Psychological and cognitive impairment of long-term migrators to high altitudes and the relationship to physiological and biochemical changes.

BACKGROUND AND PURPOSE: The present study aimed to examine how long-term migration to high-altitude regions affects mentality and cognition, and the correlation with various physiological and biochemical changes. METHODS: The WHO Neurobehavioral Core Test Battery, Raven's Standard Progressive Matrices (RSPM) and Pittsburgh Sleep Quality Index questionnaire were used to assess 141 young male subjects who lived in plain regions and 217 young male subjects who had migrated to a 4500 m high-altitude region and lived there for 1-5 years. Arterial oxyhemoglobin saturation, cerebral tissue oxygenation indices (TOIs), serum S100B and brain-derived neurotrophic factor (BDNF) were also measured. RESULTS: Long-term migrators to a high-altitude region exhibited exacerbated mood disorders, retarded color discrimination ability, decreased visual memory capacity, and impaired perceptual motor skill and motion stability. In addition, the migrators exhibited lower RSPM scores and lower sleep quality. Further analyses revealed significant correlations between sleep quality and cerebral TOIs, mood and sleep quality, mood and certain cognitive functions, mood and serum BDNF levels, and RSPM scores and serum S100B levels. CONCLUSIONS: Long-term living at high altitudes causes significant impairment of psychological and cognitive function. Cerebral hypoxic extent, sleep quality and biochemical dysfunction are major influencing factors.

Alterations in P2X and P2Y purinergic receptor expression in urinary bladder from normal cats and cats with interstitial cystitis.

Purinergic mechanisms appear to be involved in motor as well as sensory functions in the urinary bladder. ATP released from efferent nerves excites bladder smooth muscle, whereas ATP released from urothelial cells can activate afferent nerves and urothelial cells. In the present study, we used immunohistochemical techniques to examine the distribution of purinoceptors in the urothelium, smooth muscle, and nerves of the normal cat urinary bladder as well as possible changes in the expression of these receptors in cats with a chronic painful bladder condition termed feline interstitial cystitis (FIC) in which ATP release from the urothelium is increased. In normal cats, a range of P2X (P2X(1), P2X(2), P2X(3), P2X(4), P2X(5), P2X(6), and P2X(7)) and P2Y (P2Y(1), P2Y(2), and P2Y(4)) receptor subtypes was expressed throughout the bladder urothelium. In FIC cats, there is a marked reduction in P2X(1) and loss of P2Y(2) receptor staining. Both P2X(3) and P2Y(4) are present in nerves in normal cat bladder, and no obvious differences in staining were detected in FIC. Smooth muscle in the normal bladder did not exhibit P2Y receptor staining but did exhibit P2X (P2X(2), P2X(1)) staining. In the FIC bladder smooth muscle, there was a significant reduction in P2X(1) expression. These findings raise the possibility that purinergic mechanisms in the urothelium and bladder smooth muscle are altered in FIC cats. Because the urothelial cells appear to have a sensory function in the bladder, it is possible that the plasticity in urothelial purinergic receptors is linked with the painful bladder symptoms in IC.

P2 receptors in the murine gastrointestinal tract.

