Microglia are important cells involved in the regulation of neuropathic pain (NPP) and morphine tolerance. Information on their plasticity and polarity has been elucidated after determining their physiological structure, but there is still much to learn about the role of this type of cell in NPP and morphine tolerance. Microglia mediate multiple functions in health and disease by controlling damage in the central nervous system (CNS) and endogenous immune responses to disease. Microglial activation can result in altered opioid system activity, and NPP is characterized by resistance to morphine. Here we investigate the regulatory mechanisms of microglia and review the potential of microglial inhibitors for modulating NPP and morphine tolerance. Targeted inhibition of glial activation is a clinically promising approach to the treatment of NPP and the prevention of morphine tolerance. Finally, we suggest directions for future research on microglial inhibitors.
Humans ; Calcitonin Gene-Related Peptide/antagonists & inhibitors* ; Drug Tolerance ; Hypoglycemic Agents/pharmacology* ; Microglia/physiology* ; MicroRNAs/physiology* ; Minocycline/pharmacology* ; Morphine/pharmacology* ; Neuralgia/etiology* ; Plant Extracts/pharmacology* ; Signal Transduction/physiology*

AIMTo study the effect of CGRP receptor antagonist CGRP8-37 on nociceptive response and expression of nitric oxide synthase (NOS) and content of nitric oxide (NO) in the dorsal horn of the spinal cord of rats during formalin-induced inflammatory pain.

METHODSUsing formalin injection into right hind paw induced inflammatory pain. Counting the times of flinching reflex was used to observe the degree of spontaneous pain. NADPH-d histochemistry was used to observe the changes of NOS expression. The content of NO was observed by measuring the contents of nitrate/nitrite (NO3- / NO2-).

RESULTSspontaneous pain behavioral was elicited by formalin injection. The NOS expression and NO content significantly increased in the spinal cord at 24 h after formalin injection. Intrathecal injection of CGRP8-37 could significantly inhibit the response of spontaneous pain and the increases of NOS expression and NO content induced by formalin injection.

CONCLUSIONThe activation of CGRP receptors enhances NOS expression and NO production in the dorsal horn of the spinal cord during formalin-induced inflammatory pain.

Animals ; Calcitonin Gene-Related Peptide ; pharmacology ; Formaldehyde ; adverse effects ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase ; metabolism ; Pain ; chemically induced ; metabolism ; Peptide Fragments ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Calcitonin Gene-Related Peptide ; antagonists & inhibitors ; Spinal Cord ; drug effects ; metabolism

Women often complain gut symptoms during pregnancy and the luteal phase of the menstrual cycle. To investigate the relationship between ovarian steroids and the abnormal gut motility and sensitivity, the expressions of cholecystokinin (CCK), calcitonin gene-related peptide (CGRP) and their receptors in stomach were studied in ovariectomized rats. Blood samples were collected for estradiol (E(2)), progesterone (P(4)), CCK and CGRP radioimmunoassay. Expression of CCK(A) receptor in fundus was assessed by Western blot and CGRP receptor was determined by (125)I-CGRP radioligand binding assay (RBA). The replacement therapy with estradiol benzoate (EB) could dose-dependently increase the plasma CCK level and the expression of gastric CCK(A) receptor (P<0.05 respectively). P(4) replacement therapy could stimulate the release of CGRP and increase the binding sites of CGRP receptors in stomach (P<0.05 respectively). The combined effect of EB and P(4) was to stimulate the release of CCK and CGRP, and to increase the expressions of gastric CCK(A) and CGRP receptors. These results indicate that EB could inhibit gastric emptying by increasing CCK secretion and CCK(A) receptor expression in ovariectomized rats. P(4) could increase gut sensitivity by up-regulating the release of CGRP and the activity of CGRP receptor. It could be deduced from these observations that CCK(A) and CGRP receptor antagonists could be used for female patients who suffer from gastrointestinal dysfunction closely related with the menstrual cycle, such as distension, satiety, bloating and abdominal pain.
Animals ; Calcitonin Gene-Related Peptide ; blood ; Cholecystokinin ; blood ; Estradiol ; analogs & derivatives ; pharmacology ; physiology ; Female ; Gastric Emptying ; drug effects ; physiology ; Ovariectomy ; Progesterone ; pharmacology ; physiology ; Rats ; Rats, Sprague-Dawley ; Receptors, Calcitonin Gene-Related Peptide ; metabolism ; Receptors, Cholecystokinin ; metabolism ; Stomach ; metabolism ; physiology

