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Jianren Mao

Publications and source records attributed to Jianren Mao.

At least 19 recordsLinked to original sources
PubMed2006

Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats.

Spinal gamma-aminobutyric acid (GABA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have been implicated in the mechanisms of neuropathic pain after nerve injury; however, how these two receptors interact at the spinal level remains unclear. Here we show that intrathecal midazolam through activation of spinal GABAA receptors attenuated the expression and function of spinal AMPA receptors in rats following peripheral nerve injury. Thermal hyperalgesia and mechanical allodynia induced by chronic constriction nerve injury (CCI) in rats were attenuated by the short-acting benzodiazepine midazolam (20=10>5 mug>vehicle) administered intrathecally once daily for 7 postoperative days. CCI-induced upregulation of AMPA receptors within the spinal cord dorsal horn was also significantly reduced by the intrathecal midazolam (10, 20 mug) treatment. The inhibitory effects of midazolam (10, 20 mug) on neuropathic pain behaviors and AMPA receptor expression were prevented by co-administration of midazolam with the GABAA receptor antagonist bicuculline (3 mug), whereas intrathecal treatment with bicuculline (1 or 3 mug) alone in naive rats induced the upregulation of spinal AMPA receptor expression and nociceptive responses, indicating a tonic regulatory effect from endogenous GABAergic activity on the AMPA receptor expression and spinal nociceptive processing. These results indicate that modulation of spinal AMPA receptor expression and function by the GABAergic activity may serve as a mechanism contributory to the spinal nociceptive processing.

Animals↗
PubMed2006

Opioid-induced abnormal pain sensitivity.

Opioid analgesics are effective for treating many pain conditions. Opioid analgesic tolerance is a pharmacologic phenomenon that could affect the clinical use of opioid analgesics. Recent studies have shown that neural plasticity associated with the development of opioid tolerance may activate a pronociceptive mechanism that could counteract the analgesic effects of opioids. Thus, exposure to opioids could lead to two seemingly unrelated cellular processes (ie, the development of opioid tolerance and opioid-induced pain sensitivity). Their converging effects may be part of the mechanisms leading to the reduced opioid analgesic efficacy in chronic opioid therapy.

Analgesics, Opioid↗
PubMed2006

The intravenous ketamine test predicts subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients.

UNLABELLED: Fibromyalgia (FM) is a challenging pain syndrome for which no reliable pharmacologic treatment exists. Recent clinical studies suggest that N-methyl-D-aspartate receptors might play a role in the pathogenesis of this disorder. To determine whether an intravenous (IV) ketamine test predicts the response to a therapeutic trial with an oral N-methyl-D-aspartate receptor antagonist, we performed a low-dose (0.1 mg/kg) IV ketamine infusion on 34 consecutive patients with FM, which was subsequently followed by an oral dextromethorphan (DX) treatment regimen. As per previous guidelines, the cutoff value for a positive response to the IV ketamine test was designated to be 67% pain relief, and a positive response to DX treatment was 50% pain reduction at 4- to 6-week follow-up visits. The degree of correlation between pain relief with ketamine and DX was highly significant (Pearson correlation coefficient, 0.66; P < .001). Ten patients responded positively to both ketamine and DX, 19 responded to neither drug, 3 had a positive response to ketamine but not DX, and 2 obtained good pain relief with DX but not ketamine. The sensitivity of the IV ketamine test was 83%, the specificity was 86%, the positive predictive value was 77%, and the negative predictive value was 91%. An association was also found between the development of side effects to the two treatments. PERSPECTIVE: The response to an IV ketamine infusion was found to predict the subsequent response to an oral dextromethorphan treatment regimen in fibromyalgia patients, with an observed agreement of 83%. Considering the refractory nature of fibromyalgia to conventional pain treatments, the IV ketamine test might enhance patient care by saving time and reducing unnecessary treatment trials.

Administration, Oral↗
PubMed2005

Downregulation of spinal glutamate transporter EAAC1 following nerve injury is regulated by central glucocorticoid receptors in rats.

