Sigma-1 receptor agonist, (+)-pentazocine, is neuroprotective in a Brown Norway rat microbead model of glaucoma.

PURPOSE: Glaucoma is a worldwide leading cause of irreversible blindness. Standard treatments lower intraocular pressure (IOP). Novel treatments to prevent optic nerve (ON) degeneration are needed. Here, we investigate the hypothesis that sigma-1 receptor (S1R) agonist (+)-pentazocine (PTZ) is neuroprotective in a Brown Norway (BN) rat, microbead model of glaucoma. METHODS: BN rats (9-11 weeks, male and female) were treated by intraperitoneal injection, 3 times per week with (+)-PTZ (2 mg/kg) or vehicle (VEH) alone. Treatment started 1 week prior to intraocular injection of polystyrene microbeads to elevate IOP. IOP was measured 2-3 times per week. Five weeks post microbead injection, rats were euthanized. ONs were removed, then fixed and processed for 63x oil, light microscope imaging of toluidine blue stained ON cross sections. To facilitate comparison of ON morphology from VEH and (+)-PTZ treated rats with similar ocular hypertensive insults, rats were assigned to low (IOP ≤15.8 mmHg), moderate (15.8 < IOP <28.0 mmHg), and high (IOP ≥28.0 mmHg) groups based on average IOP in the microbead injected eye. Axon numbers, axon density, axonal and glial areas, axon loss, and axon size distributions of naïve, bead, and contralateral ONs were assessed using QuPath program for automated image analysis. RESULTS: (+)-PTZ treatment of BN rats protected ONs from damage caused by moderate IOP elevation. Treatment with (+)-PTZ significantly reduced axon loss and glial areas, and increased axon density and axonal areas compared to ONs from VEH treated rats with moderate IOP. (+)-PTZ-mediated neuroprotection was independent of IOP lowering effects. At average IOP ≥28.0 mmHg, (+)-PTZ treatment did not provide measurable neuroprotection. ONs from contralateral eyes exhibited subtle, complex changes in response to conditions in the bead eyes. CONCLUSIONS: S1R agonist (+)-PTZ shows promise as a neuroprotective treatment for glaucoma. Future studies to understand the complex molecular mechanisms by which (+)-PTZ provides this neuroprotection are needed.

Intra-articular injection versus interscalene brachial plexus block for acute-phase postoperative pain management after arthroscopic shoulder surgery.

BACKGROUND: The minimally invasive approach of arthroscopic shoulder surgery is beneficial; however, for optimal outcomes, perioperative pain management is essential. This cross-sectional study aimed to examine the analgesic effectiveness of intra-articular injection (IA) versus interscalene brachial plexus block (ISPB) among patients treated with arthroscopic shoulder surgeries. METHODS: We reviewed 100 consecutive patients who underwent shoulder arthroscopic surgery, of whom 50 each underwent IA (February 2019─January 2020; IA group) and ISPB (October 2018─July 2019; ISPB group). The primary outcome was the postoperative pain score measured using a Wong-Baker FACES Pain Rating Scale preoperatively and at 2, 6, 12, 24, and 48 h postoperatively. We performed multiple regression analysis to examine whether IA/ISPB selection is associated with acute-phase postoperative pain and adjusted for intra-articular injection, interscalene brachial plexus block, postoperative pain management, arthroscopic shoulder surgery, IA with 10 mg of morphine previously reported prognostic factors for postoperative pain (e.g., surgical procedures, operative time, older age, and preoperative pain). Furthermore, we examined induction time, total pentazocine dosage, and total postoperative nausea and vomiting (PONV) events. RESULTS: There were no significant differences between the IA and ISPB groups in perioperative pain control during the acute-phase periods (p = 0.12, repeated analysis of variance). The difference in anesthesia method was not a prognostic factor for acute-phase postoperative pain (p = 0.11). The IA group (15.06 ± 4.00 min) had a significantly shorter mean anesthesia induction time than the ISPB group (29.23 ± 9.22 min) (p = 0.0001). There was no significant between-group difference in the total pentazocine dosage during the first 7 days (p = 0.3934) postoperatively. PONV was observed in eight (17.0%) and two (4.2%) patients in the IA and ISPB groups, respectively. There was no significant between-group difference in the PONV incidence (p = 0.1582). CONCLUSIONS: There was no significant difference in acute-phase postoperative pain management between the IA and ISPB groups. The induction time was significantly shorter in IA. IRB: Approval number: UOEHCRB20-078, IRB approval date: September 9th, 2020; study duration: October 2018 to January 2020.

