Sigma-1 Receptors Control Neuropathic Pain and Peripheral Neuroinflammation After Nerve Injury in Female Mice: A Transcriptomic Study.

The mechanisms for neuropathic pain amelioration by sigma-1 receptor inhibition are not fully understood. We studied genome-wide transcriptomic changes (RNAseq) in the dorsal root ganglia (DRG) from wild-type and sigma-1 receptor knockout mice prior to and following Spared Nerve Injury (SNI). In wildtype mice, most of the transcriptomic changes following SNI are related to the immune function or neurotransmission.

Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Caα2δ-1 Subunit of Voltage-Gated Calcium Channel and the μ-Opioid Receptor.

The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the α2δ-1 subunit of voltage-gated calcium channels (Caα2δ-1) and the μ-opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Caα2δ-1 ligands, onto which MOR ligand pharmacophoric elements were added.

Resilience to Pain-Related Depression in σ Receptor Knockout Mice Is Associated with the Reversal of Pain-Induced Brain Changes in Affect-Related Genes.

Mice lacking the σ receptor chaperone (σR) are resilient to depressive-like behaviors secondary to neuropathic pain. Examining the resilience's brain mechanisms could help develop conceptually novel therapeutic strategies. We explored the diminished motivation for a natural reinforcer (white chocolate) in the partial sciatic nerve ligation (PSNL) model in wild-type (WT) and σR mice.

Comprehensive Preclinical Assessment of Sensory, Functional, Motivational-Affective, and Neurochemical Outcomes in Neuropathic Pain: The Case of the Sigma-1 Receptor.

Chronic pain remains a major health problem and is currently facing slow drug innovation. New drug treatments should address not only the sensory-discriminative but also functional and motivational-affective components of chronic pain. In a mouse model of neuropathic pain induced by partial sciatic nerve ligation (PSNL), we analyzed sensory and functional-like outcomes by hindpaw mechanical stimulation and automated gait analysis (CatWalk).

Administration of the sigma-1 receptor agonist PRE-084 at emerging adulthood, but not at early adolescence, attenuated ethanol-induced conditioned taste aversion in female rats.

Ethanol-induced conditioned taste aversion (CTA) is greater in late adolescence or young adulthood than in early adolescence. The role of the sigma receptor system in this age-related difference has not been extensively explored, particularly in female rats. This study assessed the effects of the activation of sigma-1 receptors (S1-R), via the selective S1-R agonist PRE-084, on ethanol-induced CTA at early or at terminal adolescence/emerging adulthood (28 or 56 days-old at the beginning of the procedures, respectively) in female Wistar rats.

Piperazinyl Bicyclic Derivatives as Selective Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels.

The synthesis and pharmacological activities of a new series of piperazinyl quinazolin-4-(3)-one derivatives acting toward the α2δ-1 subunit of voltage-gated calcium channels (Caα2δ-1) are reported. Different positions of a micromolar HTS hit were explored, and best activities were obtained for compounds containing a small alkyl group in position 3 of the quinazolin-4-(3)-one scaffold and a 3-methyl-piperazin-1-yl- or 3,5-dimethyl-piperazin-1-yl-butyl group in position 2. The activity was shown to reside in the enantiomer of the chain in position 2, and several eutomers reached single digit nanomolar affinities.

Propionamide Derivatives as Dual μ-Opioid Receptor Agonists and σ Receptor Antagonists for the Treatment of Pain.

A new series of propionamide derivatives was developed as dual μ-opioid receptor agonists and σ receptor antagonists. Modification of a high-throughput screening hit originated a series of piperazinylcycloalkylmethyl propionamides, which were explored to overcome the challenge of achieving balanced dual activity and convenient drug-like properties. The lead compound identified, , showed good analgesic effects in several animal models of both acute (paw pressure) and chronic (partial sciatic nerve ligation) pain, with reduced gastrointestinal effects in comparison with oxycodone.

Bicyclic Diazepinones as Dual Ligands of the α2δ-1 Subunit of Voltage-Gated Calcium Channels and the Norepinephrine Transporter.

The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Caα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Caα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5-pyrimido[4,5-][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality.

Sigma-1 antagonism inhibits binge ethanol drinking at adolescence.