Previous studies have shown that glucocorticoid receptors (GR) were upregulated, whereas glutamate transporters were downregulated, within the spinal cord dorsal horn after peripheral nerve injury. However, the relationship between the expression of spinal GR and glutamate transporter after nerve injury remains unknown. In the present study, we examined the hypothesis that central GR would regulate the expression of spinal glutamate transporter EAAC1 following chronic constriction nerve injury (CCI) in rats. CCI induced a significant downregulation of EAAC1 expression primarily within the ipsilateral spinal cord dorsal horn when examined on postoperative day 7 using both Western blot and immunohistochemistry. The downregulation of EAAC1 was significantly diminished after either the GR antagonist RU38486 (4 > 2 = 0.5 microg = vehicle) or a GR antisense oligonucleotide was administered intrathecally twice daily for postoperative day 1-6. Moreover, CCI induced a significant downregulation of nuclear factor kappaB (NF-kappaB) within the ipsilateral spinal cord dorsal horn, which also was attenuated by either RU38486 (4 > 2 = 0.5 microg = vehicle) or a GR antisense oligonucleotide. The immunohistochemical data indicated a pattern of colocalization between GR and EAAC1 as well as GR and NF-kappaB within the spinal cord dorsal horn. Since, NF-kappaB has been shown to regulate the expression of those cellular elements linked to inflammation and tissue injury and its activity can be negatively regulated by GR activation, these results suggest that spinal GR through NF-kappaB may play a significant role in the regulation of EAAC1 expression after peripheral nerve injury, a cellular pathway that may contribute to the development of neuropathic pain behaviors in rats.

Animals↗
PubMed2005

Activity of adenylyl cyclase and protein kinase A contributes to morphine-induced spinal apoptosis.

Our previous study has shown that chronic morphine exposure induces neuronal apoptosis within the spinal cord dorsal horn; however, the mechanisms of morphine-induced apoptosis remain unclear. Here we examined whether adenylyl cyclase (AC) and protein kinase A (PKA) would play a role in this process. Intrathecal morphine regimen (10 microg, twice daily x 7 days) that resulted in antinociceptive tolerance induced spinal apoptosis as revealed by in situ terminal deoxynucleotidyl transferase (TdT)-UTP-biotin nick end labeling (TUNEL). The TUNEL-positive cells were detected primarily in the superficial laminae of the spinal cord dorsal horn, which was associated with an increase in the expression of activated caspase-3 and mitogen-activated protein kinase (MAPK) within the same spinal region. Co-administration of morphine with a broad AC inhibitor (ddA), a PKA inhibitor (H89), or a MAPK inhibitor (PD98059) substantially reduced the number of TUNEL-positive cells, as compared with the morphine alone group. The results indicate that the spinal AC and PKA pathway through intracellular MAPK may be contributory to the cellular mechanisms of morphine-induced apoptosis.

Adenylyl Cyclases↗
PubMed2005

Expression of spinal NMDA receptor and PKCgamma after chronic morphine is regulated by spinal glucocorticoid receptor.

Spinal NMDA receptor (NMDAR), protein kinase C (PKC), and glucocorticoid receptor (GR) have all been implicated in the mechanisms of morphine tolerance; however, how these cellular elements interact after chronic morphine exposure remains unclear. Here we show that the expression of spinal NMDAR and PKCgamma after chronic morphine is regulated by spinal GR through a cAMP response element-binding protein (CREB)-dependent pathway. Chronic morphine (10 microg, i.t.; twice daily for 6 d) induced a time-dependent upregulation of GR, the NR1 subunit of NMDAR, and PKCgamma within the rat's spinal cord dorsal horn. This NR1 and PKCgamma upregulation was significantly diminished by intrathecal coadministration of morphine with the GR antagonist RU38486 or a GR antisense oligodeoxynucleotide. Intrathecal coadministration of morphine with an adenylyl cyclase inhibitor (2',5'-dideoxyadenosine) or a protein kinase A inhibitor (H89) also significantly attenuated morphine-induced NR1 and PKCgamma expression, whereas intrathecal treatment with an adenylyl cyclase activator (forskolin) alone mimicked morphine-induced expression of GR, NR1, and PKCgamma. Moreover, the expression of phosphorylated CREB was upregulated within the spinal cord dorsal horn after chronic morphine, and a CREB antisense oligodeoxynucleotide coadministered intrathecally with morphine prevented the upregulation of GR, NR1, and PKCgamma. These results indicate that spinal GR through the cAMP-CREB pathway played a significant role in NMDAR and PKCgamma expression after chronic morphine exposure. The data suggest that genomic interaction among spinal GR, NMDAR, and PKCgamma may be an important mechanism that contributes to the development of morphine tolerance.

Adenylyl Cyclases↗
PubMed2005

Central glucocorticoid receptors modulate the expression of spinal cannabinoid receptors induced by chronic morphine exposure.

