natriuretic-peptide--brain and Pain

Chronic thromboembolic pulmonary hypertension (CTEPH) results from non-resolving pulmonary thromboemboli that are resistant to plasmatic anticoagulation. Because of a secondary pulmonary arteriopathy accompanying major vessel obstruction, the disorder may be a target for vasodilator therapy.. In an open-label uncontrolled study, we investigated the prostacyclin analog treprostinil given s.c. in patients with severe inoperable CTEPH.. Between September 1999 and September 2005, 25 patients were included if their World Health Organization (WHO) functional class was III or IV, if their six-minute walking distance (6-MWD)

Topics: Aged; Antihypertensive Agents; Cardiac Output; Case-Control Studies; Chronic Disease; Epoprostenol; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Infusion Pumps; Kaplan-Meier Estimate; Male; Middle Aged; Natriuretic Peptide, Brain; Odds Ratio; Pain; Pain Measurement; Platelet Aggregation Inhibitors; Proportional Hazards Models; Prospective Studies; Pulmonary Embolism; Risk Assessment; Severity of Illness Index; Thromboembolism; Time Factors; Treatment Outcome; Vascular Resistance; Vasodilator Agents; Walking

BACKGROUND The study aimed to investigate the expression of brain natriuretic peptide (BNP) and natriuretic peptide receptor A (NPR-A) in L6-S1 dorsal root ganglia (DRG) in a rat model of chronic nonbacterial prostatitis (CNP). MATERIAL AND METHODS One hundred specific pathogen-free (SPF) male Sprague-Dawley rats were randomly divided into a control group (N=50) and a study group (N=50). The control group underwent prostatic injection of 0.1 ml of normal saline on days 3, 7, 10, 14, and 28. The study group, or rat model of CNP, underwent prostatic injection of 0.1 ml of complete Freund's adjuvant on days 3, 7, 10, 14, and 28. At the end of the study, the rats were euthanized, and the prostate tissues and L6-S1 DRG were removed. Histology was performed on the prostate tissue from the rats in the study group and control group. Real-time fluorescence-based quantitative polymerase chain reaction (PCR) and Western blot were used to study the expression of BNP and NPR-A mRNA and protein in the DRG from the rats in the study group and control group. RESULTS In the rat model of CNP, the expression of BNP and NPR-A were significantly increased in L6-S1 DRG compared with the controls. CONCLUSIONS In a rat model of CNP, the increased expression of BNP and NPR-A in L6-S1 DRG may have a role in pain signaling pathways associated with chronic prostatitis.

Topics: Animals; China; Disease Models, Animal; Freund's Adjuvant; Ganglia, Spinal; Gene Expression Regulation; Male; Natriuretic Peptide, Brain; Pain; Prostatitis; Proteins; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; RNA, Messenger; Signal Transduction; Transcriptome

A recent study by Mishra and Hoon identified B-type natriuretic peptide (BNP) as an important peptide for itch transmission and proposed that BNP activates spinal natriuretic peptide receptor-A (NPRA) expressing neurons, which release gastrin releasing peptide (GRP) to activate GRP receptor (GRPR) expressing neurons to relay itch information from the periphery to the brain (Science 340:968-971, 2013). A central premise for the validity of this novel pathway is the absence of GRP in the dorsal root ganglion (DRG) neurons. To this end, they showed that Grp mRNA in DRG neurons is either absent or barely detectable and claimed that BNP but not GRP is a major neurotransmitter for itch in pruriceptors. They showed that NPRA immunostaining is perfectly co-localized with Grp-eGFP in the spinal cord, and a few acute pain behaviors in Nppb-/- mice were tested. They claimed that BNP is an itch-selective peptide that acts as the first station of a dedicated neuronal pathway comprising a GRP-GRPR cascade for itch. However, our studies, along with the others, do not support their claims.. We were unable to reproduce the immunostaining of BNP and NPRA as shown by Mishra and Hoon. By contrast, we were able to detect Grp mRNA in DRGs using in situ hybridization and real time RT-PCR. We show that the expression pattern of Grp mRNA is comparable to that of GRP protein in DRGs. Pharmacological and genetic blockade of GRP-GRPR signaling does not significantly affect intrathecal BNP-induced scratching behavior. We show that BNP inhibits inflammatory pain and morphine analgesia.. Accumulating evidence demonstrates that GRP is a key neurotransmitter in pruriceptors for mediating histamine-independent itch. BNP-NPRA signaling is involved in both itch and pain and does not function upstream of the GRP-GRPR dedicated neuronal pathway. The site of BNP action in itch and pain and its relationship with GRP remain to be clarified.