Pharmacokinetic/Pharmacodynamic Modeling and Simulation of the Analgesic Effects of Pentazocine Using Perioperative Real-World Data.

Pentazocine (PTZ) is a widely used drug for postoperative pain. It should be administered at appropriate dosing intervals not only because of its morphine-like side effects but also because frequent inappropriate dosing can lead to dependence. Although perioperative patients reportedly have nonnegligible effects on placebo drugs and postoperative wound healing, no pharmacokinetic (PK)/pharmacodynamic (PD) model has been established and simulated using real-world data for the perioperative period. This study aimed to perform PTZ modeling and simulation and to establish an indicator of the timing of drug efficacy evaluation in clinical practice. Participants were in-hospital orthopedic surgery patients who received 15 mg of PTZ within 48 h postoperatively. Pain severity was assessed using the numerical rating scale (NRS). A two-compartment model was selected for the population PK model and an indirect response model for the PK/PD model. Using these models, a virtual population of 1000 patients with Painbase NRS of 5 and 6 and body weights of 40, 80, and 120 kg were treated with single and multiple PTZ administrations (4, 8, and 24 h apart) of 15 mg. Simulation results indicate that its analgesic efficacy should be evaluated within 1 h after administration of 15 mg of PTZ. Additional doses should be considered every 8-12 h in postoperative patients with Painbase NRS of 5 weighing 40-80 kg. Simulation using the PK/PD model developed in this study may provide useful information for determining the analgesic effects and timing of the dosing interval after PTZ administration in perioperative patients.

Novel High Affinity Sigma-1 Receptor Ligands from Minimal Ensemble Docking-Based Virtual Screening.

Sigma-1 receptor (S1R) is an intracellular, multi-functional, ligand operated protein that also acts as a chaperone. It is considered as a pluripotent drug target in several pathologies. The publication of agonist and antagonist bound receptor structures has paved the way for receptor-based in silico drug design. However, recent studies on this subject payed no attention to the structural differences of agonist and antagonist binding. In this work, we have developed a new ensemble docking-based virtual screening protocol utilizing both agonist and antagonist bound S1R structures. This protocol was used to screen our in-house compound library. The S1R binding affinities of the 40 highest ranked compounds were measured in competitive radioligand binding assays and the sigma-2 receptor (S2R) affinities of the best S1R binders were also determined. This way three novel high affinity S1R ligands were identified and one of them exhibited a notable S1R/S2R selectivity.

The efficacy of pentazocine + diclofenac versus paracetamol + diclofenac for post- caesarean section analgesia.

BACKGROUND: The most common major obstetric procedure is caesarean section (CS) and one of the greatest concerns for women after CS is to have optimal pain relief. AIM: This study aims to compare the efficacy of pentazocine + diclofenac and paracetamol + diclofenac on post-operative analgesia after CS. METHODOLOGY: This was a single-blind, randomised trial. Pregnant women that had CS were randomized into two groups. Group A received intramuscular pentazocine + rectal diclofenac postoperatively. Group B received intramuscular paracetamol + rectal diclofenac postoperatively. Post-operative pain was assessed by numeric rating scale at 1 h after the surgery, at 6 h, 12 h and 24 h. The result obtained was analysed using SPSS Version 22 and P < 0.05 was considered statistically significant. RESULTS: The median pain scores in both groups ranged from 2 to 3 across all periods of assessment. The pain relief was slightly better in the pentazocine + diclofenac group with no significant difference in the pain score between the two groups at all periods of assessment. The satisfaction level was good in 66.3% and 69.5% of the participants in the pentazocine + diclofenac and paracetamol + diclofenac group respectively but the difference was not statistically significant (χ2 = 4.14, P = 0. 12). Nausea, vomiting and drowsiness were significantly more in the pentazocine + diclofenac combination (P < 0.001). CONCLUSION: Both combination of analgesics provided adequate analgesia but pentazocine + diclofenac combination had better pain relief but was more associated with side effects.