Background: Ethanol use during adolescence is a significant health problem, yet the pharmacological treatments to reduce adolescent binge drinking are scarce. The present study assessed, in male and female adolescent Wistar rats, if the sigma-1 receptor (S1-R) antagonists S1RA or BD-1063 disrupted ethanol drinking.

Methods: Three times a week, for two weeks, the rats received the S1-R antagonists.

Trends in Sigma-1 Receptor Research: A 25-Year Bibliometric Analysis.

There are previous reviews focused on Sigma-1 receptor but no bibliometric studies examining this field as a whole. This article aims to present a global view of Sigma-1 receptor research and its intellectual structure. We used bibliometric indicators of a basic nature as well as techniques for the visualization and analysis of networks of scientific information extracted from Scopus database.

Administration of a co-crystal of tramadol and celecoxib in a 1:1 molecular ratio produces synergistic antinociceptive effects in a postoperative pain model in rats.

Drug combination for the treatment of pain is common clinical practice. Co-crystal of Tramadol-Celecoxib (CTC) consists of two active pharmaceutical ingredients (APIs), namely the atypical opioid tramadol and the preferential cyclooxygenase-2 inhibitor celecoxib, at a 1:1 molecular ratio. In this study, a non-formulated 'raw' form of CTC administered in suspension (referred to as ctc) was compared with both tramadol and celecoxib alone in a rat plantar incision postoperative pain model.

Pharmacological sensitivity of reflexive and nonreflexive outcomes as a correlate of the sensory and affective responses to visceral pain in mice.

Pain encompasses both sensory and affective dimensions which can be differentially modulated by drugs. Here, we compare the pharmacological sensitivity of the sensory and affective responses using acetic acid-induced abdominal writhings (sensory-reflexive outcome) and acetic acid-induced depression of reward seeking behaviour (RSB, affective-nonreflexive outcome) to a highly palatable food in mice. We found that the expression of RSB critically depends on factors such as sex and previous knowledge and type of the food stimulus.

Grip strength in mice with joint inflammation: A rheumatology function test sensitive to pain and analgesia.

Grip strength deficit is a measure of pain-induced functional disability in rheumatic disease. We tested whether this parameter and tactile allodynia, the standard pain measure in preclinical studies, show parallels in their response to analgesics and basic mechanisms. Mice with periarticular injections of complete Freund's adjuvant (CFA) in the ankles showed periarticular immune infiltration and synovial membrane alterations, together with pronounced grip strength deficits and tactile allodynia measured with von Frey hairs.

Pharmacological Modulation of the Sigma 1 Receptor and the Treatment of Pain.

There is a critical need for new analgesics acting through new mechanisms of action, which could increase the efficacy with respect to existing therapies and reduce their unwanted effects. Current preclinical evidence supports the modulatory role of sigma-1 receptors (σR) in nociception, mainly based on the pain-attenuated phenotype of σR knockout mice and on the antinociceptive effect exerted by σR antagonists on pains of different etiologies. σR is highly expressed in different pain areas of the CNS and the periphery (particularly dorsal root ganglia), and interacts and modulates the functionality of different receptors and ion channels .

The selective sigma-1 receptor antagonist E-52862 attenuates neuropathic pain of different aetiology in rats.

E-52862 is a selective σ1R antagonist currently undergoing phase II clinical trials for neuropathic pain and represents a potential first-in-class analgesic. Here, we investigated the effect of single and repeated administration of E-52862 on different pain-related behaviours in several neuropathic pain models in rats: mechanical allodynia in cephalic (trigeminal) neuropathic pain following chronic constriction injury of the infraorbital nerve (IoN), mechanical hyperalgesia in streptozotocin (STZ)-induced diabetic polyneuropathy, and cold allodynia in oxaliplatin (OX)-induced polyneuropathy. Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin.

Changes in saccharin preference behavior as a primary outcome to evaluate pain and analgesia in acetic acid-induced visceral pain in mice.

Reflex-based procedures are important measures in preclinical pain studies that evaluate stimulated behaviors. These procedures, however, are insufficient to capture the complexity of the pain experience, which is often associated with the depression of several innate behaviors. While recent studies have made efforts to evidence the suppression of some positively motivated behaviors in certain pain models, they are still far from being routinely used as readouts for analgesic screening.