Central cannabinoid receptors (CBRs) have been implicated in the opioid analgesic effects. However, it remains unclear as to whether the expression of central CBRs would be altered after repeated morphine exposure. Here, we show that chronic intrathecal treatment with morphine (10 microg, twice daily for 6 days) induced a time-dependent upregulation of both CB-1 and CB-2 receptors within the spinal cord dorsal horn. This morphine-induced CB-1 and CB-2 upregulation was dose-dependently attenuated by the intrathecal co-administration of morphine with the glucocorticoid receptor (GR) antagonist RU38486 (0.25, 0.5, or 2 microg). The intrathecal RU38486 treatment regimen also attenuated the development of morphine tolerance. These results indicate that the expression of spinal CBRs was altered following repeated morphine exposure and regulated by the activation of central GRs.

Analgesics, Opioid↗
PubMed2005

Glutamate transporter: an unexpected target for some antibiotics.

Glutamate transporter (GT) plays a major role in the mechanisms of glutamate homeostasis. Can this transporter system be a therapeutic target for glutamate-mediated neurological disorders? In January's edition of Nature, Rothstein et al (2005) reports that the most commonly used class of antibiotics (beta-lactam antibiotics) such as ceftriaxone promoted the expression of GLT1 and demonstrated a functional role in both in vitro and in vivo models of glutamate neurotoxicity. These findings indicate that positive promoters of GT expression may have a unique role in neuroprotection through regulating GT expression. This is also encouraging in search for new pharmacological tools for pain management.

Amino Acid Transport System X-AG↗
PubMed2005

Central glucocorticoid receptors modulate the expression and function of spinal NMDA receptors after peripheral nerve injury.

Central glucocorticoid receptors (GRs) and NMDA receptors (NMDARs) have been shown to play a significant role in the mechanisms of neuropathic pain after peripheral nerve injury; however, how central GRs and NMDARs interact in this process remains unknown. Here we show that the expression and function of spinal NMDARs after peripheral nerve injury were modulated by central GRs. Chronic constriction nerve injury (CCI) in rats induced a time-dependent upregulation of NR1 and NR2 subunits of the NMDAR within the spinal cord dorsal horn ipsilateral to CCI. The upregulation of NMDARs was significantly diminished by intrathecal administration (twice daily for postoperative days 1-6) of either the GR antagonist RU38486 or an antisense oligonucleotide against GRs. Moreover, this CCI-induced expression of NMDARs was significantly attenuated in rats receiving intrathecal treatment with an interleukin-6 (IL-6) antiserum and in mice with protein kinase Cgamma (PKCgamma) knock-out. Because IL-6 and PKCgamma mediated the upregulation of central GRs after CCI as demonstrated previously, the results suggest that IL-6 and PKCgamma served as cellular mediators contributing to the GR-mediated expression of NMDARs after CCI. Functionally, nociceptive behaviors induced by NMDAR activation and CCI were reversed by a single intrathecal administration of the GR antagonist RU38486. Conversely, a single intrathecal injection with the noncompetitive NMDAR antagonist MK-801 reversed neuropathic pain behaviors exacerbated by the GR agonist dexamethasone in CCI rats. These data suggest that interactions between central GRs and NMDARs through genomic and nongenomic regulation may be an important mechanism critical to neuropathic pain behaviors in rats.

Animals↗
PubMed2005

A rat model of unilateral hindpaw burn injury: slowly developing rightwards shift of the morphine dose-response curve.

Management of pain after burn injury is an unresolved clinical issue. In a rat model of hindpaw burn injury, we examined the effects of systemic morphine on nociceptive behaviors following injury. Injury was induced by immersing the dorsal part of one hindpaw into a hot water bath (85 degrees C) for 4, 7, or 12 s under pentobarbital anesthesia. Mechanical allodynia to von Frey filament stimulation and thermal hyperalgesia to radiant heat were assessed. Burn injury induced by the 12-s (but not 4-, or 7-s) hot water immersion resulted in reliable and lasting mechanical allodynia and thermal hyperalgesia evident by day 1. In addition, there was an upregulation of protein kinase Cgamma and a progressive downregulation of mu-opioid receptors within the spinal cord dorsal horn ipsilateral to injury as revealed by immunohistochemistry and Western blot. In both injured and sham rats, the anti-nociceptive effects of subcutaneous morphine were examined on post-injury days 7 and 14. While the morphine AD50 dose was comparable on day 7 between burn (1.61 mg/kg) and control (1.7 mg/kg) rats, the morphine dose-response curve was shifted to the right in burn-injured rats (4.6 mg/kg) on post-injury day 14 as compared with both the injured rats on post-injury day 7 and sham rats on day 14 (1.72 mg/kg). These data indicate that hindpaw burn injury reliably produces persistent mechanical allodynia and thermal hyperalgesia and that the reduced efficacy of morphine anti-nociception in chronic burn injury may be in part due to a downregulation of spinal mu-opioid receptors.