The actions of adenosine, adenosine 5'-triphosphate (ATP), 2-methylthio adenosine diphosphate ADP (2-MeSADP), 2-methylthio ATP (2-MeSATP), alpha,beta-methylene ATP (alpha,beta-meATP) and uridine triphosphate (UTP) on isolated segments of mouse stomach (fundus), duodenum, ileum and colon were investigated. The localization of P2Y(1), P2Y(2), P2Y(4), P2X(1) and P2X(2) receptors and neuronal nitric oxide synthase (NOS) were examined immunohistochemically, and P2Y(1) mRNA was examined with in situ hybridization. The order of potency for relaxation of longitudinal muscle of all regions was: 2-MeSADP>/=2-MeSATP>alpha,beta-meATP>ATP=UTP=adenosine. This is suggestive of P2Y(1)-mediated relaxation and perhaps a further P2Y receptor subtype sensitive to alpha,beta-meATP. As ATP and UTP are equipotent, the presence of a P2Y(2) receptor is indicated. ATP responses were inhibited by the P2Y(1)-selective antagonist MRS 2179, and suramin. P2Y(1) receptors were visualized immunohistochemically in the smooth muscle of the ileum and in a subpopulation for myenteric neurones, which also stained for NOS. P2Y(1) mRNA was localized in neurones in both myenteric and submucosal ganglia in the ileum. Taken together, these results suggest that ATP was acting on non-adrenergic, non-cholinergic inhibitory neurons, which release both nitric oxide (NO) and ATP. Reduced relaxations to 2-MeSADP by tetrodotoxin and N(omega)-nitro-L-arginine methyl ester, are consistent with this possibility. Adenosine acts via P1 receptors to relax smooth muscle of the mouse gut. Segments of mouse colon (in contrast to the stomach and small intestine) were contracted by nucleotides with the potency order: 2-MeSATP>alpha,betameATP>ATP; the contractions showed no desensitization and were antagonized by suramin and PPADS, consistent with responses mediated by P2X(2) receptors. Immunoreactivity to P2X(2) receptors was demonstrated on both longitudinal and circular muscle of the colon, but not in the other regions of the gut, except for a small subpopulation of myenteric neurones. In summary, neuronal P2Y(1) receptors appear to mediate relaxation, largely through NO in all regions of the mouse gut, and to a lesser extent by P2Y(1), P2Y(2) and a novel P2Y receptor subtype responsive to alpha,beta-meATP in smooth muscle, while P2X(2) receptors mediate contraction of colonic smooth muscle.

Effects of AP-V and bicuculline on somatostatin-positive neurons in hypothalamus of rats subjected to acute hypobaric hypoxia.

AIM: To investigate the effects of 2-amino-5-phosphonovalerate-pharmacology (AP-V) and bicuculline on somatostatin (SST)-positive neurons in hypothalamus of rats subjected to acute hypobaric hypoxia. METHODS: SST-immunoreactivity (IR) and somatostatin mRNA (SS mRNA)-positive neurons were measured by immunohistochemistry and in situ hybridization methods. RESULTS: Compared with control rats, SST-IR and SS mRNA-positive neurons in hypothalamic periventricular nucleus (PeV), paraventricular nucleus (PVN), and arcuate nucleus (ARC) increased after acute hypobaric hypoxia for 6 h (P < 0.01), and these effects were markedly inhibited by AP-V (10 microg, icv), a highly selective N-methyl-D-aspartate (NMDA) receptor antagonist, whereas were strongly enhanced by bicuculline (1.5 mg/kg, ip), a gamma-aminobutyric acid (GABAA) receptor antagonist. CONCLUSION: SST possibly participates in acute hypoxic reaction in hypothalamus, furthermore, glutamate and GABA can affect somatostatin release and synthesis in hypothalamus through NMDA and GABAA receptors respectively.

[Excitatory amino acid enhance prepro-somatostatin mRNA expression induced by altitude hypoxia in the rat hypothalamus].

AIM AND METHODS: Contents of glutamate (Glu), asparate (Asp) and expression of prepro-somatostatin mRNA (PPS-mRNA) in rat hypothalamus were measured by using imitated altitude hypoxia rat model, amino acid analyzer and in situ hybridization technique. RESULTS: After rats were subjected to altitude hypoxia, contents of Glu and Asp in hypothalamus and PPS-mRNA expression in periventricular nucleus (PeVN), paraventricular nucleus (PaVN) and arcuate nucleus (ArcN) were increased significantly. Ketamine, a NMDA receptor antagonist, could decrease the number of PPS-mRNA neurons in rat hypothalamus evoked by altitude hypoxia, but had no effect on Glu and Asp contents evoled by altitude hypoxia. CONCLUSION: It is suggested that somatostatin maybe paticipate in altitude hypoxia reaction, Glu can enhance PPS-mRNA expression through NMDA receptor.

[Ketamine and L-NAME inhibit NOS and somatostatin mRNA expression induced by altitude hypoxia in the rat hypothalamus].

Using altitude hypoxia model, in situ hybridization and NADPH-d histochemistry, we investigated the effects of ketamine and L-NAME (blocker of NOS) on NOS and somatostatin mRNA (SS mRNA) expression in the rat hypothalamus following acute altitude hypoxia. It was revealed that acute altitude hypoxia induced NOS and SS mRNA overexpression in the rat hypothalamus. When pretreated with NMDA receptor antagonist ketamine and L-NAME, NOS and SS mRNA expression were inhibited significantly. These results suggest that NMDA receptor activation participates in the expression of NOS and SS mRNA in the rat hypothalamus subjected to acute altitude hypoxia. Meanwhile, hypothalamic endogenous NO may mediate expression of SS mRNA.

