Pharmacology/Drug Development

Aripiprazole is an antipsychotic drug used to treat schizophrenia and bipolar disorder. Recently, its peripheral analgesic component was evaluated, however, the mechanism involved in this effect is not fully established. Therefore, the aim of the study was to obtain pharmacological evidence for the involvement of the nitric oxide system in the peripheral antinociceptive effect induced by aripiprazole. The hyperalgesia was induced via intraplantar injection of prostaglandin E in mice and the nociceptive thresholds evaluated using the paw pressure test. All drugs were injected locally into the right hind paw. The PI3K inhibitor (AS605240), but not rapamycin (mTOR kinase inhibitor), reversed the peripheral antinociceptive effect induced by Aripiprazole. Antinociception was antagonized by the non-selective inhibitor of the nitric oxide synthase (L-NOarg). The same response was observed using the selective iNOS, but not with the selective nNOS inhibitors. The selective guanylyl cyclase enzyme inhibitor (ODQ) and the non-selective potassium channel blocker tetraethylammonium were able to reverse the antinociceptive effect of aripiprazole. The same was seen using glibenclamide, an ATP-dependent K channel blocker. However, calcium-activated potassium channel blockers of small and high conductance, dequalinium chloride and paxilline respectively, did not reverse this effect. The injection of cGMP-specific phosphodiesterase type 5 inhibitor zaprinast, potentiated the antinociceptive effect induced by a low dose of aripiprazole. The results provide evidence that aripiprazole induces peripheral antinociceptive effects via PI3K/NO/cGMP/K pathway activation.

Although new drugs are being developed for cancer treatment, classical chemotherapeutic agents are still front-line therapies, despite their frequent association with severe side effects that can hamper their use. Cannabinoids may prevent or palliate some of these side effects. The aim of the present study is to review the basic research which has been conducted evaluating the effects of cannabinoid drugs in the treatment of three important side effects induced by classical chemotherapeutic agents: nausea and vomiting, neuropathic pain and cognitive impairment. Several published studies have demonstrated that cannabinoids are useful in preventing and reducing the nausea, vomits and neuropathy induced by different chemotherapy regimens, though other side effects can occur, such as a reduction of gastrointestinal motility, along with psychotropic effects when using centrally-acting cannabinoids. Thus, peripherally-acting cannabinoids and new pharmacological options are being investigated, such as allosteric or biased agonists. Additionally, due to the increase in the survival of cancer patients, there are emerging data that demonstrate an important cognitive deterioration due to chemotherapy, and because the cannabinoid drugs have a neuroprotective effect, they could be useful in preventing chemotherapy-induced cognitive impairment (as demonstrated through studies in other neurological disorders), but this has not yet been tested. Thus, although cannabinoids seem a promising therapeutic approach in the treatment of different side effects induced by chemotherapeutic agents, future research will be necessary to find pharmacological options with a safer profile. Moreover, a new line of research awaits to be opened to elucidate their possible usefulness in preventing cognitive impairment.

This article discusses publications assessing the prevalence, efficacy, and safety of opioid analgesics in patients with rheumatic diseases, including rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, and systemic sclerosis.

