capsazepine and Chronic-Disease

We examined the effects of exposure to chronic intermittent hypoxia (CIH) on baroreflex control of renal sympathetic nerve activity (RSNA) and renal excretory responses to volume expansion (VE) before and after intrarenal transient receptor potential vanilloid 1 (TRPV1) blockade by capsaizepine (CPZ). Male Wistar rats were exposed to 96 cycles of hypoxia per day for 14 days (CIH) or normoxia. Urine flow and absolute Na

Topics: Animals; Arterial Pressure; Baroreflex; Blood Volume; Capsaicin; Chronic Disease; Disease Models, Animal; Diuresis; Heart Rate; Hypoxia; Infusions, Intravenous; Kidney; Male; Natriuresis; Rats, Wistar; Saline Solution; Sympathetic Nervous System; Time Factors; TRPV Cation Channels; Urodynamics

This work aimed to determine the chemical fingerprint of hydroethanolic extract of leaves of Caryocar coriaceum (HELCC) and the gastroprotective activity. The chemical fingerprint of HELCC was analyzed by HPLC-DAD, to quantify total phenols and flavonoids were carried out by Folin-Ciocalteu reagent and aluminum chloride assay, while in vitro antioxidant activity was evaluated by the DPPH method. The methods used to determine pharmacological activity were: gastroprotective screening test in classical models of induced acute and chronic gastric lesions and physical barrier test. Further assays were performed to demonstrate the involvement of NO, prostaglandins, ATP-dependent potassium channels, TRPV, noradrenergic α2 receptors, histamines, and opioids. The DPPH method demonstrated the antioxidant activity of the extract, in vitro, explained by the presence of polyphenols and flavonoids. Oral administration of the extract, previously dissolved in deionized water, at a dose of 100 mg/kg decreased the lesions induced by indomethacin, acidified ethanol, ethanol and acetic acid by 75.0, 72.8, 69.4 and 86.2% respectively. It was demonstrated that opioid receptors, α

Topics: Animals; Antioxidants; Capsaicin; Chromatography, High Pressure Liquid; Chronic Disease; Disease Models, Animal; Ericales; Ethanol; Female; Flavonoids; Gastrointestinal Motility; Glyburide; Histamine; Indomethacin; Male; Mice; Mucus; Naloxone; NG-Nitroarginine Methyl Ester; Phenols; Phytotherapy; Plant Extracts; Plant Leaves; Protective Agents; Stomach Ulcer; Water; Yohimbine

We previously reported that vanilloid receptor type 1 (VR1, or TRPV1) was up-regulated in dorsal root ganglion (DRG) and the spinal dorsal horn after chronic inflammatory pain produced by complete Freund's adjuvant (CFA) injection into the plantar of rat hind paw. In the present study, we found that subcutaneous or intrathecal application of capsazepine (CPZ), a TRPV1 competitive antagonist, could inhibit thermal hyperalgesia on day 1 and on day 14 but not on day 28 after CFA injection. With extracellular electrophysiological recording, the effect of CPZ on noxious electrical or heat stimulation evoked responses of wide dynamic range (WDR) neurons in the deep layers of the spinal dorsal horn was evaluated. Under noxious electrical stimulation to sciatic nerve, CPZ applied to the spinal cord produced an inhibition on Adelta- and C-fiber evoked responses of WDR neurons on day 1 and 14, but not on day 28. Under radiant heat stimulation to the receptive field skin, subcutaneous application of CPZ significantly inhibited the background activity and extended the response latency of WDR neurons on day 14. These results provide new evidence for the functional significance of TRPV1 at the early stage, but not the late stage, in the rat model of CFA-induced inflammatory pain.

Topics: Animals; Capsaicin; Chronic Disease; Electric Stimulation; Evoked Potentials; Freund's Adjuvant; Hot Temperature; Hyperalgesia; Inflammation; Injections, Spinal; Male; Pain; Physical Stimulation; Posterior Horn Cells; Rats; Rats, Sprague-Dawley; Sciatic Nerve; Spinal Cord; TRPV Cation Channels

Cannabidiol, the major psycho-inactive component of cannabis, has substantial anti-inflammatory and immunomodulatory effects. This study investigated its therapeutic potential on neuropathic (sciatic nerve chronic constriction) and inflammatory pain (complete Freund's adjuvant intraplantar injection) in rats. In both models, daily oral treatment with cannabidiol (2.5-20 mg/kg to neuropathic and 20 mg/kg to adjuvant-injected rats) from day 7 to day 14 after the injury, or intraplantar injection, reduced hyperalgesia to thermal and mechanical stimuli. In the neuropathic animals, the anti-hyperalgesic effect of cannabidiol (20 mg/kg) was prevented by the vanilloid antagonist capsazepine (10 mg/kg, i.p.), but not by cannabinoid receptor antagonists. Cannabidiol's activity was associated with a reduction in the content of several mediators, such as prostaglandin E(2) (PGE(2)), lipid peroxide and nitric oxide (NO), and in the over-activity of glutathione-related enzymes. Cannabidiol only reduced the over-expression of constitutive endothelial NO synthase (NOS), without significantly affecting the inducible form (iNOS) in inflamed paw tissues. Cannabidiol had no effect on neuronal and iNOS isoforms in injured sciatic nerve. The compound's efficacy on neuropathic pain was not accompanied by any reduction in nuclear factor-kappaB (NF-kappaB) activation and tumor necrosis factor alpha (TNFalpha) content. The results indicate a potential for therapeutic use of cannabidiol in chronic painful states.