Effects of corticotrophin on pain behavior and BDNF, CRF levels in frontal cortex of rats suffering from chronic pain.

AIM: To investigate the effects of corticotrophin (Cor) on corticotropin-releasing factor (CRF), brain-derived neurotrophic factor (BDNF), and its functional receptor trkB in the frontal cortex of complete Freud's adjuvant (CFA)-induced arthritic rats. METHODS: The chronic pain rat model was modified and pain behaviour scores were assessed. BDNF-immunoreactivity (IR), trkB-IR, and CRF mRNA-positive neurons were measured by immunohistochemistry and in situ hybridization methods. RESULTS: Compared with control rats, pain behavior scores, BDNF-IR, CRF mRNA-positive, trkB-IR, and BDNF/CRF mRNA double-labeling neurons in the contralateral frontal cortex of the arthritic rats increased significantly at 24 h after injection of CFA (P < 0.05), and these effects were decreased markedly by i.p. injection of Cor (P < 0.05). The decrease in pain behavior and BDNF-IR, CRF mRNA levels in frontal cortex of arthritic rats due to Cor were partly prevented by adrenalectomy (ADX). CONCLUSION: The increment in BDNF and CRF levels in the contralateral frontal cortex of arthritic rats may be inhibited by corticotrophin.

[Effect of corticotrophin on formaldehyde-induced somatostatin of spinal cord in rats].

AIM: To study the effect of corticotrophin (Cor) on somatostatin (Som) and its synthesis in spinal dorsal horn induced by formaldehyde in rats. METHODS: Using double immunohistochemical stainings, and in situ hybridization. RESULTS: Two hours after s.c. formaldehyde (5%, 200 microL) in one hindpaw of rats, the neurons of c-fos-like immunoreactivity (FLI), somatostatin-like immunoreactivity (Som-LI), Som-LI/FLI, and perprosomatostatin mRNA (PPS-mRNA) in ipsilateral spinal dorsal horn were increased obviously, as compared with the control group. The FLI and Som-LI of spinal cord were not changed by i.p. Cor. Cor (25 or 12.5 U.kg-1, i.p.) inhibited the formaldehyde-evoked FLI, Som-LI, Som-LI/FLI, and PPS-mRNA of spinal cord in a dose-dependent manner. The decrease of c-fos or Som level due to i.p. Cor in rats of chronic pain was prevented by raphe nuclei injected cyproheptadine, but not by bicuculline, naloxone, or phentolamin injected to raphe nuclei. CONCLUSION: The formaldehyde-evoked c-fos expression, Som, and Som synthesis of spinal cord were suppressed by Cor through the serotonin receptor of raphe nuclei.

[Effect of ACTH on the expression of somatostatin and c-fos in the spinal cord and formalin evoked pain response].

In the present study, the effect of ACTH on the expression of somatostatin and c-fos in the spinal cord and formalin induced pain responses in rats were studied using immunohistochemistry and in situ hybridization. The results showed that subcutaneous injection of formalin in the right hindpaw increased c-fos-like immunoreactivity (FLI), somatostatin-like immunoreactivity (Som-LI), Som-LI/FLI and perprosomatostatin mRNA (PPS-mRNA) in neurones of right spinal dorsal horn and significantly enhanced pain intensity rating. ACTH decreased the FLI,Som-LI, Som-LI/FLI and PPS-mRNA levels of the spinal cord evoked by formalin. The decrease of c-fos or Som level due to intrathecal injection of ACTH in rats with chronic pain was prevented by injection of cyproheptadine, but not by bicuculline and naloxone. The results indicate that the serotonin receptor may be involved in ACTH induced analgesia.

Effects of intra-hippocampal injection of interleukin-2 on pain threshold and formaldehyde-induced substance P-like immunoreactivity in periaqueductal gray and spinal cord.