Distinct Regulation of σ 1 Receptor Multimerization by Its Agonists and Antagonists in Transfected Cells and Rat Liver Membranes.

Extensive studies have shown that the σ 1 receptor (σ 1R) interacts with and modulates the activity of multiple proteins with important biological functions. Recent crystal structures of σ 1R as a homotrimer differ from a dimer-tetramer model postulated earlier. It remains inconclusive whether ligand binding regulates σ 1R oligomerization. Here, novel nondenaturing gel methods and mutational analysis were used to examine σ 1R oligomerization. In transfected cells, σ 1R exhibited as multimers, dimers, and monomers. Overall, σ 1R agonists decreased, whereas σ 1R antagonists increased σ 1R multimers, suggesting that agonists and antagonists differentially affect the stability of σ 1R multimers. Endogenous σ 1R in rat liver membranes also showed similar regulation of oligomerization as in cells. Mutations at key residues lining the trimerization interface (Arg119, Asp195, Phe191, Trp136, and Gly91) abolished multimerization without disrupting dimerization. Intriguingly, truncation of the N terminus reduced σ 1R to apparent monomer. These results demonstrate that multiple domains play crucial roles in coordinating high-order quaternary organization of σ 1R. The E102Q σ 1R mutant implicated in juvenile amyotrophic lateral sclerosis formed dimers only, suggesting that dysregulation of σ 1R multimeric assembly may impair its function. Interestingly, oligomerization of σ 1R was pH-dependent and correlated with changes in [3H](+)-pentazocine binding affinity and Bmax Combined with mutational analysis, it is reasoned that σ 1R multimers possess high-affinity and high-capacity [3H](+)-pentazocine binding, whereas monomers likely lack binding. These results suggest that σ 1R may exist in interconvertible oligomeric states in a dynamic equilibrium. Further exploration of ligand-regulated σ 1R multimerization may provide novel approaches to modulate the function of σ 1R and its interacting proteins. SIGNIFICANCE STATEMENT: The σ 1 receptor (σ 1R) modulates the activities of various partner proteins. Recently, crystal structures of σ 1R were elucidated as homotrimers. This study used novel nondenaturing gel methods to examine σ1R oligomerization in transfected cells and rat liver membranes. Overall, agonist binding decreased, whereas antagonist binding increased σ 1R multimers, which comprised trimers and larger units. σ 1R multimers were shown to bind [3H](+)-pentazocine with high affinity and high capacity. Furthermore, mutational analysis revealed a crucial role of its N-terminal domain in σ 1R multimerization.

Pentazocine, a Kappa-Opioid Agonist, Is Better Than Diclofenac for Analgesia in Acute Pancreatitis: A Randomized Controlled Trial.

