative reverse transcription-polymerase chain reaction and western blots. Expression of the gamma isozyme was not affected by the oligonucleotides. The antisense also attenuated protein kinase C-mediated phosphorylation in spinal cord. These results demonstrate that selective reduction in the expression of the spinal protein kinase Calpha isozyme followed by a decrease of local protein kinase C-mediated phosphorylation will reverse spinal morphine infusion-induced tolerance. This finding is consistent with the view that tolerance produced by morphine infusion is dependent upon an increase in phosphorylation by protein kinase C, and also it emphasizes that the protein kinase Calpha isozyme and its activation in spinal cord may specifically participate in the phenomenon of opiate tolerance.
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PMID:Inhibition of spinal protein kinase Calpha expression by an antisense oligonucleotide attenuates morphine infusion-induced tolerance. 1212 88

The periaqueductal gray (PAG) is the main target site of the opioid-induced analgesia. The present study was designed to examine the roles of protein kinase A (PKA) and C (PKC) in the opioid-induced modulation of the currents activated by an inhibitory neurotransmitter, gamma-aminobutyric acid (GABA). The PAG neurons were acutely isolated and voltage-clamped under the nystatin-perforated patch-clamp mode. The GABA-activated current was sensitively blocked by a GABA(A) receptor antagonist, bicuculline, and selectively carried by chloride ions. The GABA(A) receptor-activated Cl(-) current was potentiated by a mu-opioid receptor agonist, [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin acetate (DAMGO). The GABA response was also potentiated by phorbol-12-myristate-13-acetate (PMA). Pretreatment with PMA occluded the DAMGO potentiation. However, both chelerythrine and 2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl) maleimide (GF109203X) also potentiated the GABA response. Pretreatment with chelerythrine or GF109203X also occluded the DAMGO potentiation. Meanwhile, the GABA response was potentiated by N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide (H-89), while not altered by forskolin. Pretreatment with H-89 occluded the potentiation effect of DAMGO on the GABA response. In addition, the DAMGO effect was completely blocked by pretreatment with forskolin. From the result, it can be suggested that activation of mu-opioid receptor potentiates the GABA(A) response through the mediation of PKA inhibition, and that PKC is not directly involved in the action mechanism of DAMGO.
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PMID:Roles of protein kinase A and C in the opioid potentiation of the GABAA response in rat periaqueductal gray neuron. 1266 43

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

Spinal dorsal horn (SDH) is one of important regions in both nociceptive transmission and antinociception. Opioid peptides produce analgesia via regulation of neurotransmitter release through modulation of voltage-dependent Ca(2+) channel (VDCC) in neuronal tissues. The modulatory effect of micro-opioid receptor (MOR) activation on VDCC was investigated in acutely isolated rat SDH neurons under the conventional whole-cell patch-clamp recording mode. The Ba(2+) current passing through VDCC was reversibly inhibited by a MOR agonist, [D-Ala(2),N-MePhe(4),Gly(5)-ol]-enkephalin (DAMGO, 1 microM). Among 108 SDH neurons tested, VDCC of 39 neurons (36%) were inhibited by MOR activation, while other 69 neurons (64%) were not affected. The L-, N-, P/Q-, and R-type VDCC components shared 58.4+/-18.9%, 29.3+/-12.1%, 8.7+/-7.2%, and 3.4+/-4.8% of the total VDCC, respectively. Among VDCC subtypes inhibited by MOR activation, L- and N-types were 61.4+/-12.8% and 30.7+/-14.4%, respectively, while both P/Q- and R-types were 7.9+/-11.8%. A depolarizing pre-pulse increased the amplitude of VDCC and suppressed most of the inhibitory effect of MOR activation. Application of 1 microM phorbol-12-myristate-13-acetate completely antagonized the inhibitory effect of MOR activation without any alteration of basal VDCC amplitude. In contrast, the response of MOR activation was not altered by application of 4-alpha-phorbol (1 microM), 2-[3-Dimethylaminopropyl]indol-3-yl]-3-(indol-3-yl) maleimide (GF109203X, 1 microM), forskolin (1 microM), N-(2-[p-Bromocinnamylamino]ethyl)-5-isoquinolinesulfonamide hydrochloride (H-89, 1 microM). These results indicate that activation of MOR coupled to G-proteins inhibits VDCC, and that this G-protein-mediated inhibition is antagonized by PKC-dependent phosphorylation.
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PMID:Activation of protein kinase C antagonizes the opioid inhibition of calcium current in rat spinal dorsal horn neurons. 1526 Nov 6

Systemic administration of morphine induced a hyperalgesic response in the hot plate test, at an extremely low dose (1-10 microg/kg). We have examined in vivo whether morphine, at an extremely low dose, induces acute central hypernociception following activation of the opioid receptor-mediated PLC/PKC inositol-lipid signaling pathway. The PLC inhibitor U73122 and the PKC blocker, calphostin C, dose dependently prevented the thermal hypernociception induced by morphine. This effect was also prevented by pretreatment with aODN against PLCbeta3 at 2 nmol/mouse and PKCgamma at 2-3 nmol/mouse. Low dose morphine hyperalgesia was dose dependently reversed by selective NMDA antagonist MK801 and ketamine. This study demonstrates the presence of a nociceptive PLCbeta3/PKCgamma/NMDA pathway stimulated by low concentrations of morphine, through muOR1 receptor, in mouse brain. This signaling pathway appears to play an opposing role in morphine analgesia. When mice were treated with a morphine analgesic dose (7 mg/kg), the downregulation of PLCbeta3 or PKCgamma at the same aODN doses used for the prevention of the hyperalgesic effect induced, respectively, a 46% and 67% potentiation in analgesic response. Experimental and clinical studies suggest that opioid may activate pronociceptive systems, leading to pain hypersensitivity and short-term tolerance, a phenomenon encountered in postoperative pain management by acute opioid administration. The clinical management of pain by morphine may be revisited in light of the identification of the signaling molecules of the hyperalgesic pathway.
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PMID:Signaling pathway of morphine induced acute thermal hyperalgesia in mice. 1665 May 82