BACKGROUNDRecombinant human parathyroid hormone (1-34) (rhPTH (1-34)) given by injection is a new seventh class drug of biological products, which is prepared by adopting gene recombination technique. rhPTH (1-34) is mainly used to treat osteoporosis, especially for postmenopausal women. This study compared the clinical efficacy and safety of rhPTH (1-34) with elcatonin for treating postmenopausal women with osteoporosis in 11 urban areas of China.

METHODSTwo hundred and five women with osteoporosis were enrolled in a 6-month, multicenter, randomized, controlled study. They were randomized to receive either rhPTH (1-34) 20 microg (200 U) daily or elcatonin 20 U weekly. Lumbar spine (L1-4) and femoral neck bone mineral density (BMD), as well as biochemical markers of bone turnover were measured. Adverse events were recorded.

RESULTSrhPTH (1-34) increased lumbar BMD significantly more than did elcatonin at 3 months and 6 months (2.38% vs 0.59%, P < 0.05; 5.51% vs 1.55%, P < 0.01), but there were no significant increases of BMD in these two groups at femoral neck. There were larger mean increases in bone markers in the rhPTH (1-34) group than in the elcatonin group at 3 months and 6 months (serum bone-specific alkaline phosphatase (BSAP) 36.79% vs 0.31%; 92.42% vs -0.17%; urinary N-telopeptide/creatinine (NTX/Cr) 48.91% vs -5.32%; 68.82% vs -10.86%). Both treatments were well tolerated and there were no significant differences detected between the two groups in the proportion of any adverse events and any serious adverse events (67.0% vs 59.0%; 0 vs 0).

CONCLUSIONSrhPTH (1-34) has more positive effects on bone formation, as shown by the larger increments of lumbar BMD and bone formation markers, than elcatonin, with only mild adverse events and no significant change in the liver, kidney or hematological indices.

Aged ; Calcitonin ; analogs & derivatives ; pharmacology ; therapeutic use ; Female ; Humans ; Middle Aged ; Osteogenesis ; drug effects ; Osteoporosis, Postmenopausal ; drug therapy ; Parathyroid Hormone ; pharmacology ; therapeutic use ; Recombinant Proteins ; pharmacology ; therapeutic use

Objective To investigate the effect of calcitonin gene-related peptide (CGRP) on the regulation of group 2 innate lymphoid cells (ILC2) in the peripheral blood of patients with allergic rhinitis (AR). Methods Peripheral blood mononuclear cells (PBMCs) were extracted from normal healthy individuals and AR patients, then stimulated with CGRP, interleukin 33 (IL-33) and CGRP combined with IL-33 for 3 days, with blank stimulus as control. The percentage of ILC2 in the four groups was measured by flow cytometry. After being sorted, ILC2 was given to CGRP, IL-33 and CGRP combined with IL-33 stimulation for 3 days, with blank stimulus as control. The percentage of IL-5 and IL-13 positive cells in ILC2 was detected by flow cytometry, and the levels of IL-5 and IL-13 in ILC2 supernatant were measured by ELISA. Results The percentage of ILC2 in the peripheral blood of AR patients was significantly higher than that of the control group. The levels of IL-5⁺ILC2 and IL-13⁺ILC2 were significantly increased by IL-33 single stimulation after culturing PBMCs. After adding IL-33 combined with CGRP stimulation, the levels of IL-5⁺ILC2 and IL-13⁺ILC2 in PBMCs were significantly reduced; after CGRP single stimulation, the levels of IL-5⁺ILC2 and IL-13⁺ILC2 in PBMCs were further decreased. After ILC2 was sorted and cultured, the levels of IL-5⁺ILC2 and IL-13⁺ILC2 showed significant increase after IL-33 single stimulation. The levels of IL-5⁺ILC2 and IL-13⁺ILC2 were decreased by IL-33 and CGRP co-stimulation, and they were further reduced after CGRP single stimulation. Compared to IL-33 single stimulation, IL-5 and IL-13 levels dropped significantly due to the IL-33 and CGRP co-stimulation. The levels of IL-5 and IL-13 were further reduced by CGRP single stimulation. Conclusion CGRP inhibits the proliferation and activation of peripheral blood ILC2 in AR and exert anti-inflammatory effects in AR.
Humans ; Calcitonin Gene-Related Peptide/pharmacology* ; Leukocytes, Mononuclear ; Immunity, Innate ; Interleukin-33/pharmacology* ; Interleukin-13 ; Lymphocytes ; Interleukin-5/pharmacology* ; Rhinitis, Allergic ; Cell Proliferation

