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Exogenous and endogenous opioids have been shown to modulate the immune system. Morphine-induced immunosuppression has been investigated extensively. However, the immune-regulating function of endogenous opioid peptides is unclear. The present study aimed to evaluate the difference in effects on cellular immune function between recombinant rat β-endorphin (β-EP; 50 µg/kg) and plant source morphine (10 mg/kg) via intraperitoneal injection treatment in a rat model of bone cancer pain. Walker 256 cells were injected into a tibial cavity injection to establish the bone cancer pain model. The paw withdrawal thresholds and body weights were measured prior to surgery, at 6 days after surgery, and following 1, 3,6 and 8 treatments. The spleen cells were harvested for detection of T cell proliferation, natural killer (NK) cell cytotoxicity, and the relative quantities of T cell subtypes (CD3+, CD4+ and CD8+ cells). Plasma levels of interleukin-2 (IL-2) were also determined. It was found that single or multiple treatments with β-EP (a homogenous opioid peptide) and morphine (a heterogenous opioid) had good analgesic effects on bone cancer pain, while the analgesia provided by morphine was stronger than that of β-EP. Treatment with β-EP 3, 6 and 8 times increased the body weight gain in the rat model of bone cancer pain, while morphine treatment had on effect on it. With regard to immunomodulatory functions, β-EP treatment increased T cell proliferation and NK cell cytotoxicity, and increased the relative quantities of T cell subtypes, but no effect on T cell secretion. However, morphine treatment decreased T cell proliferation and the levels of T cell subtypes. These data indicate that opioids from different sources have different effects on cellular immune function in vivo. A small dose of homogenous opioid peptide exhibited positive effects (analgesia and immune enhancement) on cancer pain. These results provide experimental evidence supporting the exploitation of human opioids for the treatment of cancer pain.

Yuanyuan Wu,1 Xinmiao Yao,2 Yongliang Jiang,1 Xiaofen He,1 Xiaomei Shao,1 Junying Du,1 Zui Shen,1 Qiaoying He,1 Jianqiao Fang1 1Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, 2The Third Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, China Abstract: Pain is considered a multidimensional conscious experience that includes a sensory component and a negative affective-motivational component. The negative affective-motivational component of pain is different from the sensory component and amplifies the pain experience. Nowadays, a significant number of preclinical research groups have focused their attention on the affective symptoms of pain. In the present study, we investigated the pain aversion and anxiety-like behavior of the complete Freund’s adjuvant (CFA)-induced chronic pain model. CFA rats experienced spontaneous pain during pain-paired conditioning (pain aversion) and spontaneous pain produces an affective response (anxiety-like behavior). Moreover, pain aversion was gradually attenuated, while the anxiety-like behavior increased in 4 weeks. Therefore, although the negative effect (including pain aversion and anxiety) is always associated with hyperalgesia, the manifestations of negative effect may follow different time courses, which may influence the progress of primary disease. The findings illustrate that targeted therapy should focus on a specific aspect in different stages of pain. Our study emphasizes the necessity of using multiple tests to study pain comorbidities. Keywords: pain, pain aversion, pain affection, anxiety-like behavior, chronic inflammatory pain, rat&nbsp

The pain-depression dyad is becoming widespread in the clinic and is attracting increasing attention. A previous study by our group found that 100-Hz electro-acupuncture (EA), but not 2-, 50- and 2/100-Hz EA, was effective against the reserpine-induced pain-depression dyad. This finding is in contrast to the fact that low-frequency EA is commonly used to treat supraspinal-originating diseases. The present study aimed to investigate the mechanism underlying the effects of 100-Hz EA on the pain-depression dyad. Repeated reserpine injection was found to induce allodynia and depressive behaviors in rats. It decreased 5-hydroxytryptamine (5-HT) levels and immunoreactive expressions in the dorsal raphe nucleus (DRN). 100-Hz EA alleviated the pain-depression dyad and upregulated 5-HT in the DRN of reserpine-injected rats. Intracerebroventricular injection of para-chlorophenylalanine, an inhibitor of 5-HT resynthesis, suppressed the upregulation of 5-HT in the DRN by 100-Hz EA and partially counteracted the analgesic and anti-depressive effects of 100-Hz EA. The present study was the first to demonstrate that 5-HT in the DRN is involved in mediating the analgesic and anti-depressive effects of 100-Hz EA on the pain-depression dyad. This finding provided a scientific basis for high-frequency EA as a potential treatment for the pain-depression dyad.

Objective To observe and compare the effects of mild moxibustion and Chinese medicine on the paw edema and pain threshold in rats with experimental arthritis.

