RGS14 prevents morphine from internalizing Mu-opioid receptors in periaqueductal gray neurons

Opioid agonists display different capacities to stimulate mu-opioid receptor (MOR) endocytosis, which is related to their ability to provoke the phosphorylation of specific cytosolic residues in the MORs. Generally, opioids that efficiently promote MOR endocytosis and recycling produce little tolerance, as is the case for [d-Ala², N-MePhe⁴,Gly-ol⁵] encephalin (DAMGO). However, morphine produces rapid and profound antinociceptive desensitization in the adult mouse brain associated with little MOR internalization. The regulator of G-protein signaling, the RGS14 protein, associates with MORs in periaqueductal gray matter (PAG) neurons, and when RGS14 is silenced morphine increased the serine 375 phosphorylation in the C terminus of the MOR, a GRK substrate. Subsequently, these receptors were internalized and recycled back to the membrane where they accumulated on cessation of antinociception. These mice now exhibited a resensitized response to morphine and little tolerance developed. Thus, in morphine-activated MORs the RGS14 prevents GRKs from phosphorylating those residues required for β-arresting-mediated endocytosis. Moreover morphine but not DAMGO triggered a process involving calcium/calmodulin-dependent kinase II (CaMKII) in naïve mice, which contributes to MOR desensitization in the plasma membrane. In RGS14 knockdown mice morphine failed to activate this kinase. It therefore appears that phosphorylation and internalization of MORs disrupts the CaMKII-mediated negative regulation of these opioid receptors.     

Opioid sensitivity of analgesia induced by microinjections of nonsteroidal anti-inflammatory drugs into the <Emphasis Type="Italic">nucleus raphe magnus</Emphasis>

Our recent investigations demonstrated that microinjections of three nonsteroidal anti-inflammatory drugs (NSAIDs), Analgin, ketorolac, or xefocam, into the central nucleus of the amygdala produce tolerance to these drugs and cross-tolerance to morphine. We observed the same phenomenon in the midbrain periaqueductal gray matter. In this report, we show that microinjections of NSAIDs into the nucleus raphe magnus (NRM) produces antinociception, as indicated by latency increases in both tail-flick (TF) and hot-plate (HP) reflexes compared to controls with saline microinjected into the same nucleus. Furthermore, microinjection of the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs characterized by the TF and HP latencies on the 1st experimental day. On the 2nd day, naloxone also provided some trend effects in both TF and HP tests. These results strongly support the suggestion that the endogenous opioid system is significantly involved in NSAID-induced antinociception and tolerance.     

The role of T-type calcium channels in morphine analgesia,development of antinociceptive tolerance and dependence to morphine,and morphine abstinence syndrome

Involvement of T-type voltage dependent Ca2+ channels (VDCCs) on morphine antinociception, in the development of tolerance and dependence to morphine, and naloxone-precipitated abstinence syndrome in morphine dependent mice was examined by using mibefradil, a T-type VDCCs blocker. Mice were rendered tolerant and dependent on morphine by subcutaneous (s.c.) implantation of a morphine pellet containing 75 mg of morphine base for 72 hr. The tail-flick test was used to assess the nociceptive threshold. Coadministration of acute mibefradil (10 mg/kg, i.p.) with morphine enhanced the antinociceptive effects of acute morphine. Repeated mibefradil administration (10 mg/kg, i.p., just before, 24 and 48 hr after morphine pellet implantation) completely blocked the development of tolerance to the antinociceptive effect of morphine and even by this effect reached supersensitivity to morphine. However, repeated mibefradil treatment did not alter the development of dependence to morphine assessed by the A(50) values of naloxone (s.c.) required to precipitate withdrawal jumping 72 hr after morphine pellet. But, acute mibefradil (10, 30, and 50 mg/kg, i.p.) dose dependently decreased the expression of morphine abstinence syndrome when given directly 30 min prior to naloxone (0,05 mg/kg, s.c.) 72 hr after morphine pellet. These results indicate a critical role of T-type VDCCs in morphine antinociception, the development of tolerance to the antinociceptive effects of morphine and in morphine abstinence syndrome.     