OBJECTIVES: The ideal analgesic is not known for patients with acute pancreatitis (AP). Concerns have been raised about serious adverse effects of opioid analgesics increasing the severity of AP. We hypothesized that nonsteroidal anti-inflammatory drugs might be better analgesics because of their anti-inflammatory effect. Our objective was to compare pentazocine, an opioid, and diclofenac, a nonsteroidal anti-inflammatory drug, for adequate analgesia in patients with AP. METHODS: In a double-blind randomized controlled trial, patients with AP were randomized to either intravenous diclofenac 75 mg or pentazocine 30 mg. Fentanyl was given as a rescue analgesic through a patient-controlled analgesia pump. Primary outcome was pain relief measured objectively by the dose of fentanyl required as the rescue analgesic, pain-free period, and numbers of effective and ineffective demands of fentanyl. Secondary outcome was adverse events. RESULTS: Fifty patients were randomized, 24 to the pentazocine group and 26 to the diclofenac group. Baseline characteristics were comparable between the groups. Pentazocine was found to be better than diclofenac in terms of significantly lower dose of the rescue analgesic (fentanyl) required (126 µg (interquartile range (IQR) 65-218 µg) vs 225.5 µg (IQR 133-427 µg); P = 0.028) and longer pain-free period (31.1 ± 8.2 vs 27.9 ± 6.6 hours, P = 0.047). The number of effective and ineffective demands was lower in the pentazocine group compared with the diclofenac group (11.5 (IQR 8-15) vs 16 (IQR 13-20), P = 0.098) although not statistically significant. Adverse events were similar between the groups. CONCLUSIONS: Pentazocine, a kappa-opioid receptor agonist, was significantly better than diclofenac for pain relief in AP (Trial registration number: CTRI/2016/09/007326).

A Novel Mechanism of Sigma 1 Receptor Neuroprotection: Modulation of miR-214-3p.

Retinitis pigmentosa (RP) is a blinding disease for which there is no known cure. In a recent study, we reported dramatic rescue of cones in the rd10 mouse model of RP when mice were treated systemically with (+)-pentazocine ((+)-PTZ), a high-affinity ligand for sigma 1 receptor (Sig1R). The molecular mechanisms by which Sig1R provides neuroprotection are unclear. In this report, we used a miRNA PCR array to compare 84 abundantly expressed, well-characterized miRNAs in rd10/Sig1R-/- vs. rd10 and rd10 + PTZ vs. rd10 mice. We found that 13 miRNAs were significantly increased in rd10/Sig1R-/- retinas but were significantly decreased in rd10 + PTZ retinas. The miRNAs were miR-9-5p, miR-27a-3p, miR-126a-5p, miR-146a-5p, miR-10a-5p, miR-34c-5p, miR-503-5p, miR-30c-5p, miR-199-5p, miR-541-5p, miR-214-3p, miR-218-5p, and miR-335-5p. Of these, miR-214-3p is closely related to oxidative stress modulation, which is relevant to degenerative retinopathy. MiR-214-3p expression is ~fivefold higher in rd10/Sig1R-/- vs. rd10. In contrast, miR-214-3p is decreased ~twofold in rd10 + PTZ vs. rd10. Interestingly, miR-214-3p is predicted to bind to Sig1R and Nrf2, a key transcription factor for modulation of oxidative stress. To our knowledge, this is the first evidence that Sig1R may interact with miRNAs in retina. This observation is the underpinning of our hypothesis that a novel mechanism by which Sig1R mediates cone rescue is via interaction with miR-214-3p.

Relationship between Sigma-1 receptor and BDNF in the visual system.

Glaucoma is an incurable optic neuropathy characterized by dysfunction and death of retinal ganglion cells (RGCs). Brain derived neurotrophic factor (BDNF) is an essential neurotrophin that supports RGC function and survival. Despite BDNF's importance, our knowledge of molecular mechanisms that modulate BDNF processing and secretion is incomplete. Sigma-1 receptor (S1R) is associated with increased BDNF in hippocampus and with BDNF secretion by brain-derived astrocytes and neuronal cell lines. Much less is known about the relationship between S1R and BDNF in the visual system. Here, we examine how S1R activation and deletion alter expression of mature BDNF (mBDNF) and proBDNF in retina and cultured optic nerve head (ONH) astrocytes. For S1R activation, the S1R agonist (+)-pentazocine (PTZ, 0.5 mg/kg) was administered by intraperitoneal injection to C57BL/6J mice, 3 times per week, for 5 weeks. Expression of proBDNF and mBDNF was also examined in S1R knockout and age-matched C57BL/6J mice. In vitro, cultured ONH astrocytes were treated with 3 µM PTZ for 24 h followed by collection of media and ONH astrocyte lysates. Results showed that treatment with (+)-PTZ increased mBDNF protein in both retina and hippocampus. In contrast, S1R deletion was associated with retinal mBDNF deficits. In ONH astrocytes S1R agonist (+)-PTZ significantly increased levels of secreted BDNF and proBDNF in cell lysates. These findings support a role for S1R in the modulation of BDNF levels within the retina and optic nerve head. Treatment with S1R agonists might provide benefit in diseases such as glaucoma by increasing BDNF levels from endogenous sources.