Background A deviant motor behaviour at age 3 to 5 months is predictive of cerebral palsy (CP). Particular features of the early motor repertoire even proved predictive of the degree of functional limitations as classified on the Gross Motor Function Classification System (GMFCS) in children with CP, born preterm. Aims We aimed to determine whether an association between the early motor repertoire and the GMFCS also holds true for children born at term. Study design Longitudinal study. Subjects 79 infants (60 boys and 19 girls; 47 infants born at term; video recorded for the assessment of movements and posture at age 9 to 20 weeks postterm age) who developed CP. Outcome measures The GMFCS was applied at age 2 to 5 years. Results Motor optimality at age 3 to 5 months showed a significant correlation with functional mobility and activity limitation as classified on the GMFCS at age 2 to 5 years in both children born at term (Spearman rho = − 0.66, p

Hypothermia is a potential therapy for cerebral hypoxic ischemic injury in adults and neonates. However, the mechanism of hypothermia neuroprotection after hypoxic-ischemia (HI) on the developing rat brain remains unclear. In this research, 7-day-old rats were subjected to left carotid artery ligation followed by 8% oxygen for 2 h. They were divided into hypothermia (rectal temperature, 32–33 °C for 24 h) and normothermia (36–37 °C for 24 h) groups immediately after hypoxia-ischemia. All rats were given 50 mg/kg/day 5-bromodeoxyuridine (BrdU) intraperitoneally at 4–6 days and sacrificed at 1 or 2 weeks after HI. There was a significant decrease in infarct volume in the hypothermia group at 7 days after HI compared with that in the normothermia group. The numbers of nestin-labeled cells did not change greatly, but β-tubulin III (Tuj-1) immuno-positive cells increased significantly in the striatum at 1 and 2 weeks after HI in the hypothermia compared to normothermia group. Neurogenesis was assessed by double immunohistochemical/immunofluorescent labeling of BrdU with nestin, Tuj-1 or microtubule-associated protein 2 (Map-2). Newborn neural progenitors (BrdU+-nestin+) did not change dramatically, but newborn immature (BrdU+-Tuj-1+) and mature (BrdU+-Map-2+) neurons increased significantly in the hypothermia compared with normothermia group. Meanwhile, the apoptosis rate of neural precursors, immature and mature neurons, assessed by double labeling of active Casp-3 with nestin/Tuj-1/Map-2, decreased noticeably in the hypothermia compared with normothermia group. We also found that hypothermia significantly increased expression of Bcl-2, which coexisted with nestin/Tuj-1/Map-2. Inhibition of Bcl-2 expression reversed the decreased apoptosis rate of neural precursors and neurons in hypothermia animal striatum of neonatal rat brain. These results suggest that neuroprotection effects of hypothermia on injured developing rat brain may associate with enhanced generation of neuronal cells and Bcl-2-mediated reduction of apoptosis of these cells. These observations are noteworthy regarding clinical hypothermia therapy following cerebral HI injury during the perinatal period.

We investigated the neuroprotective efficacy of hypothermia after status epilepticus (SE) in immature rats. In addition, the expression levels of NMDAR1 and c-Jun were measured to establish a possible signaling mechanism for hypothermia-induced neuroprotection. Pilocarpine-treated rats were randomly divided into 2 groups: group D (diazepam) and group DH (diazepam plus hypothermia). Compared to the control (group NS) rats, Pilocarpine-induced SE significantly enhanced the expression of NMDAR1 and c-Jun in the hippocampus, and also significantly increased the numbers of necrotic and apoptotic pyramidal neurons. The DH group exhibited significantly fewer necrotic and apoptotic hippocampal pyramidal neurons and reduced NMDAR1 expression than group D. In contrast, early expression of c-Jun was significantly higher in the hippocampi of hypothermia-treated rats than in the hippocampi of group D, while late c-Jun expression was significantly lesser than group D. Our results show mild post-ictal hypothermia partially rescues neuronal cell death in the hippocampus following SE. We further suggest that elevated NMDAR1 expression exacerbates SE-induced neuronal death in pilocarpine-treated rats, while early c-Jun overexpression, concomitant with hypothermia, suppresses subsequent neuronal death.

