Pro-inflammatory cytokines and nitric oxide (NO) are considered responsible for exacerbating brain injury. Activated microglia produce these potentially cytotoxic factors during neuron destruction. The beneficial effects of hypothermia on neuroprotection are considered to be due, in part, to suppression of post-injury inflammatory factors by microglia. However, the underlying mechanisms remain unclear. In particular, the hypothermia's role in modulating anti-inflammatory cytokines is unknown. We examined whether altering culture temperature modifies microglial production of cytokines and NO. Microglia isolated from neonatal rats were cultured with 1 microg/mL lipopolysaccharide (LPS) under hypothermic, normothermic, and hyperthermic conditions for 72 h. Interleukin (IL)-6 and IL-10 levels in supernatants were measured by enzyme-linked immunosorbent assay (ELISA). NO production was analyzed by colorimetric assay of nitrite accumulated in the medium. Compared to normothermia, hypothermia decreased LPS-induced IL-6 production at 6 h of culture. In contrast, hyperthermia reduced IL-6 production throughout culture. IL-10 production was reduced by hypothermia but augmented by hyperthermia at 24-72 h. NO production was reduced by hypothermia throughout culture, while no significant differences in NO production were observed between normothermia and hyperthermia. In this study, hypothermia reduced production of IL-6, IL-10, and NO by LPS-activated microglia, suggesting that the neuroprotective effects of hypothermia might involve not only the inhibition of inflammatory factors, but also anti-inflammatory factor(s). Hyperthermia specifically increased IL-10 production in these cells. These temperature-dependent changes in IL-10 production may imply an important clinical marker for this cytokine in hypothermia-related neuronal protection and in hyperthermia-related neuronal injury.

We investigated the brain activation associated with sweet taste-induced analgesia by 3-T functional magnetic resonance imaging, the mechanism of which is considered to involve the central nervous system. After 12 healthy individuals ingested tasteless gelatin (nonsweet condition) or sweet glucose (sweet condition) in a magnetic resonance imaging scanning gantry, the cold pressor test was applied to their medial forearm. Under both conditions, the cold pressor test robustly activated the pain-related neural network, notably the anterior cingulate cortex, insula, posterior parietal cortex, and thalamus, although such activations under the sweet condition weakened with pain threshold increase, compared with those under the nonsweet condition. Together with emotional changes in pain appraisal, our findings provide objective representation of sweet taste-induced analgesia in the human brain.

Neuropathic pain concurrent with mood disorder from peripheral nerve injury is a serious clinical problem that significantly affects quality of life. Recent studies have suggested that a lack of brain-derived neurotrophic factor (BDNF) in the limbic system may cause this pain-emotion. BDNF is induced in cultured neurons by 4-methylcatechol (4-MC), but the role of 4-MC-induced BDNF in pain-emotion is poorly understood. Thus, we assessed the possible involvement of BDNF in brain in depression-like behavior during chronic pain following peripheral nerve injury. In addition, we examined whether intracerebroventricular (i.c.v.) 4-MC prevents chronic pain in rats and produces an antidepressant effect. Sprague-Dawley rats implanted intracerebroventricularly with a PE-10 tube were subjected to chronic constriction injury (CCI). Pain was assessed by a reduction in paw withdrawal latency (PWL) to heat stimuli after CCI. We also used a forced swimming testing (FST; time of immobility, in seconds) from day 14 to day 21 after CCI. Modulation of pain and emotional behavior was performed by injection of PD0325901 (a MEK1/2 inhibitor). 4-MC (100 nM) was continuously administered i.c.v. for 3 days during the period from day 14 to day 21 after CCI. To block analgesic and antidepressant effects, anti-BDNF antibody or K252a (a TrkB receptor inhibitor) was injected in combination with 4-MC. Naloxone was also coadministered to confirm the analgesic effect of 4-MC. During the chronic stage after CCI, the rats showed a sustained decrease in PWL (thermal hyperalgesia) associated with extension of the time of immobility (depression-like behavior). PD0325901 significantly reduced the decrease in PWL and the increased time of immobility after CCI. The decreased PWL and increased time of immobility were also reduced by 4-MC and by treatment with an ERK1/2 inhibitor. These effects of 4-MC i.c.v. were reversed by anti-BDNF and K252a. The analgesic effect of 4-MC i.c.v. was also antagonized by naloxone. Based on these results, we suggest that a lack of BDNF and activation of ERK1/2 in the pain-emotion network in the CNS may be involved in depression-like behavior during chronic pain. 4-MC i.c.v. ameliorates chronic pain and depression-like behavior by producing of BDNF and normalization of ERK1/2 activation. Therefore, enhancement of BDNF may be a new treatment strategy for chronic pain associated with depression.

This study aimed to examine whether or not there are gender differences in sweet stimulus-induced analgesia for cold pain in adults. In a randomized cross-over design, twenty men and 20 women held either a 24% sucrose solution or distilled water in their mouth before and while they immersed their hand in cold water and their pain response was examined. Unlike the women, when the men held the sucrose solution in their mouth, the latency of the onset of pain significantly increased, compared with the distilled water. Meanwhile, the level of pain tolerance was not significantly different for both sexes. The findings reveal that the analgesic effect of a sweet stimulus on the pain threshold is influenced by gender differences in human adults, indicating that sweet stimulus-induced analgesia has a brief analgesic effect, particularly for men. Although more research is warranted, the sweet stimulus could be put to practical application as an adjunct to acute pain management for men.

No abstract