Thiamylal Plus Pentazocine Shows Similar Efficacy as Ketamine Plus Midazolam for Painful Procedures in Children With Leukemia.

This retrospective study compared the use of thiamylal plus pentazocine (TP) to ketamine plus midazolam (KM) in children with leukemia who were undergoing bone marrow aspiration and/or intrathecal chemotherapy. A total of 268 procedures in 35 children with leukemia were retrospectively analyzed for efficacy and adverse events. All procedures were successfully completed without severe adverse events. TP induced significantly faster sedation. The incidents of desaturation were significantly greater in the TP group, but were transient and recovered by oxygen supplementation alone. Therefore, TP can be a useful combination with a similar efficacy as KM for painful procedures in children.

Enhancement of Dissolution and Skin Permeability of Pentazocine by Proniosomes and Niosomal Gel.

Proniosomes (PN) are the dry water-soluble carrier systems that may enhance the oral bioavailability, stability, and topical permeability of therapeutic agents. The low solubility and low oral bioavailability due to extensive first pass metabolism make Pentazocine as an ideal candidate for oral and topical sustained release delivery. The present study was aimed to formulate the PNs by quick slurry method that are converted to niosomes (liquid dispersion) by hydration, and subsequently formulated to semisolid niosomal gel. The PNs were found in spherical shape in the SEM and stable in the physicochemical and thermal analysis (FTIR, TGA, and XRD). The quick slurry method produced high recovery (> 80% yield) and better flow properties (θ = 28.1-37.4°). After hydration, the niosomes exhibited desirable entrapment efficiency (44.45-76.23%), size (4.98-21.3 µm), and zeta potential (- 9.81 to - 21.53 mV). The in vitro drug release (T100%) was extended to more than three half-lives (2-4 h) and showed good fit to Fickian diffusion indicated by Korsmeyer-Peppas model (n = 0.136-0.365 and R2 = 0.9747-0.9954). The permeation of niosomal gel was significantly enhanced across rabbit skin compared to the pure drug-derived gel. Therefore, the PNs are found promising candidates for oral as dissolution enhancement and sustained release for oral and topical delivery of pentazocine for the management of cancer pain.

Prophylactic Pentazocine Reduces the Incidence of Pruritus After Cesarean Delivery Under Spinal Anesthesia With Opioids: A Prospective Randomized Clinical Trial.