Topics: Animals; Ganglia, Spinal; Gastrin-Releasing Peptide; Gene Expression Regulation; Inflammation; Male; Mice; Mice, Inbred C57BL; Natriuretic Peptide, Brain; Pain; Pruritus; Receptors, Atrial Natriuretic Factor; Receptors, Bombesin; RNA, Messenger; Signal Transduction; Spinal Cord

B-type natriuretic peptide (BNP) has been known to be secreted from cardiac myocytes and activate its receptor, natriuretic peptide receptor-A (NPR-A), to reduce ventricular fibrosis. However, the function of BNP/NPR-A pathway in the somatic sensory system has been unknown. In the present study, we report a novel function of BNP in pain modulation. Using microarray and immunoblot analyses, we found that BNP and NPR-A were expressed in the dorsal root ganglion (DRG) of rats and upregulated after intraplantar injection of complete Freund's adjuvant (CFA). Immunohistochemistry showed that BNP was expressed in calcitonin gene-related peptide (CGRP)-containing small neurons and IB4 (isolectin B4)-positive neurons, whereas NPR-A was present in CGRP-containing neurons. Application of BNP reduced the firing frequency of small DRG neurons in the presence of glutamate through opening large-conductance Ca2+-activated K+ channels (BKCa channels). Furthermore, intrathecal injection of BNP yielded inhibitory effects on formalin-induced flinching behavior and CFA-induced thermal hyperalgesia in rats. Blockade of BNP signaling by BNP antibodies or cGMP-dependent protein kinase (PKG) inhibitor KT5823 [(9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester] impaired the recovery from CFA-induced thermal hyperalgesia. Thus, BNP negatively regulates nociceptive transmission through presynaptic receptor NPR-A, and activation of the BNP/NPR-A/PKG/BKCa channel pathway in nociceptive afferent neurons could be a potential strategy for inflammatory pain therapy.

Topics: Analysis of Variance; Animals; Antibodies; Biophysical Phenomena; Calcitonin Gene-Related Peptide; Carbazoles; Disease Models, Animal; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Excitatory Postsynaptic Potentials; Freund's Adjuvant; Ganglia, Spinal; Gene Expression Regulation; Glutamic Acid; Hyperalgesia; Inflammation; Lectins; Male; Membrane Potentials; Natriuretic Peptide, Brain; Pain; Pain Measurement; Patch-Clamp Techniques; Peptides; Rats; Rats, Sprague-Dawley; Receptors, Atrial Natriuretic Factor; Sensory Receptor Cells; Signal Transduction; Time Factors

To test the hypothesis that B-type natriuretic peptide is elevated in patients with both lumbar spinal stenosis and cardiopulmonary dysfunction who reported sleep-interrupting low back pain, the "symptomatic group," as compared with an analogous cohort not experiencing nocturnal low back pain, i.e., the "control group." B-type natriuretic peptide is a hormonal product of the myocardium, which increases with an elevation in blood volume. Even without clinical symptoms, the more the myocardial stretch, the higher the B-type natriuretic peptide.. In both groups, all of the patients were identified as having lumbar spinal stenosis and a history of cardiopulmonary dysfunction. However, all of the symptomatic group reported initially falling asleep and then experiencing sleep interrupting low back pain. However, in both groups, their cardiac status remained clinically stable. Main outcome measures included both the B-type natriuretic peptide titer and lumbar spinal magnetic resonance imaging.. There were 10 patients with nocturnal pain and eight who were pain-free at night. The magnetic resonance imaging in both cohorts demonstrated a spectrum of moderate to severe lumbar spinal stenosis. Their previous cardiac history varied from the presence of arrhythmias to that of congestive heart failure. Other risk factors including age, among others, were similar in both cohorts. The mean B-type natriuretic peptide titer in the control group was 67.88 +/- 46.58 pg/ml. In the symptomatic group it was significantly elevated to 136.90 +/- 62.14 pg/ml.. In this clinical care series, the B-type natriuretic peptide titer was significantly increased in the symptomatic group as compared with the control group. The standard error of the mean was 19.65 in this group and 16.47 in the control group. An elevated B-type natriuretic peptide reflects a decrement in cardiac efficiency which may not be clinically evident. It also has a profound hypotensive effect because of its diuretic, natriuretic, and vascular dilatory properties. As a direct consequence of the increased right heart filling pressure, retrograde engorgement of the paravertebral plexus of veins surrounding the spinal neural elements may occur. Dilation of these valveless veins within an already stenotic spinal canal may induce the symptoms of Vesper's Curse, i.e., sleep-disrupting lumbar pain as a symptom of spinal stenosis in patients with a history of cardiopulmonary disease.

Topics: Aged; Aged, 80 and over; Cardiovascular Diseases; Case-Control Studies; Female; Humans; Low Back Pain; Lumbar Vertebrae; Magnetic Resonance Imaging; Male; Middle Aged; Natriuretic Peptide, Brain; Pain; Predictive Value of Tests; Severity of Illness Index; Sleep Wake Disorders; Spinal Stenosis