Josué Vidal Espinosa-Juárez

Antinociceptive effects of a new sigma-1 receptor antagonist (N-(2-morpholin-4-yl-ethyl)-2-(1-naphthyloxy)acetamide) in two types of nociception

Pain has become an active clinical challenge due its etiological heterogeneity, symptoms and mechanisms of action. In the search for new pharmacological therapeutic alternatives, sigma receptors have been proposed as drug targets. This family consists of sigma-1 and sigma-2 receptors. The sigma-1 system is involved in nociception through its chaperone activity. Additionally, it has been shown that agonist to these receptors promote related sensitisation and pain hypersensitisation, suggesting the possible use of antagonists for sigma-1 receptors as an alternative therapy. The aim of this study was to evaluate the antinociceptive effect of a new sigma-1 receptor antagonist N-(2-morpholin-4-yl-ethyl)-2-(1-naphthyloxy)acetamida (NMIN) in two types of pain (arthritic and neuropathic) and to compare its efficacy and potency with reference drugs. The antinociceptive effects of NMIN were quantitatively evaluated using the pain-induced functional impairment model in the rat and the acetone test in a rat model of neuropathic pain. NMIN (sigma-1 receptor affinity of 324nM) did not show any antinociceptive activity in the arthritic pain model but showed a dose-dependent anti-allodynic effect in neuropathic pain. NMIN showed a similar efficacy compared to the effects obtained with morphine and the sigma-1 antagonist BD-1063. However, these reference drugs showed increased potency compared with NMIN. Our results suggest that sigma-1 receptors may play an important direct role in neuropathic pain but not in arthritic pain, supporting the hypothesis that NMIN may be useful for the treatment of neuropathic pain.

The Antinociceptive Effects of Tramadol and/or Gabapentin on Rat Neuropathic Pain Induced by a Chronic Constriction Injury

Preclinical Research

Haloperidol Decreases Hyperalgesia and Allodynia Induced by Chronic Constriction Injury

Neuropathic pain has proven to be a difficult condition to treat, so investigational therapy has been sought that may prove useful, such as the use of sigma‐1 antagonists. Haloperidol (HAL) is a compound that shows a high affinity with these receptors, acting as an antagonist. Therefore, the objective of this study was to demonstrate its effect in an experimental model of neuropathic pain and corroborate its antagonistic action of the sigma‐1 receptors under these conditions. BD‐1063 was used as a sigma‐1 antagonist control, and gabapentin (Gbp) was used as a positive control. The antihyperalgesic and anti‐allodynic effects of the drugs were determined after single‐dose trials. In every case, the effects increased in a dose‐dependent manner. HAL had the same efficacy as both BD‐1063 and Gbp. In the analysis of pharmacological potency, in which the ED50 were compared, HAL was the most potent drug of all. The effect of HAL on chronic constriction injury (CCI) rats was reversed by the sigma‐1 agonist (PRE‐084). HAL reversed the hyperalgesic and allodynic effects of PRE‐084 in naïve rats. The dopamine antagonist, (‐)‐sulpiride, showed no effect in CCl rats. These results suggest that HAL presents an antinociceptive effect via sigma‐1 receptor antagonism at the spinal level in the CCl model.

Antinociceptive Interactions Between Meloxicam and Gabapentin in Neuropathic Pain Depend on the Ratio used in Combination in Rats.

Preclinical Research

Nociceptive Alteration by High Sucrose Diet in Hypoestrogenic Wistar Rats.

Preclinical Research

Beneficial effects of lipidic extracts of saladette tomato pomace and Serenoa repens on prostate and bladder health in obese male Wistar rats: Effects of natural extracts on prostate and bladder health in obese rats

BACKGROUND Obesity is associated with increased risk of a number of serious medical conditions, including urological disorders. This study investigated the effect of lipidic extracts of saladette tomato pomace (STP) and Serenoa repens (SR) on the prostate and bladder in a rat obese model induced by high-carbohydrate diet. RESULTS High-sucrose-fed rats showed higher prostate weight as well as increased contractility and stromal and epithelial hyperplasia in the prostate. Treatment with STP and SR improved contractility and diminished hyperplasia and hypertrophy in the prostate. Obese animals also showed impaired bladder contractility, but neither extract reversed this deterioration. In the histological study, a disarray in the process of smooth muscle cell proliferation with non-parallel fibers was observed; interestingly, treatment with STP and SR led to improvement in this derangement. CONCLUSION These findings indicated impaired contractility and hyperplasia in the prostate and bladder of obese rats induced by high sucrose. STP and SR could enhance prostate function by reducing contractility and hyperplasia and improve smooth muscle fiber structure and decrease cell proliferation in the bladder, suggesting their possible health-beneficial effects on lower urinary tract symptoms.

N-(2-morpholin-4-yl-ethyl)−2-(1naphthyloxy)acetamide inhibits the chronic constriction injury-generated hyperalgesia via the antagonism of sigma-1 receptors

&NA; The most used therapeutic treatment to relieve neuropathic pain is that of neuromodulators such as anti‐epileptics or anti‐depressants; however, there are alternatives that may be potentially useful. The sigma‐1 receptor is a therapeutic target that has shown favorable results at preclinical levels. The aim of this study was to evaluate the anti‐hyperalgesic effect of N‐(2‐morpholin‐4‐yl‐ethyl)‐2‐(1‐naphthyloxy) acetamide (NMIN) in a chronic constriction injury model (CCI) and compare it both a sigma‐1 antagonist (BD‐1063) and also Gabapentin, as well as determine its possible role as an antagonist of sigma‐1 receptors. The anti‐hyperalgesic effects of Gabapentin (10.0, 17.8, 31.6, 56.2 and 100 mg/kg, s.c.), BD‐1063 (5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg, s.c.) and NMIN (31.6, 10.0, 316 mg/kg and 562 mg/kg, s.c.) were determined after single‐doses, using the von Frey test in the CCI model. NMIN had the same efficacy as BD‐1063, but both show less efficacy than Gabapentin. In an analysis of pharmacological potency, the ED50 were compared with it being found that BD‐1063 is the most potent drug, followed by Gabapentin and NMIN. The anti‐hyperalgesic effect of NMIN on CCI rats was reversed by (+)‐pentazocine (s.c. route) and by PRE‐084 (i.t. route), both sigma‐1 agonists. Furthermore, NMIN reversed the hyperalgesic effect of PRE‐084 in naïve rats. These results suggest that NMIN has an anti‐hyperalgesic effect on the CCI model, and that one of its mechanisms of action is as a sigma‐1 antagonist, being a significant role the blocking of these receptors at the spinal level.

Antinociceptive Effect of Racemic Flurbiprofen and Caffeine Co-Administration in an Arthritic Gout-Type Pain in Rats

Preclinical Research