BACKGROUND: The incidence of pruritus after cesarean delivery under spinal anesthesia with opioids is high, ranging from 50% to 100%. Pruritus is difficult to prevent; however, pentazocine has been shown to be an effective treatment. Despite this, the prophylactic effect of pentazocine on pruritus has not been defined. This randomized double-blind trial aimed to evaluate the effect of intraoperative IV pentazocine on the incidence of opioid-induced pruritus within the first 24 hours after administration of neuraxial opioids. METHODS: We obtained institutional review board approval and written informed consent from the 122 patients (American Society of Anesthesiologists [ASA] physical status II; aged 20-40 years) scheduled for elective cesarean delivery who were included in this study. Spinal anesthesia was performed with 10 mg of 0.5% hyperbaric bupivacaine, 10 µg of fentanyl, and 100 µg of morphine. After delivery of the baby and placenta, the parturient women were randomized to intravenously receive 15 mg (1 mL) of pentazocine or 1 mL of saline. All women received postoperative analgesia with the epidural infusion of 0.15% levobupivacaine. The presence of pruritus within the first 24 hours after intrathecal administration of opioids was recorded, and severity of itch, numerical rating scale (NRS) for pain, and adverse effects were also recorded at the time of the arrival on the ward, as well as 3, 6, 12, and 24 hours after the intrathecal administration of opioids. RESULTS: A total of 119 women completed the study. IV pentazocine reduced the overall incidence of pruritus within the first 24 hours compared to IV saline, with an estimated relative risk of 69% (95% confidence interval [CI], 52%, 90%; P = .007). IV pentazocine also reduced the severity of pruritus. The incidence of nausea and vomiting was not significantly different. There were no significant differences in postoperative NRS scores. CONCLUSIONS: A single 15-mg dose of IV pentazocine after delivery can reduce both the incidence and severity of pruritus in women who have received subarachnoid opioids during cesarean delivery.

Cohort study of pain symptoms and management following impacted mandibular third molar extraction.

OBJECTIVE: The aim of this study was to investigate the possibility of intravenous sedation as a useful pain-relieving option for impacted third molar extractions. SUBJECTS AND METHODS: A prospective cohort study was conducted among patients who underwent bilateral mandibular third molar extractions under local anaesthesia and intravenous sedation (sedation group) and patients who underwent unilateral mandibular third molar extraction under local anaesthesia alone (local anaesthesia group). The frequency of use of postoperative oral analgesia and the intensity of pain assessed using the full cup test were compared between the two groups. RESULTS: The maximum pain intensity (0-100) on postoperative day 1 in the sedation and local anaesthesia groups was 72.8 ± 16.98 and 84.8 ± 15.84, respectively, and the mean pain intensity was 42.2 ± 16.00 and 49.6 ± 18.94. The maximum and mean pain intensities in the sedation group were significantly milder than those in the local anaesthesia group. The number of oral analgesic doses in the sedation group was significantly smaller on the day of surgery and on postoperative day 1 than in the local anaesthesia group. CONCLUSIONS: The results of this study suggest that bilateral impacted mandibular third molar extractions under intravenous sedation could be a recommended treatment option.

Blockade of Cocaine or σ Receptor Agonist Self Administration by Subtype-Selective σ Receptor Antagonists.

The identification of sigma receptor (σR) subtypes has been based on radioligand binding and, despite progress with σ1R cellular function, less is known about σR subtype functions in vivo. Recent findings that cocaine self administration experience will trigger σR agonist self administration was used in this study to assess the in vivo receptor subtype specificity of the agonists (+)-pentazocine, PRE-084 [2-(4-morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride], and 1,3-di-o-tolylguanidine (DTG) and several novel putative σR antagonists. Radioligand binding studies determined in vitro σR selectivity of the novel compounds, which were subsequently studied for self administration and antagonism of cocaine, (+)-pentazocine, PRE-084, or DTG self administration. Across the dose ranges studied, none of the novel compounds were self administered, nor did they alter cocaine self administration. All compounds blocked DTG self administration, with a subset also blocking (+)-pentazocine and PRE-084 self administration. The most selective of the compounds in binding σ1Rs blocked cocaine self administration when combined with a dopamine transport inhibitor, either methylphenidate or nomifensine. These drug combinations did not decrease rates of responding maintained by food reinforcement. In contrast, the most selective of the compounds in binding σ2Rs had no effect on cocaine self administration in combination with either dopamine transport inhibitor. Thus, these results identify subtype-specific in vivo antagonists, and the utility of σR agonist substitution for cocaine self administration as an assay capable of distinguishing σR subtype selectivity in vivo. These results further suggest that effectiveness of dual σR antagonism and dopamine transport inhibition in blocking cocaine self administration is specific for σ1Rs and further support this dual targeting approach to development of cocaine antagonists.

