Shuxing Wang

Brain indoleamine 2,3-dioxygenase contributes to the comorbidity of pain and depression

Pain and depression are frequently comorbid disorders, but the mechanism underlying this association is unknown. Here, we report that brain indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism, plays a key role in this comorbidity. We found that chronic pain in rats induced depressive behavior and IDO1 upregulation in the bilateral hippocampus. Upregulation of IDO1 resulted in the increased kynurenine/tryptophan ratio and decreased serotonin/tryptophan ratio in the bilateral hippocampus. We observed elevated plasma IDO activity in patients with both pain and depression, as well as in rats with anhedonia induced by chronic social stress. Intra-hippocampal administration of IL-6 in rats, in addition to in vitro experiments, demonstrated that IL-6 induces IDO1 expression through the JAK/STAT pathway. Further, either Ido1 gene knockout or pharmacological inhibition of hippocampal IDO1 activity attenuated both nociceptive and depressive behavior. These results reveal an IDO1-mediated regulatory mechanism underlying the comorbidity of pain and depression and suggest a new strategy for the concurrent treatment of both conditions via modulation of brain IDO1 activity.

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 Cγ (PKCγ) knock-out. Because IL-6 and PKCγ mediated the upregulation of central GRs after CCI as demonstrated previously, the results suggest that IL-6 and PKCγ 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.

Altered quantitative sensory testing outcome in subjects with opioid therapy

ABSTRACT Preclinical studies have suggested that opioid exposure may induce a paradoxical decrease in the nociceptive threshold, commonly referred as opioid‐induced hyperalgesia (OIH). While OIH may have implications in acute and chronic pain management, its clinical features remain unclear. Using an office‐based quantitative sensory testing (QST) method, we compared pain threshold, pain tolerance, and the degree of temporal summation of the second pain in response to thermal stimulation among three groups of subjects: those with neither pain nor opioid therapy (group 1), with chronic pain but without opioid therapy (group 2), and with both chronic pain and opioid therapy (group 3). We also examined the possible correlation between QST responses to thermal stimulation and opioid dose, opioid treatment duration, opioid analgesic type, pain duration, or gender in group 3 subjects. As compared with both group 1 (n = 41) and group 2 (n = 41) subjects, group 3 subjects (n = 58) displayed a decreased heat pain threshold and exacerbated temporal summation of the second pain to thermal stimulation. In contrast, there were no differences in cold or warm sensation among three groups. Among clinical factors, daily opioid dose consistently correlated with the decreased heat pain threshold and exacerbated temporal summation of the second pain in group 3 subjects. These results indicate that decreased heat pain threshold and exacerbated temporal summation of the second pain may be characteristic QST changes in subjects with opioid therapy. The data suggest that QST may be a useful tool in the clinical assessment of OIH.

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 μg) 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 μg/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 Cγ (PKCγ), because intrathecal treatment with an IL-6 antiserum, a PKC inhibitor (cheryrithrine), or PKCγ 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.

Expression of Spinal NMDA Receptor and PKCγ 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 PKCγ after chronic morphine is regulated by spinal GR through a cAMP response element-binding protein (CREB)-dependent pathway. Chronic morphine (10 μg, i.t.; twice daily for 6 d) induced a time-dependent upregulation of GR, the NR1 subunit of NMDAR, and PKCγ within the rats spinal cord dorsal horn. This NR1 and PKCγ 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 PKCγ expression, whereas intrathecal treatment with an adenylyl cyclase activator (forskolin) alone mimicked morphine-induced expression of GR, NR1, and PKCγ. 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 PKCγ. These results indicate that spinal GR through the cAMP-CREB pathway played a significant role in NMDAR and PKCγ expression after chronic morphine exposure. The data suggest that genomic interaction among spinal GR, NMDAR, and PKCγ may be an important mechanism that contributes to the development of morphine tolerance.

The effect of opioid dose and treatment duration on the perception of a painful standardized clinical stimulus.