Actins↗
PubMed2005

Spinal glucocorticoid receptors contribute to the development of morphine tolerance in rats.

BACKGROUND: Opioid analgesic tolerance is a pharmacologic phenomenon involving the mechanisms of cellular adaptation. Central glucocorticoid receptors (GRs) have been implicated in the cellular mechanism of neuronal plasticity that has many cellular steps in common with the mechanism of opioid tolerance. In a rat model of morphine tolerance, the authors examined the hypothesis that spinal GRs would play a significant role in the development of tolerance to the antinociceptive effect of morphine. METHODS: In experiment 1, each group of rats received the GR antagonist RU38486 (0.5 or 1 microg), the mineralocorticoid receptor antagonist spironolactone (3 microg), or a vehicle, given intrathecally with morphine (10 microg) twice daily for 6 days. In experiment 2, four groups of rats were used, and each group received intrathecally 10 microg morphine plus 5 micromol GR antisense oligodeoxynucleotide, sense oligodeoxynucleotide, mixed-base oligodeoxynucleotide, or vehicle. Western blotting was used to examine the expression of GRs within the spinal cord dorsal horn. In experiment 3, the GR agonist dexamethasone (4 microg) was given intrathecally twice daily in combination with 10 microg morphine. For all experiments, the development of morphine antinociceptive tolerance was assessed using the tail-flick test. RESULTS: The development of tolerance to the antinociceptive effect of morphine was substantially attenuated when the GR antagonist RU38486 (1 > 0.5 microg > vehicle) but not spironolactone was coadministered with morphine for 6 days. A single treatment with RU38486 did not affect morphine antinociception, nor did it reverse morphine tolerance on day 7. A similar reduction of morphine tolerance was observed in those rats treated with a GR antisense oligodeoxynucleotide but not a sense or mixed-base oligodeoxynucleotide. The administration of the GR antisense oligodeoxynucleotide also prevented GR up-regulation within the spinal cord dorsal horn. Moreover, the GR agonist dexamethasone facilitated the development of morphine tolerance. CONCLUSIONS: The results indicate an important role of spinal GRs in the cellular mechanisms of morphine tolerance in rats and may have significant implications in clinical opioid therapy.

Analgesics, Opioid↗
PubMed2004

Evidence for a long-term influence on morphine tolerance after previous morphine exposure: role of neuronal glucocorticoid receptors.

Opioid analgesic tolerance is a pharmacological phenomenon that overtime diminishes the opioid analgesic effect. However, it remains unknown as to whether a previous opioid exposure would have a long-term influence on opioid tolerance upon subsequent opioid administration. Here, we show that the onset and degree of antinociceptive tolerance to a subsequent cycle of morphine exposure were substantially exacerbated in rats made tolerant to and then recovered from previous morphine administration, indicating a long-term influence from a previous morphine exposure on the development of morphine tolerance. Mechanistically, morphine exposure induced a cyclic AMP and protein kinase A-dependent upregulation of neuronal glucocorticoid receptors (GR) within the spinal cord dorsal horn, which was maintained after discontinuation of morphine administration and significantly enhanced upon a second cycle of morphine exposure. Prevention of the GR upregulation with GR antisense oligonucleotides as well as inhibition of GR activation with the GR antagonist RU38486 effectively prevented the exacerbated morphine tolerance after subsequent cycles of morphine exposure. The results indicate that a previous morphine exposure could induce lasting cellular changes mediated through neuronal GR and influence morphine analgesia upon a subsequent exposure. These findings may have significant implications in clinical opioid therapy and substance abuse.

Animals↗
PubMed2004

cAMP and protein kinase A contribute to the downregulation of spinal glutamate transporters after chronic morphine.

Our previous study has shown that spinal glutamate transporters (GTs) are downregulated following chronic morphine administration; however, how spinal GTs are regulated in this process remains unclear. Here we show that the downregulation of spinal GTs (EAAC1 and GLT-1) induced by a 6-day intrathecal morphine (10 microg, twice daily) treatment regimen was prevented by co-administration of morphine with 2',5'-dideoxyadenosine (ddA, 1 microg, a broad adenylyl cyclase inhibitor) or H89 (10 microg, a selective protein kinase A inhibitor). When co-administered with morphine, ddA or H89 also effectively attenuated the development of morphine tolerance in the same rats, while ddA or H89 alone did not affect the baseline nociceptive response. These results indicate that the downregulation of spinal GTs following chronic morphine is at least in part mediated through the intracellular cyclic AMP and protein kinase A pathway, suggesting that this cellular mechanism of GT regulation may be contributory to the development of morphine tolerance in rats.