Possible involvement of mu1-opioid receptors in the fentanyl- or morphine-induced antinociception at supraspinal and spinal sites

Fentanyl has been shown to be a potent analgesic with a lower propensity to produce tolerance and physical dependence in the clinical setting. The present study was designed to investigate the mechanisms of fentanyl- or morphine-induced antinociception at both supraspinal and spinal sites. In the mouse tail-flick test, the antinociceptive effects induced by both fentanyl and morphine were blocked by either the mu1-opioid receptor antagonist naloxonazine or the mu1/mu2-opioid receptor antagonist beta-funaltrexamine (beta-FNA) after s.c., i.c.v. or i.t. injection. In contrast, both fentanyl and morphine given i.c.v. or i.t. failed to produce antinociception in mu1-deficient CXBK mice. These findings indicate that like morphine, the antinociception induced by fentanyl may be mediated predominantly through mu1-opioid receptors at both supraspinal and spinal sites in mice. We also determined the ED50 values for s.c.-, i.c.v.- and i.t.-administered fentanyl- or morphine-induced antinociception in mice. The ED50 values for s.c.-, i.c.v.- and i.t.-administered fentanyl-induced antinociception were 73.7, 18.5 and 1.2-fold lower than that of morphine, respectively. The present data clearly suggest the usefulness of peripheral treatment with fentanyl for the control of pain.     

Antinociceptive and behavioral activation responses elicited by d-Pro(2)-endomorphin-2 in the ventrolateral periaqueductal gray are sensitive to sex and gonadectomy differences in rats

Sex differences have been observed in antinociception after morphine administered into either the lateral ventricles, rostral ventromedial medulla, or ventrolateral periaqueductal gray such that male rats exhibit significantly greater antinociception than female rats. Adult gonadectomy produced small, but significant changes in morphine antinociception relative to same-sex sham-operated controls. The present study examined whether sex and adult gonadectomy differences were observed in antinociceptive responses after D-Pro(2)-Endomorphin-2 (1-50 microg) elicited from the ventrolateral periaqueductal gray (vlPAG) on the tail-flick and jump tests in rats, and compared these effects with morphine antinociception. D-Pro(2)-Endomorphin-2 antinociception in the vlPAG was significantly greater in estrous-phase, sham-operated and ovariectomized female rats relative to sham-operated and castrated male rats on the tail-flick, but not jump test that differed markedly from the greater magnitude of morphine antinociception noted for male rats on both tests. In testing whether D-Pro(2)-Endomorphin-2's antinociceptive sex differences were secondary to alterations in activity, similar decreases in the pattern of total activity were observed after D-Pro(2)-Endomorphin-2 in the vlPAG in male and female rats. In evaluating whether male and female rats differed in their behavioral activation responses after D-Pro(2)-Endomorphin-2 in the vlPAG, significantly more excessive grooming, seizures, barrel rolls and explosive running behaviors were observed after D-Pro(2)-Endomorphin-2 in male, but not female rats during the precise periods of time when they were failing to display robust antinociceptive responses on the tail-flick test. Thus, the different patterns of sex differences after D-Pro(2)-Endomorphin-2 in the vlPAG appear to be attributable to sex-dependent alterations in behavioral activation rather than nociceptive processing per se.     

Tolerance Effects Induced by NSAID Microinjections into the Central Nucleus of the Amygdala in Rats

Recent investigations have shown that microinjections of non-opioid analgesics, nonsteroidal anti-inflammatory drugs, NSAIDs, into some brain areas, particularly, into the midbrain periaqueductal gray matter (PAG) and rostral ventro-medial medulla (RVM), cause antinociception with some effects of tolerance. Our preliminary findings have also shown the same effects of tolerance after intraperitoneal injections. The present study was designed to examine whether microinjections of metamizole (Analgin), ketorolac, and xefocam into the central nucleus of the amygdala (Ce) lead to the development of tolerance in rats, and to ascertain whether this nucleus is the pain-modulating pathway through PAG. Our investigation revealed that microinjections of NSAIDs into the Ce both unilaterally (the left side) and bilaterally produced antinociception, as indicated by a latency increase in tail-flick reflex (TF) compared to controls with saline, on the first experimental day for Analgin (P < 0.001), ketorolac (P < 0.001), and xefocam (P < 0.001). However, when these drug microinjections were repeated during subsequent days, the antinociceptive effects progressively diminished so that on the fifth experimental day the TF latency was similar to that in the rats that received repeated injections of only saline. These results show that, alongside with PAG and RVM, the Ce is an important site of the endogenous antinociceptive system, which triggers the descending pain control mechanism and thus inhibits nociceptive transmission. On the other hand, our data confirm the results of other authors that NSAIDs are closely related to endogenous opioids, and tolerance to these non-opioid drugs probably depends on opioid tolerance.     