This article describes the preparation of salmon calcitonin ultra-flexible liposomes and their hypocalcemia effect after intranasal administration in rats. Both the conventional liposomes and ultra-flexible liposomes were prepared by rotary evaporation-sonication and extrusion. The morphology of ultra-flexible liposomes was observed with transmission electronic microscope. The size and size distribution and their zeta potential were determined by dynamic light scattering. The mean size of ultra-flexible liposomes with DC-Chol was no more than 120 nm, while the mean size of the conventional liposomes was 256.5 nm. The results showed the content of sodium deoxycholate have significant effect on the mean particle size of liposomes. The ultra-flexible liposomes were intranasal administrated at the dose of 5.0 microg x kg(-1); the concentration of serum calcium was determined by OCPC method. The results showed that the salmon calcitonin solution only slightly lowered serum calcium levels and the conventional liposomes could improve the effect of decreased serum calcium level (D%), and the ultra-flexible liposomes had the best effect on the decreased serum calcium level, and the hypocalcemia effect was correlated with the content of sodium deoxycholate which was present in the liposomes. Moreover the ciliotoxicity of ultra-flexible nanoliposomes on nasal mucocilia was investigated with the electron microscope scanning. The results showed that the ultra-flexible liposomes markedly reduced the ciliotoxicity of sodium deoxycholate on nasal mucous. Thereby the ultra-flexible liposomes significantly enhanced the hypocalcemia effect of serum calcium after intranasal administration in rats. The ultra-flexible liposomes could be an effective carrier for intranasal delivery of the peptide and protein drugs.
Administration, Intranasal ; Animals ; Calcitonin ; administration & dosage ; pharmacology ; Calcium ; blood ; Liposomes ; Male ; Particle Size ; Rats ; Rats, Sprague-Dawley

Animals ; Calcitonin Gene-Related Peptide ; pharmacology ; Ischemic Postconditioning ; Male ; Myocardial Reperfusion Injury ; prevention & control ; Myocardium ; metabolism ; Rats ; Rats, Sprague-Dawley

Angiotensin II (Ang II) and calcitonin gene-related peptide (CGRP) play important roles in vascular injury and protection. In order to determine the role of CGRP receptor component protein (RCP) in signal transduction whereby CGRP and Ang II mediate the expression of vascular peroxidase-1 (VPO1) in vascular smooth muscle cell (VSMC), mouse derived A10 vascular smooth muscle cell line (A10VSMC) was cultured with CGRP or/and Ang II in vitro. RCP-specific small interference RNA (siRNA-RCP) was used to silence oligonucleotide sequence. Western blot and RT-PCR were used to determine the protein and mRNA expressions of RCP and VPO1, respectively. The results showed that the expressions of RCP and VPO1 were increased in the presence of CGRP or Ang II in the quiescent A10VSMC. But the protein expressions of RCP and VPO1 induced by Ang II were decreased by pretreatment of CGRP (P < 0.05). The expressions of VPO1 were decreased in all the groups treated with siRNA-RCP, compared with those of wide-type counterparts. Meanwhile, the expression of VPO1 was significantly induced by CGRP but not Ang II in the siRNA-RCP treated A10VSMCs. Ang II in combination with CGRP increased the protein expression of VPO1 in the siRNA-RCP-transfected cells, compared with Ang II alone, and this effect could be abolished by catalase. The results suggest that RCP may play an important role in the integration of signal transduction whereby CGRP and Ang II receptors jointly regulate VPO1 expression in VSMC.
Angiotensin II ; pharmacology ; Animals ; Calcitonin Gene-Related Peptide ; pharmacology ; Mice ; Muscle, Smooth, Vascular ; cytology ; Myocytes, Smooth Muscle ; metabolism ; Peroxidases ; metabolism ; RNA, Small Interfering ; Signal Transduction