Topics: Administration, Oral; Animals; Cannabidiol; Cannabinoid Receptor Antagonists; Cannabis; Capsaicin; Chronic Disease; Dinoprostone; Freund's Adjuvant; Hyperalgesia; Inflammation; Lipid Peroxides; Male; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Pain; Pain Measurement; Rats; Rats, Wistar; Sciatic Neuropathy; Tumor Necrosis Factor-alpha

The cold- and menthol-sensitive receptor TRPM8 (transient receptor potential melastatin 8) has been suggested to play a role in cold allodynia, an intractable pain seen clinically. We studied how TRPM8 is involved in cold allodynia using rats with chronic constrictive nerve injury (CCI), a neuropathic pain model manifesting cold allodynia in hindlimbs. We found that cold allodynic response in the CCI animals was significantly attenuated by capsazepine, a blocker for both TRPM8 and TRPV1 (transient receptor potential vanilloid 1) receptors, but not by the selective TRPV1 antagonist I-RTX (5-iodoresiniferatoxin). In L5 dorsal root ganglion (DRG) sections of the CCI rats, immunostaining showed an increase in the percentage of TRPM8-immunoreactive neurons when compared with the sham group. Using the Ca2+-imaging technique and neurons acutely dissociated from the L5 DRGs, we found that CCI resulted in a significant increase in the percentage of menthol- and cold-sensitive neurons and also a substantial enhancement in the responsiveness of these neurons to both menthol and innocuous cold. These changes occurred in capsaicin-sensitive neurons, a subpopulation of nociceptive-like neurons. Using patch-clamp recordings, we found that membrane currents evoked by both menthol and innocuous cold were significantly enhanced in the CCI group compared with the sham group. By retrograde labeling afferent neurons that target hindlimb skin, we showed that the skin neurons expressed TRPM8 receptors, that the percentage of menthol-sensitive/cold-sensitive/capsaicin-sensitive neurons increased, and that the menthol- and cold-evoked responses were significantly enhanced in capsaicin-sensitive neurons after CCI. Together, the gain of TRPM8-mediated cold sensitivity on nociceptive afferent neurons provides a mechanism of cold allodynia.

Topics: Animals; Capsaicin; Cells, Cultured; Chronic Disease; Cold Temperature; Disease Models, Animal; Female; Ganglia, Spinal; Hyperalgesia; Ligation; Male; Menthol; Neurons, Afferent; Pain Measurement; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy; Skin; TRPM Cation Channels

Vanilloid receptor 1 (VR1, TRPV1) is a cation-selective ion channel that is expressed on primary afferent neurons and is upregulated following inflammation and nerve damage. Blockers of this channel may have utility in the treatment of chronic nociceptive and neuropathic pain. Here, we describe the optimization from a high throughput screening hit, of a series of 6-aryl-7-isopropylquinazolinones that are TRPV1 antagonists in vitro. We also demonstrate that one compound is active in vivo against capsaicin-induced hyperalgesia and in models of neuropathic and nociceptive pain in the rat.

Topics: Animals; Blood-Brain Barrier; Caco-2 Cells; Cell Membrane Permeability; CHO Cells; Chronic Disease; Cricetinae; Cricetulus; Disease Models, Animal; Humans; In Vitro Techniques; Mice; Micronucleus Tests; Microsomes, Liver; Pain; Quinazolines; Rats; Solubility; Structure-Activity Relationship; TRPV Cation Channels

We have cloned a guinea pig Vanilloid receptor 1 (VR1) from a dorsal root ganglion cDNA library and expressed it in CHO cells. The receptor has been functionally characterized by measuring changes in intracellular calcium produced by capsaicin, low pH and noxious heat. Capsaicin produced a concentration-dependent increase in intracellular calcium in guinea pig VR1-CHO cells with an estimated EC(50) of 0.17 +/- 0.0065 micro M, similar to that previously reported for rat and human VR1. Olvanil and resiniferatoxin were also effective agonists (EC(50) values of 0.0087 +/- 0.0035 micro M and 0.067 +/- 0.014 micro M, respectively), but 12-phenylacetate 13-acetate 20-homovanillate (PPAHV) and anandamide showed little agonist activity up to 10 micro M. As with human and rat VR1, guinea pig VR1 was also activated by pH below 6.0 and by noxious heat (>42 degrees C). Capsazepine acted as an antagonist of capsaicin responses in guinea pig VR1-CHO cells (IC(50) of 0.324 +/- 0.041 micro M ), as seen at rat VR1. However, in contrast to its lack of activity against pH and heat responses at rat VR1, capsazepine was an effective antagonist of these responses at guinea pig VR1. Capsazepine displayed an IC(50) of 0.355 +/- 25 micro M against pH 5.5, and provided complete blockade of heat responses at 1 micro M. Thus, capsazepine can significantly inhibit calcium influx due to heat and pH 5.5 at guinea pig VR1 and human VR1 but is inactive against these activators at rat VR1.

Topics: Aequorin; Amino Acid Sequence; Animals; Calcium; Capsaicin; CHO Cells; Chronic Disease; Cloning, Molecular; Cricetinae; Fluorescent Dyes; Fura-2; Guinea Pigs; Heart; Hydrogen-Ion Concentration; Luminescent Measurements; Molecular Sequence Data; Pain; Rats; Receptors, Drug; TRPV Cation Channels