Background and Objectives: The concept of opioid‐induced hyperalgesia has recently gained prominence as a contributing factor for opioid tolerance and long‐term treatment failure. But whereas the preclinical data for this phenomenon are strong, the mixed clinical data derive primarily from experimental pain models conducted in volunteers and heroin addicts, and nonstandardized clinical stimuli, e.g., surgery. The primary objective of this study is to delineate the effect of opioid dose and treatment duration on pain intensity and unpleasantness ratings following a standardized clinical pain stimulus. Methods: Three hundred and fifty‐five patients, on a steady regimen of analgesic medications and scheduled for an interventional procedure, received a standardized subcutaneous injection of lidocaine prior to a full dose of local anesthetic. Before and immediately following the injection, subjects were asked to rate pain and unpleasantness intensity on a 0 to 10 numerical rating scale. Subjects were stratified into 6 groups based on opioid dosage. A control group of 27 volunteers who had no pain and were taking no analgesics were also injected. Results: Both opioid dose and duration of treatment directly correlated with pain intensity and unpleasantness scores. Baseline pain intensity was also positively associated with both outcome variables. Gender was found to be associated with pain intensity and unpleasantness, with females scoring higher in both categories than males. Compared with patients not receiving opioid treatment, patients receiving opioid therapy were more likely to rate the standardized pain stimulus as being more unpleasant than painful. Conclusions: The results of this study bolster preclinical and experimental pain models demonstrating enhanced pain perception in subjects receiving opioid therapy. This simple clinical model may provide a useful tool in examining opioid‐induced hyperalgesia.

Exacerbated mechanical allodynia in rats with depression-like behavior.

Although a clinical connection between pain and depression has long been recognized, how these two conditions interact remains unclear. Here we report that both mechanical allodynia and depression-like behavior were significantly exacerbated after peripheral nerve injury in Wistar-Kyoto (WKY) rats, a genetic variation of Wistar rats with demonstrable depression-like behavior. Administration of melatonin into the anterior cingular cortex contralateral to peripheral nerve injury prevented the exacerbation of mechanical allodynia with a concurrent improvement of depression-like behavior in WKY rats. Moreover, there was a lower plasma melatonin concentration and a lower melatonin receptor expression in the anterior cingular cortex in WKY rats than in Wistar rats. These results suggest that there exists a reciprocal relationship between mechanical allodynia and depression-like behavior and the melatoninergic system in the anterior cingular cortex might play an important role in the interaction between pain and depression.

Spinal leptin contributes to the pathogenesis of neuropathic pain in rodents

Pain after nerve injury, a phenomenon referred to as neuropathic pain, is a debilitating clinical condition, but the underlying mechanisms remain unclear. As leptin, an adipocytokine produced mainly by nonneuronal tissue, has been implicated in the regulation of neuronal functions, we examined the role of leptin in neuropathic pain using a rat model of the condition chronic constriction sciatic nerve injury (CCI). We report that leptin critically contributed to pain behaviors following CCI. Specifically, spinal administration of a leptin antagonist prevented and reversed neuropathic pain behaviors in rats. Further examination revealed that levels of both leptin and the long form of the leptin receptor (Ob-Rb) were substantially increased within the ipsilateral spinal cord dorsal horn after peripheral nerve injury. Mechanistic studies showed that leptin upregulated the expression of both the spinal NMDA receptor and IL-1beta through the JAK/STAT pathway. Furthermore, these CCI-induced behavioral and cellular responses were diminished in leptin-deficient mice and mimicked by spinal administration of exogenous leptin in naive rats. Our findings reveal a critical role for spinal leptin in the pathogenesis of neuropathic pain and suggest what we believe to be a novel form of nonneuronal and neuronal interactions in the mechanisms of pathological pain.

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

&NA; 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.

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

&NA; 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 °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 Cγ and a progressive downregulation of μ‐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 μ‐opioid receptors.