Insulin-like growth factor (IGF-1) markedly increases myelination and glial numbers in white matter after ischemia in near-term fetal sheep; however, it is unclear whether this is due to reduced cell loss or increased secondary proliferation. Brain injury was induced in near-term fetal sheep by 30 minutes of bilateral carotid artery occlusion. Ninety minutes after the occlusion, fetuses were given, intracerebroventricularly, either a single dose of IGF-1 (either 3 or 30 micro g), or 3 micro g followed by 3 micro g over 24 hours (3 + 3 micro g). White matter was assessed 4 days after reperfusion. Three micrograms, but not 30 micro g of IGF-1 prevented loss of oligodendrocytes and myelin basic protein density (P < 0.001) compared to the vehicle-treated ischemia controls. No additional effect was observed in the 3 + 3 micro g group. IGF-1 treatment was associated with reduced caspase-3 activation and increased glial proliferation in a similar dose-dependent manner. Caspase-3 was only expressed in oligodendrocytes that showed apoptotic morphology. Proliferating cell nuclear antigen co-localized with both oligodendrocytes and astrocytes and microglia. Thus, increased oligodendrocyte numbers after IGF-1 treatment is partly due to suppression of apoptosis, and partly to increased proliferation. In contrast, the increase in reactive glia was related only to proliferation. Speculatively, reactive glia may partly mediate IGF-1 white matter protection.

The protective effects of huperzine A, a novel acetylcholinesterase inhibitor, on hypoxic-ischemic (HI) brain injury were investigated in neonatal rats. A unilateral HI brain injury was produced by the ligation of left common carotid artery followed by 1 h hypoxia with 7.7% oxygen in 7-day-old rat pups. After 5 weeks, HI brain injury in rat pups resulted in working memory impairments shown by increased escape latency in a water maze and reduced time spent in the target quadrant. The combination of common carotid artery ligation and exposure to a hypoxic environment caused the damage in the striatum, cortex, and hippocampus in the ipsilateral hemisphere, and the neuronal loss in the CA1 region. Huperzine A was administrated daily at the dose of 0.05 or 0.1 mg/kg i.p. for 5 weeks after HI injury. The significant protection against HI injury on behavior and neuropathology was produced by huperzine A at the dose of 0.1 mg/kg. These findings suggest that huperzine A might be beneficial in the treatment of hypoxic-ischemic encephalopathy in neonates.

The gastrointestinal tract is the largest surface area of the body and the primary site for microorganisms, foreign antigens and toxins to gain entry to the host's internal milieu. The use of enteral feedings enriched with immune-enhancing ingredients is attracting considerable interest because there is increasing application of enteral feeding and appreciation of the role of the gut in the development of infection and of multiple organ failure in critically ill patients. Conclusion: in this review, we will discuss nutrients, such as glutamine, arginine, omega 3 fatty acids, nucleotides, probiotics, and lactoferrin, and how they might be used as immunonutrients in neonatal clinics.

Objective In this prospective, observational study, we determined whether serum protein C and protein S (PC/PS) activity correlated with necrotizing enterocolitis (NEC) stages II and III in premature infant. We hypothesized that PC/PS measurement if used as an adjunct to abdominal radiographs would improve the identification and predication of infants with NEC. Methods Serum PC/PS activity was measured according to protocol at early stage and recover stage of NEC. When clinical signs persisted and the initial abdominal radiographs were abnormal, follow-up radiographs were obtained. Results. Of 45 infants who were evaluated for gastrointestinal signs, only 2 had ileus or benign pneumatosis intestinalis with persistently normal PC/PS; gastrointestinal manifestations resolved within 48 hours, antibiotics were discontinued in Conclusions In infants with suspected NEC, normal PC/PS values would favor aborted antibiotic therapy and early resumption of feedings. PC/PS becomes significantly lower in both stage II and stage III NEC. In infants with NEC, persistently decreased PC/PS after initiation of appropriate medical management suggests associated complications, which may require surgical intervention.

Objective To investigate the efficacy and safety of selective head cooling with mild systemic hypothermia in hypoxic-ischemic encephalopathy (HIE) in newborn infants. Study design Infants with HIE were randomly assigned to the selective head cooling or control group. Selective head cooling was initiated within 6 hours after birth to a nasopharyngeal temperature of 34° ± 0.2°C and rectal temperature of 34.5° to 35.0°C for 72 hours. Rectal temperature was maintained at 36.0° to 37.5°C in the control group. Neurodevelopmental outcome was assessed at 18 months of age. The primary outcome was a combined end point of death and severe disability. Results One hundred ninety-four infants were available for analysis (100 and 94 infants in the selective head cooling and control group, respectively). For the selective head cooling and control groups, respectively, the combined outcome of death and severe disability was 31% and 49% (OR: 0.47; 95% CI: 0.26-0.84; P = .01), the mortality rate was 20% and 29% (OR:0.62; 95% CI: 0.32-1.20; P = .16), and the severe disability rate was 14% (11/80) and 28% (19/67) (OR: 0.40; 95% CI: 0.17-0.92; P = .01). Conclusions Selective head cooling combined with mild systemic hypothermia for 72 hours may significantly decrease the combined outcome of severe disability and death, as well as severe disability.