Sigma-1 receptor and inflammatory pain.

Introduction: The sigma-1 receptor (Sig-1R) is a unique ligand-regulated molecular chaperone that interacts with several protein targets such as G protein-coupled receptors and ion channels to modulate their activity. Sig-1R is located in areas of the central and peripheral nervous system that are key to pain control. Previous preclinical studies have suggested a potential therapeutic use of Sig-1R antagonists for the management of neuropathic pain.

S1RA, a selective sigma-1 receptor antagonist, inhibits inflammatory pain in the carrageenan and complete Freund's adjuvant models in mice.

The therapeutic potential of S1RA (E-52862), a selective sigma-1 receptor (σ1R) antagonist, has been explored in experimental neuropathic pain, but not in inflammatory pain models. The present study investigated the effect of the intraperitoneal administration of S1RA on the hind paw withdrawal response to thermal and mechanical stimulation following an intraplantar injection of carrageenan (CARR) and complete Freund's adjuvant (CFA), which are two well-characterized models of acute and chronic inflammatory pain, respectively. S1RA fully reversed both mechanical [dose of drug that produced half of its maximal response (ED50)=35.

"Bedside-to-Bench" Behavioral Outcomes in Animal Models of Pain: Beyond the Evaluation of Reflexes.

Despite the myriad promising new targets and candidate analgesics recently identified in preclinical pain studies, little translation to novel pain medications has been generated. The pain phenotype in humans involves complex behavioral alterations, including changes in daily living activities and psychological disturbances. These behavioral changes are not reflected by the outcome measures traditionally used in rodents for preclinical pain testing, which are based on reflexes evoked by sensory stimuli of different types (mechanical, thermal or chemical).

Predicting the antinociceptive efficacy of σ(1) receptor ligands by a novel receptor fluorescence resonance energy transfer (FRET) based biosensor.

We have developed a novel methodology for monitoring the σ1 receptor activation switch in living cells. Our assay uncovered the intrinsic nature of σ1 receptor ligands by recording the ligand-mediated conformational changes of this chaperone protein. The change triggered by each ligand correlated well with its ability to attenuate formalin induced nociception in an animal model of pain.

A bibliometric analysis of research in psychopharmacology by psychology departments (1987-2007).

From the very outset of scientific Psychology, psychologists have shown interest for drugs and their effects on behavior. This has given rise to numerous contributions, mostly in the form of Psychopharmacology publications. The aim of this study was to quantitatively evaluate these contributions and compare them with other academic disciplines related to Psychopharmacology.

Pharmacological activation of 5-HT7 receptors reduces nerve injury-induced mechanical and thermal hypersensitivity.

The involvement of the 5-HT(7) receptor in nociception and pain, particularly chronic pain (i.e., neuropathic pain), has been poorly investigated.

Sigma-1 receptors regulate activity-induced spinal sensitization and neuropathic pain after peripheral nerve injury.

Sigma-1 receptor (sigma(1)R) is expressed in key CNS areas involved in nociceptive processing but only limited information is available about its functional role. In the present study we investigated the relevance of sigma(1)R in modulating nerve injury-evoked pain. For this purpose, wild-type mice and mice lacking the sigma(1)R gene were exposed to partial sciatic nerve ligation and neuropathic pain-related behaviors were investigated.

Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice.

Rationale: Formalin-induced pain is reduced in sigma-1 (sigma1) receptor knockout mice; therefore, we hypothesized that haloperidol and its metabolites I and II, which have affinity for sigma1 receptors, may modulate formalin-induced pain.

Results: Intraplantar administration of formalin (2.5%) to CD-1 mice produced a biphasic period of pain.

Formalin-induced pain is reduced in sigma(1) receptor knockout mice.

The role of sigma1 receptors in non-acute pain has not been explored. In this study we show that both phases of formalin-induced pain were reduced by approximately 55% in sigma1 receptor knockout mice in comparison to wild-type animals. These results suggest that the tonic pain induced by formalin is altered in mice lacking sigma1 receptors, and highlight the potential usefulness of further studies of the role of sigma1 receptors in models of non-acute pain.