Pain is the primary reason that people seek medical care. At present, chronic unremitting pain is the third greatest health problem after heart disease and cancer. Chronic pain is an economic burden in lost wages, lost productivity, medical expenses, legal fees and compensation. Chronic pain is defined as a pain of greater than 2 months duration. It can be of inflammatory or neuropathic origin that can arise following nerve injury or in the absence of any apparent injury. Chronic pain is characterized by an altered pain perception that includes allodynia (a response to a normally non-noxious stimuli) and hyperalgesia (an exaggerated response to a normally noxious stimuli). This type of pain is often insensitive to the traditional analgesics or surgical intervention. The study of the cellular and molecular mechanisms that contribute to chronic pain are of the up-most importance for the development of a new generation of analgesic agents. Protein kinase C isozymes are under investigation as potential therapeutics for the treatment of chronic pain conditions. The anatomical localization of protein kinase C isozymes in both peripheral and central nervous system sites that process pain have made them the topic of basic science research for close to two decades. This review will outline the research to date on the involvement of protein kinase C in pain and analgesia. In addition, this review will try to synthesize these works to begin to develop a comprehensive mechanistic understanding of how protein kinase C may function as a master regulator of the peripheral and central sensitization that underlies many chronic pain conditions.
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PMID:Protein kinase C in pain: involvement of multiple isoforms. 1754 7

The diverse family of Regulators of G protein signaling (RGS) proteins are widely distributed proteins with multiple functions, including GAP activity for heterotrimeric G protein alpha subunits. Three members of the RGS family, RGS9-2, RGS4 and RGSz, have been shown to play an essential modulatory role in psychostimulant and opiate drug actions. Interestingly, these proteins show distinct structure, distribution pattern and cellular localization. In addition, each of these proteins is differentially regulated by drugs of abuse in particular brain networks and appears to modulate distinct signal transduction events. The striatal enriched RGS9 plays a prominent role in opiate and psychostimulant drug reward; RGS4 appears to modulate opiate dependence via actions in the locus coeruleus, whereas RGSz modulates analgesia via activation of the PKC pathway.
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PMID:A role of RGS proteins in drug addiction. 1788 Sep 27

We evaluated the ability of spinally administered 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective antagonist of the metabotropic glutamate receptor subtype 5 (mGluR5), and 2-chloro-5-hydroxyphenylglycine (CHPG), an mGluR5 agonist, to modulate the antinociceptive action and tolerance of intrathecal (i.t.) morphine infusion in rats, and assessed the expression of spinal nitric oxide synthase (NOS). MPEP co-infused with morphine not only preserved the analgesia and retarded the development of antinociceptive tolerance, but also partially inhibited the up-regulation of spinal nNOS protein. However, the loss of morphine antinociceptive effect and tolerance were accelerated when CHPG and morphine were co-infused, while spinal nNOS activity was significantly up-regulated. We hypothesize that activation of mGluR5 and NMDA receptors occurs after the appearance of antinociceptive tolerance to morphine. The activation of these receptors might stimulate an increased concentration of intracellular calcium and activation of PKC, which both play a vital role in the development of morphine antinociceptive tolerance and expression of spinal NOS. The synergistic effect which seems to exist between mGluRs and iGluRs may also contribute to this phenomenon.
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PMID:Inhibition of MPEP on the development of morphine antinociceptive tolerance and the biosynthesis of neuronal nitric oxide synthase in rat spinal cord. 1839 42

Prevention of opiate tolerance is a critical issue in pain management. The present study was designed to characterize the pharmacological properties of sensory neuron-specific receptors (SNSR; also known as Mas-related gene receptors, or Mrg) for their modulation in the development of morphine tolerance and to investigate the underlying mechanism(s). Daily coadministration of the SNSR agonist BAM8-22 at a dose of 0.01 or 0.001, but not 1.0, nmol with morphine (intrathecally, or i.t., 20 microg/day) for 6 days significantly decreased the development of morphine tolerance. Coadministration of BAM8-22 (i.t., 1.0 nmol) on days 1, 3, and 5 completely blocked tolerance to morphine-induced analgesia. Intermittent coadministration of the structurally dissimilar SNSR agonist (Tyr(6))-2-MSH-6-12 (MSH; 5 nmol) also produced similar modulation. Chronic administration of morphine (20 microg, i.t.) increased expression of neuronal nitric oxide synthase (nNOS) and calcitonin gene-related peptide (CGRP) in superficial layers of the spinal cord and dorsal root ganglia. All these increases were abolished when BAM8-22 or MSH was intermittently coadministered. Furthermore, intermittent administration of BAM8-22 inhibited morphine-induced increase in protein kinase C gamma (PKC gamma) in both membrane and cytosol of spinal dorsal horn neurons. These results suggest that moderate activation of SNSR modulated morphine tolerance by inhibition of the PKC signaling pathway, leading to abolishment of enhancement of nNOS and CGRP. As SNSR are uniquely located ina subset of small-sized neurons in dorsal root and trigeminal ganglia, intermittent combination of SNSR agonist could be a promising adjunct for sustained use of opiates without central nervous system side effects.
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PMID:Modulation of sensory neuron-specific receptors in the development of morphine tolerance and its neurochemical mechanisms. 2056 89


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