AIMTo investigate the effect of capsaicin on IA and IK in cultured rat trigeminal ganglion (TG) neurons.

METHODSWhole-cell patch clamp technique was used to record the IA and IK before and after capsaicin perfusion at different concentrations.

RESULTSIn capsaicin-sensitive (CS) neurons, capsaicin was shown to selectively inhibit IA in dose-dependent manner, the IC50 was 0.99 micromol x L(-1). Yet capsaicin showed no inhibitory effect on IK, capsaicin (10 micromol x L(-1)) only slightly inhibited IK by 13.2%. In capsaicin-insensitive (CIS) neurons, capsaicin (1 micromol x L(-1)) showed no significant inhibitory effect on IA and IK, capsaicin (10 micromol x L(-1)) only slightly inhibited IA and IK by 16.8% and 15.3%, respectively. Neither 1 micromol x L(-1) nor 10 micromol x L(-1) capsaicin showed effect on the G-V curve of IA and IK.

CONCLUSIONCapsaicin was found to selectively inhibit the IA current in CS neurons, and this effect may contribute to hyperalgesia when capsaicin was first used.

Animals ; Capsaicin ; pharmacology ; Cells, Cultured ; Female ; Male ; Neurons ; physiology ; Patch-Clamp Techniques ; Potassium Channels, Voltage-Gated ; drug effects ; Rats ; Rats, Sprague-Dawley ; Trigeminal Ganglion ; cytology ; physiology

The present study aimed to investigate whether cannabinoids could modulate the response mediated by ATP receptor (P2X purinoceptor). Whole-cell patch-clamp recording was performed on cultured rat trigeminal ganglionic (TG) neurons. The majority of TG neurons were sensitive to ATP (67/75, 89.33%). Extracellular pretreatment with WIN55212-2, a cannabinoid receptor 1 (CB1 receptor) agonist, reduced ATP-activated current (I(ATP)) significantly. This inhibitory effect was concentration-dependent and was blocked by AM281, a specific CB1 receptor antagonist. Pretreatment with WIN55212-2 at 1×10(-13), 1×10(-12), 1×10(-11), 1×10(-10), 1×10(-9) and 1×10(-8) mol/L reduced I(ATP) (induced by 1×10(-4) mol/L ATP) by (8.14±3.14)%, (20.11±2.72)%, (46.62±3.51)%, (72.16±5.64)%, (80.21±2.80)% and (80.59±3.55)%, respectively. The concentration-response curves for I(ATP) pretreated with and without WIN55212-2 showed that WIN55212-2 shifted the curve downward, and decreased the maximal amplitude of I(ATP) by (58.02±4.21)%. But the threshold value and EC(50) (1.15×10(-4) mol/L vs 1.27×10(-4) mol/L) remained unchanged. The inhibition of I(ATP) by WIN55212-2 was reversed by AM281, suggesting that the inhibition was mediated via the CB1 receptor. Pretreatment with forskolin [an agonist of adenylyl cyclase (AC)] or 8-Br-cAMP reversed the inhibition of I(ATP) by WIN55212-2. These results suggest that the inhibitory effect of cannabinoids on I(ATP) is mediated via the CB1 receptors, that lead to inhibition of the AC-cAMP-PKA signaling pathway.
Adenosine Triphosphate ; physiology ; Animals ; Benzoxazines ; pharmacology ; Cannabinoids ; pharmacology ; Morpholines ; pharmacology ; Naphthalenes ; pharmacology ; Neurons ; drug effects ; physiology ; Patch-Clamp Techniques ; Pyrazoles ; pharmacology ; Rats ; Receptor, Cannabinoid, CB1 ; agonists ; antagonists & inhibitors ; Signal Transduction ; Trigeminal Ganglion ; drug effects ; physiology

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). This study assessed the efficacy and safety of tofacitinib in Chinese patients with RA enrolled in Phase 3 and long-term extension (LTE) studies. Methods: ORAL Sync was a 1-year, randomized, placebo-controlled, Phase 3 trial. Patients received tofacitinib 5 or 10 mg twice daily (BID) or placebo advanced to tofacitinib 5 or 10 mg BID at 3 or 6 months. All patients remained on ≥1 background conventional synthetic disease-modifying antirheumatic drug. ORAL Sequel is an open-label LTE study (data-cut: March 2015; data collection and analyses were ongoing, and study database was not locked at the time of analysis; study was closed in 2017). Efficacy outcomes: American College of Rheumatology (ACR) 20/50/70 response rates and Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-4 [ESR]). Patient- and physician-reported outcomes: Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient and Physician Global Assessment of Arthritis, and pain (visual analog scale). Safety was assessed throughout. Results: ORAL Sync included 218 patients; 192 were subsequently enrolled into ORAL Sequel. In ORAL Sync, more patients achieved ACR20 (tofacitinib 5 mg BID, 67.4%; 10 mg BID, 70.6%; placebo, 34.1%) and DAS28-4 (ESR) <2.6 (tofacitinib 5 mg BID, 7.1%; 10 mg BID, 13.1%; placebo, 2.3%) with tofacitinib versus placebo at Month 6. Mean changes from baseline in HAQ-DI were greater with tofacitinib versus placebo at Month 6. In ORAL Sequel, efficacy was consistent to Month 48. Incidence rates for adverse events of special interest in tofacitinib-treated patients were similar to the global population. Conclusions: Tofacitinib significantly reduced signs/symptoms and improved physical function and quality of life in Chinese patients with moderate-to-severely active RA up to Month 48. The safety profile was consistent with the global population. Clinical Trial Identifier NCT00856544 and NCT00413699.
Administration, Oral ; Adult ; Aged ; Arthritis, Rheumatoid ; drug therapy ; Asian Continental Ancestry Group ; Female ; Humans ; Male ; Middle Aged ; Piperidines ; adverse effects ; therapeutic use ; Protein Kinase Inhibitors ; adverse effects ; therapeutic use ; Pyrimidines ; adverse effects ; therapeutic use ; Pyrroles ; adverse effects ; therapeutic use ; Surveys and Questionnaires ; Young Adult