Supraspinal circuitry mediating opioid antinociception: Antagonist and synergy studies in multiple sites

Supraspinal opioid antinociception is mediated by sensitive brain sites capable of supporting this response following microinjection of opioid agonists. These sites include the ventrolateral periaqueductal gray (vIPAG), the rostral ventromedial medulla (RVM), the locus coeruleus and the amygdala. Each of these sites comprise an interconnected anatomical and physiologically relevant system mediating antinociceptive responses through regional interactions. Such interactions have been identified using two pharmacological approaches: (1) the ability of selective antagonists delivered to one site to block antinociception elicited by opioid agonists in a second site, and (2) the presence of synergistic antinociceptive interactions following simultaneous administration of subthreshold doses of opioid agonists into pairs of sites. Thus, the RVM has essential serotonergic, opioid, cholinergic and NMDA synapses that are necessary for the full expression of morphine antinociception elicited from the vIPAG, and the vIPAG has essential opioid synapses that are necessary for the full expression of opioid antinociception elicited from the amygdala. Further, the vIPAG, RVM, locus coeruleus and amygdala interact with each other in synergistically supporting opioid antinociception.     

Modulating micro-opioid receptor phosphorylation switches agonist-dependent signaling as reflected in PKCepsilon activation and dendritic spine stability

A new role of G protein-coupled receptor (GPCR) phosphorylation was demonstrated in the current studies by using the μ-opioid receptor (OPRM1) as a model. Morphine induces a low level of receptor phosphorylation and uses the PKCε pathway to induce ERK phosphorylation and receptor desensitization, whereas etorphine, fentanyl, and [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAMGO) induce extensive receptor phosphorylation and use the β-arrestin2 pathway. Blocking OPRM1 phosphorylation (by mutating Ser363, Thr370 and Ser375 to Ala) enabled etorphine, fentanyl, and DAMGO to use the PKCε pathway. This was not due to the decreased recruitment of β-arrestin2 to the receptor signaling complex, because these agonists were unable to use the PKCε pathway when β-arrestin2 was absent. In addition, overexpressing G protein-coupled receptor kinase 2 (GRK2) decreased the ability of morphine to activate PKCε, whereas overexpressing dominant-negative GRK2 enabled etorphine, fentanyl, and DAMGO to activate PKCε. Furthermore, by overexpressing wild-type OPRM1 and a phosphorylation-deficient mutant in primary cultures of hippocampal neurons, we demonstrated that receptor phosphorylation contributes to the differential effects of agonists on dendritic spine stability. Phosphorylation blockage made etorphine, fentanyl, and DAMGO function as morphine in the primary cultures. Therefore, agonist-dependent phosphorylation of GPCR regulates the activation of the PKC pathway and the subsequent responses.     

Differentiation-associated genes regulated by TPA-induced c-Jun expression via a PKC/JNK pathway in KYSE450 cells

A group of potential differentiation-associated genes had been identified by microarray analysis as c-Jun/AP-1 target genes essential for epithelial differentiation program. Our previous study showed that c-Jun/AP-1 could bind and activate these gene promoters in vivo using chromatin immunoprecipitation. To further understand how the mitogen-activated protein kinase signaling pathways regulate AP-1 activity and expression of c-Jun target genes, our strategy was based on the use of 12-o-tetradecanoylophorbol-13-acetate (TPA) and pharmacological reagents to induce or block c-Jun expression. The mRNA and protein expression of these genes increased in response to TPA-induced c-Jun/AP-1 expression. Inhibitors of JNK (SP600125) and PKC (GF109203X) mainly blocked expression and phosphorylation of c-Jun, while inhibition of MEK-ERK activity with PD98059 (an inhibitor of MEK) had little effect. Expression of involucrin and keratin 4 in response to TPA was attenuated by pretreatments with GF109203X and SP600125, but not PD98059, suggesting involvement of PKC and JNK in this response. Taken together, these results suggested that differentiation-associated genes were regulated by TPA-induced c-Jun/AP-1 mainly via a PKC/JNK pathway in esophageal cancer cell line KYSE450.     

