Upregulation of neuronal kynurenine 3-monooxygenase mediates depression-like behavior in a mouse model of neuropathic pain.

Pain and depression often co-occur, but the underlying mechanisms have not been elucidated. Here, we used the spared nerve injury (SNI) model in mice to induce both neuropathic pain and depression-like behavior. We investigated whether brain interleukin (IL)-1 signaling and activity of kynurenine 3-monoxygenase (KMO), a key enzyme for metabolism of kynurenine into the neurotoxic NMDA receptor agonist quinolinic acid, are necessary for comorbid neuropathic pain and depression-like behavior. SNI mice showed increased expression levels of Il1b and Kmo mRNA in the contralateral side of the brain. The SNI-induced increase of Kmo mRNA was associated with increased KMO protein and elevated quinolinic acid and reduced kynurenic acid in the contralateral hippocampus. The increase in KMO-protein in response to SNI mostly took place in hippocampal NeuN-positive neurons rather than microglia. Inhibition of brain IL-1 signaling by intracerebroventricular administration of IL-1 receptor antagonist after SNI prevented the increase in Kmo mRNA and depression-like behavior measured by forced swim test. However, inhibition of brain IL-1 signaling has no effect on mechanical allodynia. In addition, intracerebroventricular administration of the KMO inhibitor Ro 61-8048 abrogated depression-like behavior without affecting mechanical allodynia after SNI. We show for the first time that the development of depression-like behavior in the SNI model requires brain IL-1 signaling and activation of neuronal KMO, while pain is independent of this pathway. Inhibition of KMO may represent a promising target for treating depression.

[Effect of Electroacupuncture Intervention on CaMK II-CREB Pathway in Spinal Cord in Rats with Spared Nerve Injury].

OBJECTIVE: To observe the effect of electroacupuncture (EA) stimulation of "Weizhong" (BL 40)-"Huantiao" (GB 30) on expression of phosphorylated calcium/calmodulin dependent protein kinase II (p-CaMK II) and cAMP response element binding protein (p-CREB) in the spinal cord in rats with spared nerve injury (SNI), so as to explore its mechanism underlying easing neuropathic pain. METHODS: Sixty SD rats were randomly divided into five groups: control (sham-operation) , model, EA, AP-5 (a NMDA receptor antagonist) and L-NAME (a non-selective nitric oxide synthase, NOS inhibitor) (n = 12 in each group). The neuropathic pain model was established by sectioning the right tibal nerve and common peroneal nerve. EA intervention (2 Hz, 1 mA, increasing 1 mA/10 min) was applied to "Weizhong" (BL 40) and "Huantiao" (GB 30) on the injured side for 30 min, once a day for 7 days. Rats of the AP-5 and L-NAME groups were treated by intragastric administration of AP-5 (0.7 mg · kg(-1) · d(-1)) and L-NAME (60 mg · kg(-1) · d(-1)) respectively from the 11 th day after operation, once daily for 7 days. The mechanical pain thresholds were measured before the SNI procedure (baseline) and at the 10th and 16th day after the procedure. The expression of p-CaMK II protein and p-CREB protein and gene of the spinal cord (L4-L6 segments) was determined by Western blot and fluorescence quantitative-polymerase chain reaction (PCR), separately. RESULTS: In comparison to the control group, the mechanical pain threshold was significantly decreased in the model group (P < 0.01). After EA intervention, the mechanical pain thresholds of the EA, AP-5 and L-NAME groups were obviously increased (P < 0.01, P < 0.05) on day 16 post SNI procedure. The expression levels of p-CaMK II and p-CREB proteins and CREB mRNA in the spinal cord were significantly higher in the model group than in the control group (P < 0.05). Compared with the model group, the expression levels of spinal p-CaMK II and p-CREB proteins and CREB mRNA were obviously down-regulated in the EA group (P < 0.05), but not in the AP-5 group and the L-NAME group (P > 0.055. CONCLUSION: EA intervention of BL 40-GB 30 may alleviate pain in neuropathic pain rats, which may be related to its effects in down-regulating spinal CaMK II-CREB pathway function.

Effects of hyperbaric oxygen on pain-related behaviors and nitric oxide synthase in a rat model of neuropathic pain.

BACKGROUND: Neuropathic pain is complex, and a satisfactory therapeutic method of treatment has yet to be developed; therefore, finding a new and effective therapeutic method is an important issue in the field of neuropathic pain. OBJECTIVE: To determine the effects of hyperbaric oxygen (HBO) on pain-related behaviours and nitric oxide synthase (NOS) expression in a rat model of neuropathic pain. METHODS: Forty male Sprague Dawley rats were randomly divided into five groups (eight rats per group) including control, sham operation, sciatic nerve with chronic constriction injury (CCI), HBO pretreatment (pre-HBO) and HBO post-treatment (post-HBO) groups. Pain-related behaviours and NOS expression in the spinal cord were compared among the five groups. RESULTS: Compared with the CCI group, the mechanical withdrawal threshold was significantly increased and thermal withdrawal latency was significantly extended in the pre-HBO and post-HBO groups (all P<0.05). After CCI, expression of spinal neuronal NOS and inducible NOS were increased. Expression of spinal neuronal NOS and inducible NOS were significantly decreased in the pre-HBO and post-HBO groups compared with the CCI group (all P<0.05). Spinal eNOS expression changed very little. DISCUSSION: HBO has been used as an effective and noninvasive method for the treatment of spinal cord injuries and high-altitude sickness, and in immunosuppression and stem-cell research; however, it has yet to be applied to the treatment of neuropathic pain. The present study indicated that HBO effectively increased mechanical withdrawal threshold and thermal withdrawal latency, demonstrating that HBO has therapeutic effects on neuropathic pain. CONCLUSION: HBO inhibits pain in rats with CCI through the regulation of spinal NOS expression.