The effects of adrenomedullin (ADM) on intracellular calcium concentration ([Ca(2+)](i)) were investigated in cultured hippocampal neurons. Changes in [Ca(2+)](i) were detected by laser scanning confocal microscopy using Fluo 3-AM as the calcium fluorescent probe. [Ca(2+)](i) was represented by relative fluorescent intensity. The results showed that: (1) ADM (0.01-1.0 micromol/L) decreased the resting [Ca(2+)](i) in a concentration-dependent manner. (2) Calcitonin gene-related peptide receptor antagonist CGRP(8-37) significantly inhibited the effects of ADM. (3) ADM significantly reduced the increase in [Ca(2+)](i) induced by high K(+). (4) ADM markedly inhibited the inositol 1,4,5-trisphosphate (IP(3))-induced increase in [Ca(2+)](i), while did not influence ryanodine-evoked increase in [Ca(2+)](i). These results suggest that ADM reduces [Ca(2+)](i) in cultured hippocampal neurons through suppressing Ca(2+) release from IP(3)-sensitive stores. Although ADM does not alter resting Ca(2+) influx, it significantly suppresses Ca(2+) influx activated by high K(+). These effects may be partly mediated by CGRP receptors. ADM in the CNS may act as a cytoprotective factor in ischemic/hypoxic conditions.
Adrenomedullin ; Animals ; Animals, Newborn ; Calcitonin Gene-Related Peptide ; metabolism ; Calcium ; metabolism ; Cells, Cultured ; Embryo, Mammalian ; Hippocampus ; cytology ; metabolism ; Inositol 1,4,5-Trisphosphate ; antagonists & inhibitors ; Neurons ; cytology ; metabolism ; Peptides ; pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Calcitonin Gene-Related Peptide ; antagonists & inhibitors ; metabolism

OBJECTIVETo explore the effect of Compound Tongtu Granule (CTG) on intestinal permeability in elderly sepsis patients.

METHODSEighty elderly sepsis patients were randomly assigned to the experimental group and the control group by randomized double blinded method, 40 in each group. On the basis of conventional antiseptic treatment program, patients in the experimental group took CTG, while those in the control group took placebos. The dosage for CTG or placebos was 14.3 g each package, one package each time, twice daily for 14 successive days. Patients' abdominal symptoms and signs, levels of serum inflammatory factors (high-sensitivity C-reactive protein and procalcitonin), levels of plasma endotoxin, and the intestinal permeability (IP, represented by urinary lactulose/mannitol excretion rate) were compared between the two groups before and after treatment.

RESULTSAfter 14-day treatment, patients in the experimental group had improved abdominal symptoms, increased frequency of defecation, significantly decreased levels of plasma endotoxin and IP, when compared with the control group (P < 0.05).

CONCLUSIONCTG could improve the intestinal barrier function in elderly sepsis patients.

Aged ; C-Reactive Protein ; metabolism ; Calcitonin ; metabolism ; Calcitonin Gene-Related Peptide ; Defecation ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Endotoxins ; metabolism ; Humans ; Intestines ; metabolism ; Permeability ; Protein Precursors ; metabolism ; Sepsis ; drug therapy ; physiopathology