AIM: To study the effects of intra-hippocampal injection of interleukin-2 (IL-2) on the substance P-like immunoreactivity (SP-LI) in both periaqueductal gray (PAG) and spinal cord, and on pain threshold in rats. METHODS: Immunohistochemistry technique was used and the paw withdrawal threshold to radiant heat was measured. RESULTS: Microinjection of hIL-2 480 U in hippocampus (Hip) increased the pain threshold (93% +/- 57%, P < 0.01). Injection of formaldehyde (For) in one hindpaw decreased SP-LI neuron number on both sides of PAG (2.9 +/- 2.8 vs 22.1 +/- 0.7, 12.3 +/- 2.0 vs 22.4 +/- 1.0, P < 0.01) and increased SP-LI in ipsilateral spinal cord (0.836 +/- 0.015 vs 0.59 +/- 0.09, P < 0.01). Microinjection of hIL-2 480 U in Hip inhibited the effects of For on the SP-LI on both sides of the PAG (11.3 +/- 2.3 vs 2.9 +/- 2.8, 16.9 +/- 3.4 vs 12.3 +/- 2.0, P < 0.05) and spinal cord (0.71 +/- 0.03 vs 0.836 +/- 0.015, P < 0.01). The combination of intraperitoneal injection of corticotropin and intra-hippocampal injection of IL-2 increased the number of SP-LI neurons in PAG furtherly as compared with IL-2 240 U alone (13.6 +/- 3.6 vs 7.6 +/- 4.3, P < 0.05). CONCLUSION: The analgesic effects of intra-hippocampal injection of IL-2 are mediated, possibly, via the increased of SP in PAG and the decrease of SP in the spinal cord. There is a synergetic relation between IL-2 and corticotropin.

Intrathecal injection of corticotropin inhibited nitric-oxide synthase-positive neuron increase in rat spinal cord after formalin-induced hyperalgesia.

AIM: To study the effects of corticotropin (Cor) on formalin-induced hyperalgesia and the change of nitric-oxide synthase (NOS)-positive neurons in spinal dorsal horn in rats. METHODS: Measurement of pain intensity rating (PIR), NADPH-d histochemistry, and Fos immunohistochemistry were adopted. RESULTS: The increases of NOS-positive neurons, Fos, NOS/Fos double labelling neurons of the spinal dorsal horn and the PIR after formalin injection were markedly inhibited by intrathecal injecting (ith) Cor (0.5-1.5 U), which were obviously attenuated by L-arginine (Arg, 5-15 nmol, ith), the substrate of NOS. CONCLUSION: Cor inhibits formalin-induced hyperalgesia by the decrease of NOS-positive neurons in the spinal dorsal horn of rats.

[Effects of morphine on the formalin induced IL-2R beta mRNA expression of rat hippocampus].

Using method of in situ hybridization, the effects of subcutaneous injection (s.c.) of formalin (For) into one hindpaw (hyperalgesia) on IL-2R beta mRNA expression in hippocampus (Hip) were studied. In addition, the effects of coadministration of morphine (i.p.) or ACTH (i.p.) with For (s.c.) were studied also. It was found that IL-2R beta mRNA was present in normal rat's Hip, intensely in granular cells of dentate gyrus and CA1-CA4 neurons. Subcutaneous injection of For increased IL-2R beta mRNA from 6 h to at least 24 h, reaching a peak at 12 h. Coadministration with morphine enhanced the effects of For on IL-2R beta mRNA expression, but no significant change was found with coadministration of ACTH. The above results suggest that IL-2R might be involved in pain modulation.

[Effect of corticotropin on formalin-evoked c-fos expression of spinal cord and receptors analysis in rat].

AIM: To study the effect of corticotropin (Cor) on c-fos expression induced by formalin in spinal cord of rat and the role of receptors. METHODS: Using immunohistochemistry and adrenalectomy. RESULTS: Cor inhibited the formalin-evoked c-fos expression in rat spinal cord in a dose-dependent manner. No obvious effect was seen by i.p. Cor 10 U.kg-1, but 25 U.kg-1 reduced the evoked c-fos expression, that was blocked by phentolamine, naloxone, or verapamil, but not much changed by adrenalectomy. CONCLUSION: The formalin-evoked c-fos expression of rat spinal cord was suppressed by Cor through the alpha-adrenergic receptors, opiate receptors and calcium, but no relation to adrenal glands.

[Somatostatin inhibited pain modulation action of substance P in spinal cord].

In the present study, the effect of somatostatin (SST) on pain modulation induced by substance P in spinal cord was studied. The results showed that intrthecal injection of SST increases pain threshold, prevented pain response and c-fos expression in spinal cord induced by SP. Injection of formalin in the hindpaw induced pain response and increased the SP-LI, which could be inhibited by injection of SST. It is suggested that the analgesic effect of SST may be resulted from the inhibition of the noxious response induced by SP.