Mechanisms of pentazocine-induced ventilatory depression and antinociception in anesthetized rats.

This study was performed to clarify mechanisms underlying pentazocine-induced ventilatory depression and antinociception. Spontaneous ventilation and hind leg withdrawal response against nociceptive thermal stimulation were simultaneously recorded in anesthetized rats. Pentazocine decreased minute volume resulting from depression of the ventilatory rate and tracheal airflow, and prolonged the latency of withdrawal response. Pre-treatment of ß-funaltorexamine, but not nor-binaltorphimine, significantly attenuated pentazocine-induced ventilatory depression, while either antagonist weakened its analgesic potency. Comparing with effects of fentanyl and U50488, the present results suggest that ventilatory depression induced by pentazocine is mediated by mainly µ receptors and analgesia by both µ and κ receptors.

The sigma-1 receptors are present in monomeric and oligomeric forms in living cells in the presence and absence of ligands.

The sigma-1 receptor (S1R) is a 223-amino-acid membrane protein that resides in the endoplasmic reticulum and the plasma membrane of some mammalian cells. The S1R is regulated by various synthetic molecules including (+)-pentazocine, cocaine and haloperidol and endogenous molecules such as sphingosine, dimethyltryptamine and dehydroepiandrosterone. Ligand-regulated protein chaperone functions linked to oxidative stress and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS) and neuropathic pain have been attributed to the S1R. Several client proteins that interact with S1R have been identified including various types of ion channels and G-protein coupled receptors (GPCRs). When S1R constructs containing C-terminal monomeric GFP2 and YFP fusions were co-expressed in COS-7 cells and subjected to FRET spectrometry analysis, monomers, dimers and higher oligomeric forms of S1R were identified under non-liganded conditions. In the presence of the prototypic S1R agonist, (+)-pentazocine, however, monomers and dimers were the prevailing forms of S1R. The prototypic antagonist, haloperidol, on the other hand, favoured higher order S1R oligomers. These data, in sum, indicate that heterologously expressed S1Rs occur in vivo in COS-7 cells in multiple oligomeric forms and that S1R ligands alter these oligomeric structures. We suggest that the S1R oligomerization states may regulate its function(s).

A randomized controlled trial comparing Pentazocine and Chamomilla recutita for labor pain relief.

BACKGROUND: Traditional birth attendants in Pakistan sometimes use a homeopathic remedy, Chamomilla for labor pain relief. Our study compares this homeopathic remedy for pain relief in labor with a commonly used parenteral analgesic in a hospital setting. No systematic study has been conducted previously to study the effect of chamomile, which may be affordable and available in community settings. METHODS: A double blind randomized controlled trial was carried out at Islamic International Medical College Trust. Ninety-nine normal pregnant women were randomly assigned into three groups. Each group received one of the three trial drugs; Chamomile, Pentazocine or placebo. The efficacy of labor analgesia was assessed by using Visual Analogue Scale (VAS) for pain intensity. Indicators of maternal and child health were recorded as were adverse effects of the drugs. RESULTS: Mean pain scores in the three groups were calculated and compared. The difference in mean VAS scores in Pentazocine and Chamomilla recutita group as compared with placebo was not statistically significant. No significant adverse effects were noticed in any group except slight headache and dizziness in three parturients in Pentazocine group. CONCLUSION: Neither Pentazocine, or Chamomilla recutita offer substantial analgesia during labor.

PENTAZOCINE VERSUS PENTAZOCINE WITH RECTAL DICLOFENAC FOR POSTOPERATIVE PAIN RELIEF AFTER CESAREAN SECTION- A DOUBLE BLIND RANDOMIZED PLACEBO CONTROLLED TRIAL IN A LOW RESOURCE AREA.