Amino Acid Transport System X-AG↗
PubMed2004

Expression of central glucocorticoid receptors after peripheral nerve injury contributes to neuropathic pain behaviors in rats.

Peripheral glucocorticoid receptors (GRs) play a significant role in the anti-inflammatory effects of glucocorticoids; however, the role of central GRs in nociceptive behaviors after peripheral nerve injury (neuropathic pain behaviors) remains unknown. Here we show that the development of neuropathic pain behaviors (thermal hyperalgesia and mechanical allodynia) induced by chronic constriction nerve injury (CCI) in rats was attenuated by either the GR antagonist RU38486 (4 = 2 > 1 = 0.5 microg) or a GR antisense oligonucleotide administered intrathecally twice daily for postoperative days 1-6. The development of thermal hyperalgesia and mechanical allodynia after CCI also was prevented in adrenalectomized rats, whereas the GR agonist dexamethasone (100 microg/kg) given subcutaneously twice daily for postoperative day 1-6 restored CCI-induced neuropathic pain behaviors in the adrenalectomized rats. Mechanistically, CCI induced a time-dependent and region-specific expression of neuronal GRs primarily within the spinal cord dorsal horn ipsilateral to nerve injury, which showed a time course parallel to that of the development of neuropathic pain behaviors. Moreover, the expression of neuronal GR after CCI was mediated in part through an elevated spinal level of interleukin-6 (IL-6) and protein kinase Cgamma (PKCgamma), because intrathecal treatment with an IL-6 antiserum, a PKC inhibitor (cheryrithrine), or PKCgamma knock-out substantially reduced the expression of neuronal GRs as well as neuropathic pain behaviors after CCI. These findings indicate a central role of neuronal GRs in the mechanisms of neuropathic pain behaviors in rats and suggest a potential role for GR antagonists in clinical management of neuropathic pain.

Adrenalectomy↗
PubMed2004

The intravenous ketamine test: a predictive response tool for oral dextromethorphan treatment in neuropathic pain.

IV infusion tests performed to predict subsequent response to oral analgesics are an increasingly popular method used to enhance medical care and conserve resources. Because no infusion test is completely accurate, the potential benefits of these tests must be weighed against the frustration and waste in resources encountered with false-positive results, and the failure to use a potentially beneficial treatment with false-negative results. In recent years, drugs that act antagonistically at N-methyl-d-aspartate receptors have been shown to be valuable adjuncts in the treatment of pain. To determine the predictive value of small-dose (0.1 mg/kg) IV ketamine on an oral dextromethorphan (DX) treatment regimen, we analyzed the analgesic response to these drugs in 25 patients at 2 tertiary care military treatment facilities, institutions at which DX is not readily accessible. When >/=50% response for both drugs was used as the outcome measure for success, the positive predictive value of the ketamine test was 64%, the negative predictive value 73%, and the observed agreement 68%. However, when >/=67% relief with ketamine was used as an outcome measure (as determined by a receiver operating characteristic curve), the positive predictive value was 90%, the negative predictive value 80%, and the observed agreement increased to 84%. Based on these results, we conclude that an IV ketamine test may be useful in predicting response to oral DX. More research is needed to determine the ideal candidates for such a test, and the optimal dose and cutoff value for the response to ketamine.

Administration, Oral↗
PubMed2004

Opioid tolerance and neuroplasticity.

Opioid analgesics are highly effective for treating many forms of acute and chronic pain. The development of opioid analgesic tolerance is a pharmacological phenomenon indicative of the cellular and system adaptation that could affect the clinical use of opioid analgesics. Activation of N-methyl-D-aspartate receptors and protein kinase C as well as regulation of glutamate transporters has been implicated in the mechanisms of opioid tolerance, suggesting a possible link between neural plasticity and the mechanisms of opioid tolerance. More recent studies have shown that neural plasticity associated with the development of opioid tolerance may activate a pronociceptive mechanism within the central nervous system that could counteract the analgesic effects of opioids. Thus, exposure to opioids could lead to two seemingly unrelated cellular processes, i.e. (1) the development of opioid tolerance--a negative sign of cellular adaptation, and (2) the development of opioid-induced pain sensitivity--a positive sign of cellular adaptation. The converging effects of these cellular mechanisms would significantly reduce the opioid analgesic efficacy. The current evidence also suggests new approaches for improving the clinical use of opioid analgesics.

Amino Acid Transport System X-AG↗