Mu opioid receptor activation of ERK1/2 is GRK3 and arrestin dependent in striatal neurons

In this study we investigated the mechanisms responsible for MAP kinase ERK1/2 activation following agonist activation of endogenous mu opioid receptors (MOR) normally expressed in cultured striatal neurons. Treatment with the MOR agonist fentanyl caused significant activation of ERK1/2 in neurons derived from wild type mice. Fentanyl effects were blocked by the opioid antagonist naloxone and were not evident in neurons derived from MOR knock-out (-/-) mice. In contrast, ERK1/2 activation by fentanyl was not evident in neurons from GRK3-/- mice or neurons pretreated with small inhibitory RNA for arrestin3. Consistent with this observation, treatment with the opiate morphine (which is less able to activate arrestin) did not elicit ERK1/2 activation in wild type neurons; however, transfection of arrestin3-(R170E) (a dominant positive form of arrestin that does not require receptor phosphorylation for activation) enabled morphine activation of ERK1/2. In addition, activation of ERK1/2 by fentanyl and morphine was rescued in GRK3-/- neurons following transfection with dominant positive arrestin3-(R170E). The activation of ERK1/2 appeared to be selective as p38 MAP kinase activation was not increased by either fentanyl or morphine treatment in neurons from wild type, MOR-/-, or GRK3-/- mice. In addition, U0126 (a selective inhibitor of MEK kinase responsible for ERK phosphorylation) blocked ERK1/2 activation by fentanyl. These results support the hypothesis that MOR activation of ERK1/2 requires opioid receptor phosphorylation by GRK3 and association of arrestin3 to initiate the cascade resulting in ERK1/2 phosphorylation in striatal neurons.     

Modulation of delta opioid agonist-induced antinociception by repeated morphine pretreatment in rhesus monkeys

AimsRepeated treatment with morphine increases antinociceptive effects of delta opioid agonists in rodents by a mechanism that may involve increased cell-surface expression of delta receptors. The present study evaluated effects of repeated morphine treatment on behavioral effects of the delta agonist SNC80 and the mu agonist fentanyl in rhesus monkeys.Main methodsIn an assay of schedule-controlled responding, three monkeys responded for food reinforcement under a fixed-ratio 30 schedule. In an assay of thermal nociception, tail-withdrawal latencies were evaluated in three monkeys using thermal stimulus intensities of 48 and 54 °C. In both assays, the effects of SNC80 (0.032–3.2 mg/kg) and fentanyl (0.001–0.056 mg/kg) were evaluated after repeated treatment with saline or a regimen of morphine doses modeled on the regimen that enhanced delta agonist antinociception and apparent delta receptor availability in previous rodent studies.Key findingsBoth SNC80 and fentanyl dose-dependently decreased rates of schedule-controlled responding, and repeated morphine treatment did not significantly alter these effects. In the assay of thermal nociception, SNC80 had little effect on tail-withdrawal latencies from water heated to 48 or 54 °C, whereas fentanyl increased tail-withdrawal latencies at both temperatures. Repeated morphine tended to increase the antinociceptive effects of SNC80 and to decrease the antinociceptive effects of fentanyl, but these effects of repeated morphine were small and were significant only at the higher stimulus intensity (54 °C).SignificanceThese results provide limited support for the proposition that prior stimulation of mu receptors selectively increases the antinociceptive effects of delta agonists in rhesus monkeys.     

Chimeric peptide of Met-enkephalin and FMRFa induces antinociception and attenuates development of tolerance to morphine antinociception.

A synthetic chimeric peptide of Met-enkephalin and FMRFamide (YGGFMKKKFMRFa), based on MERF was synthesized. This peptide was tested for possible antinociceptive effects using the tail flick test in mice. The effect of the chimeric peptide on morphine antinociception and development of tolerance to the antinociceptive action of morphine was also investigated. The chimeric peptide produced significant, dose-dependent antinociception (40, 60 and 90 mg/kg) in the tail flick test. Pretreatment with naloxone (5 mg/kg, IP) significantly attenuated the antinociceptive effect induced by the chimeric peptide (90 mg/kg, IP), indicating involvement of an opioidergic mechanism. In combination experiments with morphine, the antinociceptive dose of the chimeric peptide (60 mg/kg, IP) potentiated morphine (7 mg/kg, IP) antinociception. A low dose of the chimeric peptide (10 mg/kg, IP), that did not produce significant antinociception on its own, also potentiated morphine antinociception. In the tolerance studies, male albino mice received twice daily injections of morphine (20 mg/kg, IP) followed by either saline (0.1 ml) or chimeric peptide (80 mg/kg, IP) for a period of 4 days. A control group received twice daily injections of saline (0.1 ml) for the same period. When tested on Day 5, tolerance to antinociceptive action of morphine (15 mg/kg, IP) was evidenced by decreased response in chronic morphine plus saline treated mice compared to control group. Concurrent administration of chimeric peptide (80 mg/kg, IP) with morphine significantly attenuated the development of tolerance to the antinociceptive action of morphine. The preliminary results of this study demonstrate that peripherally administered chimeric peptide can produce dose dependent, naloxone reversible, antinociception; potentiate morphine antinociception and attenuate morphine tolerance, indicating a possible role of these type of amphiactive sequences in antinociception and its modulation. These chimeric peptides may also prove to be useful tools for further ascertaining the role of FMRFa family of peptides in mechanisms leading to opiate tolerance and dependence.     