BACKGROUND: The unimodal approach of using pentazocine as post-cesarean section pain relief is inadequate, hence the need for a safer, easily available and more effective multimodal approach. AIM: To evaluate the effectiveness of rectal diclofenac combined with intramuscular pentazocine for postoperative pain following cesarean section. METHODS: In this double blind clinical trial, 130 pregnant women scheduled for cesarean section under spinal anesthesia were randomly assigned to two groups. Group A received 100mg diclofenac suppository and group B received placebo suppository immediately following surgery, 12 and 24h later. Both groups also received intramuscular pentazocine 30mg immediately following surgery and 6 hourly postoperatively in the first 24 h. Postoperative pain was assessed by visual analogue scale at end of surgery and 2, 12 and 24 h after surgery. Patient satisfaction scores were also assessed. RESULTS: One hundred and sixteen patients completed the study. Combining diclofenac and pentazocine had statistically significant reduction in pain intensity at 2, 12, and 24 hours postoperatively compared to pentazocine alone (p <0.05). No significant side effects were noted in both groups. The combined group also had significantly better patient satisfaction scores. CONCLUSION: The addition of diclofenac suppository to intramuscular pentazocine provides better pain relief after cesarean section and increased patient satisfaction.

NMDA receptors are upregulated and trafficked to the plasma membrane after sigma-1 receptor activation in the rat hippocampus.

Sigma-1 receptors (σ-1Rs) are endoplasmic reticulum resident chaperone proteins implicated in many physiological and pathological processes in the CNS. A striking feature of σ-1Rs is their ability to interact and modulate a large number of voltage- and ligand-gated ion channels at the plasma membrane. We have reported previously that agonists for σ-1Rs potentiate NMDA receptor (NMDAR) currents, although the mechanism by which this occurs is still unclear. In this study, we show that in vivo administration of the selective σ-1R agonists (+)-SKF 10,047 [2S-(2α,6α,11R*]-1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(2-propenyl)-2,6-methano-3-benzazocin-8-ol hydrochloride (N-allylnormetazocine) hydrochloride], PRE-084 (2-morpholin-4-ylethyl 1-phenylcyclohexane-1-carboxylate hydrochloride), and (+)-pentazocine increases the expression of GluN2A and GluN2B subunits, as well as postsynaptic density protein 95 in the rat hippocampus. We also demonstrate that σ-1R activation leads to an increased interaction between GluN2 subunits and σ-1Rs and mediates trafficking of NMDARs to the cell surface. These results suggest that σ-1R may play an important role in NMDAR-mediated functions, such as learning and memory. It also opens new avenues for additional studies into a multitude of pathological conditions in which NMDARs are involved, including schizophrenia, dementia, and stroke.

The oligomeric states of the purified sigma-1 receptor are stabilized by ligands.

Sigma-1 receptor (S1R) is a mammalian member of the ERG2 and sigma-1 receptor-like protein family (pfam04622). It has been implicated in drug addiction and many human neurological disorders, including Alzheimer and Parkinson diseases and amyotrophic lateral sclerosis. A broad range of synthetic small molecules, including cocaine, (+)-pentazocine, haloperidol, and small endogenous molecules such as N,N-dimethyltryptamine, sphingosine, and steroids, have been identified as regulators of S1R. However, the mechanism of activation of S1R remains obscure. Here, we provide evidence in vitro that S1R has ligand binding activity only in an oligomeric state. The oligomeric state is prone to decay into an apparent monomeric form when exposed to elevated temperature, with loss of ligand binding activity. This decay is suppressed in the presence of the known S1R ligands such as haloperidol, BD-1047, and sphingosine. S1R has a GXXXG motif in its second transmembrane region, and these motifs are often involved in oligomerization of membrane proteins. Disrupting mutations within the GXXXG motif shifted the fraction of the higher oligomeric states toward smaller states and resulted in a significant decrease in specific (+)-[(3)H]pentazocine binding. Results presented here support the proposal that S1R function may be regulated by its oligomeric state. Possible mechanisms of molecular regulation of interacting protein partners by S1R in the presence of small molecule ligands are discussed.