Opioid analgesics are widely used to treat acute, postoperative, and chronic pain. However, opioid receptor activation can result in severe respiratory depression. In this study, we demonstrated that Tandospirone (TS), a selective serotonin-1A receptor partial agonist, is effective against opioid-induced respiratory depression. Fentanyl was used to establish a respiratory depression model in rodents. We observed the effects of TS on respiratory depression in rats by using plethysmographic recordings and arterial oxygen saturation. In addition, we evaluated the effects of TS on fentanyl-induced sedation and analgesia by using the loss of righting reflex (LORR) and hot-plate tests, respectively. Rats (n = 5) were treated with TS or saline 5 min prior to fentanyl administration. TS [2 mg/kg, intravenous (i.v.)] dose-dependently attenuated fentanyl-induced respiratory depression versus saline + fentanyl group. Furthermore, pre-treatment with TS (2 mg/kg, i.v.) increased arterial oxygen saturation to 76.5 ± 2.0% at 5 min after fentanyl injection, compared with 35.9 ± 2.5% in saline pre-treated rats (P < 0.001), whereas the time to induction of LORR (P > 0.99) and duration of LORR (P = 0.95) did not differ between the "TS + fentanyl" and "saline + fentanyl" group. The antinociceptive effect of fentanyl was not affected by the administration of TS (P = 0.99) in mice (n = 10). In conclusion, we found that TS, a novel non-benzodiazepine anxiolytic/antidepressant drug, could attenuate severe fentanyl-induced respiratory depression and did not affect the analgesic/sedative effect of fentanyl. The clinical application of TS could significantly improve pain management.

P2X receptors are ATP-gated trimeric nonselective cation channels that are important for various physiological and pathological processes, including synaptic transmission, pain perception, immune regulation and apoptosis. Accordingly, they attract a wide range of interest as drug targets, such as those for chronic cough, neuropathic pain and depression. After the zebrafish P2X4 receptor structure was reported in 2009, various other P2X receptor structures have been reported, extending our understanding of the molecular mechanisms of P2X receptors. This review article describes the recent progress on understanding the structures and mechanisms of P2X receptors, especially of the mechanisms underlying ATP binding and conformational changes during the gating cycle. In addition, since several antagonists for different P2X subtypes have entered into clinical trials, this review also summarizes the binding sites and regulatory mechanisms of these antagonists, which may contribute to new strategies of targeting P2X receptors for drug discovery. This article is protected by copyright. All rights reserved.

Long-term opioid treatment in patients with chronic pain is often ineffective and possibly harmful. These patients are often managed by general practitioners, who are calling for a clear overview of effective opioid reduction strategies for primary care.

Nowadays, there are various methods to manage pain after laparoscopic cholecystectomy. The aim of this study was to compare the effectof preemptive versus postoperative use of ultrasound-guided transversus abdominis plane (USG-TAP) block on pain relief after laparoscopic cholecystectomy. In this single-blinded randomized clinical trial, the patients who were candidates for laparoscopic cholecystectomy were randomly divided into the two groups (n = 38 per group). In the preemptive group (PG) after the induction of anesthesia and in the postoperative group (POG) after the end of surgery and before the extubation, bilateral ultrasound-guided transversus abdominis plane (TAP) block was performed on patients using 20 cc of ropivacaine 0.25%. Both groups received patient controlled IV analgesia (PCIA) containing Acetaminophen (20 mg/ml) plus ketorolac (0.6 mg/ml) as a standard postoperative analgesia and meperidine 20 mg q 4 h PRN for rescue analgesia. Using the numerical rating scales (NSR), the patients' pain intensity was assessed at time of arrival to the PACU and in 2th, 4th, 8th, 12th, 24th h. Primary outcome of interest is NSR at rest and coughing in the PACU and in 2th, 4th, 8th, 12th, 24th h. Secondary outcomes of interests were the time to first post-surgical rescue analgesic and level of patients' pain control satisfaction in the first 24 h. The USG-TAP block significantly decreased pain score in the POG compared to the PG, and also the pain was relieved at rest especially in 8 and 12 h (p value ≤ 0.05) after the surgery. Pain score after coughing during recovery at 2, 8 and 12 h after the operation were significantly decreased. (p value ≤ 0.05) The patient satisfaction scores in the POG were significantly higher in all times. There was a statistically significant difference between the two groups in terms of rate of postoperative nausea and vomiting (PONV), indicating that patients in the POG had significantly lower incidences of the PONV compared tothe PG. The time to first analgesic request was significantly shorterin the POG, which was statistically significant (p value = 0.089). There was no statistically significant difference between the two groups in terms of consumption of analgesics. The postoperative TAP block could offer better postoperative analgesia than preepmtive TAP block.