Effect of EGF on [3H]-thymidine incorporation and cell cycle regulatory proteins in primary cultured chicken hepatocytes: Involvement of Ca2+/PKC and MAPKs

The reported studies on the metabolism in chicken hepatocytes in comparison with those of mammals are quite different. Therefore, this study examined the effect of EGF on DNA synthesis along with its related signal cascades in primary cultured chicken hepatocytes. EGF stimulated DNA synthesis in a dose (> or =10 ng/ml)-dependent manner, which correlated with the increase in CDK-2 and CDK-4 expression. The EGF-induced increase in [3H]-thymidine incorporation was blocked by AG 1478 (an EGF receptor tyrosine kinase antagonist), genistein, and herbimycin A (tyrosine kinase inhibitors), suggesting a role in the activation and tyrosine phosphorylation of the EGF receptor. In addition, the EGF-induced stimulation of [3H]-thymidine incorporation was prevented by staurosporine, H-7, or bisindolylmaleimide I (protein kinase C inhibitors), suggesting a role of PKC. In addition, PD 98059 (a MEK inhibitor), SB 203580 (a p38 MAPK inhibitor), and SP 600125 (a JNK inhibitor) blocked the EGF-induced stimulation of [3H]-thymidine incorporation and CDK-2/4 expression. Indeed, EGF increased the translocation of PKC from the cytosol to the membrane fraction, and increased the activation of p44/42 MAPK, p38 MAPK, and JNK. Moreover, EGF increased the CDK-2, CDK-4, cyclin D1, and cyclin E expression levels but decreased the p21 and p27 expression levels. These EGF-induced increases were blocked by an EGF receptor antagonist, tyrosine kinase inhibitors, PKC inhibitors, and MAPKs inhibitors. In conclusion, EGF stimulates DNA synthesis of primary cultured chicken hepatocytes via Ca2+/PKC and the MAPKs signaling pathways.     

Chronic ethanol consumption in rats produces opioid antinociceptive tolerance through inhibition of mu opioid receptor endocytosis

It is well known that the mu-opioid receptor (MOR) plays an important role in the rewarding properties of ethanol. However, it is less clear how chronic ethanol consumption affects MOR signaling. Here, we demonstrate that rats with prolonged voluntary ethanol consumption develop antinociceptive tolerance to opioids. Signaling through the MOR is controlled at many levels, including via the process of endocytosis. Importantly, agonists at the MOR that promote receptor endocytosis, such as the endogenous peptides enkephalin and β-endorphin, show a reduced propensity to promote antinociceptive tolerance than do agonists, like morphine, which do not promote receptor endocytosis. These observations led us to examine whether chronic ethanol consumption produced opioid tolerance by interfering with MOR endocytosis. Indeed, here we show that chronic ethanol consumption inhibits the endocytosis of MOR in response to opioid peptide. This loss of endocytosis was accompanied by a dramatic decrease in G protein coupled receptor kinase 2 (GRK2) protein levels after chronic drinking, suggesting that loss of this component of the trafficking machinery could be a mechanism by which endocytosis is lost. We also found that MOR coupling to G-protein was decreased in ethanol-drinking rats, providing a functional explanation for loss of opioid antinociception. Together, these results suggest that chronic ethanol drinking alters the ability of MOR to endocytose in response to opioid peptides, and consequently, promotes tolerance to the effects of opioids.     