[Effects of new constituents L-6a and L-10 from leaves of Luffa cylinderica on learning, memory, and hippocampal somatostatin in rats].

AIM: To study the effects of two constituents L-6a and L-10 from the leaves of Luffa cylinderica Roem on learning, memory, and hippocampal somatostatin in rats. METHODS: The learning and memory in rats were determined using the passive avoidance response of shuttle-box, by i.c.v. Somatostatin in hippocampus was determined with immunohistochemical and images analyses. RESULTS: L-6a 25 micrograms raised memory-keeping activity (P < 0.05) in rats. L-6a 25 micrograms increased the surface density and number density of somatostatin-like immureactant (Som-LI) (P < 0.05). L-10 25 and 50 micrograms increased the surface density and number density of Som-LI (P < 0.05). CONCLUSION: L-6a 25 micrograms enhanced memory-keeping activity and increased the surface density and number density of Som-LI in rats. L-10 shows a tendency to enhance memory-keeping activity but no evident, but it increases the surface density and number density of Som-LI.

[Somatostatin and electroacupuncture inhibited c-fos expression in spinal cord of arthritic rats].

AIM: To observer the effect of intrathecal injection of somatostatin (Som) associated with electroacupuncture (EA) at "Jiaji" points on c-fos protein expression of spinal cord in pain rats. METHODS: Rats with adjuvant arthritis were used as pain model and the c-fos-like immunoreactivity (FLI) was detected by immunohistochemistry. RESULTS: The c-fos protein expression induced by arthritis were found in all of the I-X laminae of ipsilateral spinal cord of rats, and most of the labeled cells were located in the laminae I-II and V-VI. Som and EA suppressed the c-fos expression and the lessening of FLI cells in the spinal cord. CONCLUSION: Pathological pain following arthritis activated pain sensitive neurons (PSN) and evoked c-fos expression in spinal cord, Som and EA suppressed activities of these PSN, producing the effect of analgesia.

Effect of 5-HT on pain modulation of substance P in spinal cord of rats.

AIM: To study the effect of serotonin (5-HT) on pain modulation of substance P (SP) in spinal cord of rats. METHODS: Using immunohisto-chemistry and measurement of pain threshold. RESULTS: The c-fos expression evoked by intrathecal injection (it) SP 10 micrograms and sc 5% formaldehyde (For) 150 microL in the hindpaw was densely distributed in the laminae I, II, V, and VI of spinal dorsal horn. The pain threshold in the SP group was decreased while the pain intensity rating measured by behavioral method in the For group was increased. The c-fos expression induced by it 5-HT 20 micrograms was mostly distributed in the spinal dorsal horn in laminae III-IV and the pain threshold was increased. SP and For induced c-fos expressions in the spinal cord and the pain responses were reduced by 5-HT and increased by 5-HT depletor fenclonine 300 mg.kg-1. CONCLUSION: SP mainly played an algogenesia in the spinal cord. 5-HT inhibited the c-fos expression in the spinal cord evoked by SP and participated in pain modulation of SP.

[Relationship between the content of central substance P and the analgesic effect of electroacupuncture in rats].

Substance P(SP) immunoreactivity in the rat brain and spinal cord were measured by radioimmunoassay and studied to correlate with the analgesic effect induced by electroacupuncture (EA). The results showed following: (1) There was a significant elevation in SP levels sn the hippocampus, hypothalamus and striatum after 30 min of EA. There was a markedly fall in the spinal cord. Statistical analysis revealed a positive correlation between the EA effect and the SP content in hypothalamus, striatum and statistical analysis revealed a correlation. In the spinal cord. (p less than 0.01), while the SP content in the hippocampus exhibited a similar degree of elevation in non responsive and good responsive animals to EA stimulation. (2) SP levels in the hippocampus, hypothalamus and striatum were increased by electroacupuncture stimulation (3v). The frequency of 1.5Hz was no obvious difference as compared with 100Hz in the effects on brain SP content. (3) SP content in the spinal cord decreased only using electroacupuncture stimulations of combination of higher intensity (3v) and higher frequency (100 Hz). (4) This effect could be blocked by the naloxone (i.p) and LSD (icv), but icv injection of Met-enkephalin antibodies had no affects on them.