Molecular interaction in the mouse PAG between NMDA and opioid receptors in morphine-induced acute thermal nociception

Previous evidence demonstrates that low dose morphine systemic administration induces acute thermal hyperalgesia in normal mice through μOR stimulation of the inositol signaling pathway. We investigated the site of action of morphine and the mechanism of action of μOR activation by morphine to NMDA receptor as it relates to acute thermal hyperalgesia. Our experiments show that acute thermal hyperalgesia is blocked in periaqueductal gray with the μOR antagonist CTOP, the NMDA antagonist MK801 and the protein kinase C inhibitor chelerythrine. Therefore, a site of action of systemically administered morphine low dose on acute thermal hyperalgesic response appears to be located at the periaqueductal gray. At this supraspinal site, μOR stimulation by systemically morphine low dose administration leads to an increased phosphorylation of specific subunit of NMDA receptor. Our experiments show that the phosphorylation of subunit 1 of NMDA receptor parallels the acute thermal hyperalgesia suggesting a role for this subunit in morphine-induced hyperalgesia. Protein kinase C appears to be the key element that links μOR activation by morphine administration to mice with the recruitment of the NMDA/glutamatergic system involved in the thermal hyperalgesic response.     

Hepatocyte resistance to oxidative stress is dependent on protein kinase C-mediated down-regulation of c-Jun/AP-1

The prevention of injury from reactive oxygen species is critical for cellular resistance to many death stimuli. Resistance to death from the superoxide generator menadione in the hepatocyte cell line RALA255-10G is dependent on down-regulation of the c-Jun N-terminal kinase (JNK)/AP-1 signaling pathway by extracellular signal-regulated kinase 1/2 (ERK1/2). Because protein kinase C (PKC) regulates both oxidant stress and JNK signaling, the ability of PKC to modulate hepatocyte death from menadione through effects on AP-1 was examined. PKC inhibition with Ro-31-8425 or bisindolylmaleimide I sensitized this cell line to death from menadione. Menadione treatment led to activation of PKCmicro, or protein kinase D (PKD), but not PKCalpha/beta, PKCzeta/lambda, or PKCdelta/. Menadione induced phosphorylation of PKD at Ser-744/748, but not Ser-916, and translocation of PKD to the nucleus. PKC inhibition blocked menadione-induced phosphorylation of PKD, and expression of a constitutively active PKD prevented death from Ro-31-8425/menadione. PKC inhibition led to a sustained overactivation of JNK and c-Jun in response to menadione as determined by in vitro kinase assay and immunoblotting for the phosphorylated forms of both proteins. Cell death from PKC inhibition and menadione treatment resulted from c-Jun activation, since death was blocked by adenoviral expression of the c-Jun dominant negative TAM67. PKC and ERK1/2 independently down-regulated JNK/c-Jun, since inhibition of either kinase failed to affect activation of the other kinase, and simultaneous inhibition of both pathways caused additive JNK/c-Jun activation and cell death. Resistance to death from superoxide therefore requires both PKC/PKD and ERK1/2 activation in order to down-regulate proapoptotic JNK/c-Jun signaling.     

Opioidergic effects of nonopioid analgesics on the central nervous system

1. The analgesic effect of nonsteroidal anti-inflammatory drugs (NSAIDs) is partly due to the fact that they act upon the periaqueductal gray matter (PAG) and the rostral ventromedial medulla of the brain stem and thus activate the descending pain-control system, which inhibits nociceptive transmission at the spinal dorsal horn.2. The analgesic action of dipyrone (metamizol) and of lysine-acetylsalicylate (LASA), two well-known NSAIDs, whether microinjected into the PAG or given systemically, can be reverted by naloxone. Repeated administration of dipyrone or LASA induces tolerance to their antinociceptive effect, with cross-tolerance to morphine, and a withdrawal syndrome upon naloxone administration. Dipyrone tolerance can be reverted by proglumide, a cholecystokinin antagonist.3. These findings reveal a close association between the central action of NSAIDs and endogenous opioids.     

蛋白激酶C与吗啡耐受

蛋白激酶C(protein kinase C,PKC)属于AGC蛋白激酶家族(即PKA/PKG/PKC激酶家族),在吗啡介导的μ-阿片受体脱敏及吗啡耐受中具有重要作用,因此研究PKC的细胞信号传导机制对吗啡耐受的治疗具有重要的临床意义。本文综述了PKC在吗啡耐受中的作用。     

Morphine analgesia: 2-way cross tolerance between systemic and intracerebral (periaqueductal gray) administrations.

Two-way analgesic cross tolerance was obtained between systematic and intracerebral morphine injections in the periaqueductal gray. When rats were pretreated with intraperitoneal morphine and tested with intracerebral morphine in the periaqueductal gray, a dose-dependent reduction in analgesia as a function of morphine pretreatment level was obtained. Conversely, when rats were pretreated with intracerebral morphine, significant reductions in analgesia were obtained. These results are further confirmation that the periaqueductal gray matter is an important site for morphine analgesia.