Enrique Portillo-Salido

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

ABSTRACT Sigma‐1 receptor (σ1R) 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 σ1R in modulating nerve injury‐evoked pain. For this purpose, wild‐type mice and mice lacking the σ1R gene were exposed to partial sciatic nerve ligation and neuropathic pain‐related behaviors were investigated. To explore underlying mechanisms, spinal processing of repetitive nociceptive stimulation and expression of extracellular signal‐regulated kinase (ERK) were also investigated. Sensitivity to noxious heat of homozygous σ1R knockout mice did not differ from wild‐type mice. Baseline values obtained in σ1R knockout mice before nerve injury in the plantar, cold‐plate and von Frey tests were also indistinguishable from those obtained in wild‐type mice. However, cold and mechanical allodynia did not develop in σ1R null mice exposed to partial sciatic nerve injury. Using isolated spinal cords we found that mice lacking σ1R showed reduced wind‐up responses respect to wild‐type mice, as evidenced by a reduced number of action potentials induced by trains of C‐fiber intensity stimuli. In addition, in contrast to wild‐type mice, σ1R knockout mice did not show increased phosphorylation of ERK in the spinal cord after sciatic nerve injury. Both wind‐up and ERK activation have been related to mechanisms of spinal cord sensitization. Our findings identify σ1R as a constituent of the mechanisms modulating activity‐induced sensitization in pain pathways and point to σ1R as a new potential target for drugs designed to alleviate neuropathic pain.

Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization

BACKGROUND AND PURPOSE The sigma‐1 (σ1) receptor is a ligand‐regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of σ1 receptor ligands used as pharmacological tools are unclear and the demonstration that σ1 receptor antagonists have efficacy in reversing central sensitization‐related pain sensitivity is still missing.

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

&NA; The involvement of the 5‐HT7 receptor in nociception and pain, particularly chronic pain (i.e., neuropathic pain), has been poorly investigated. In the present study, we examined whether the 5‐HT7 receptor participates in some modulatory control of nerve injury‐evoked mechanical hypersensitivity and thermal (heat) hyperalgesia in mice. Activation of 5‐HT7 receptors by systemic administration of the selective 5‐HT7 receptor agonist AS‐19 (1 and 10 mg/kg) exerted a clear‐cut reduction of mechanical and thermal hypersensitivities that were reversed by co‐administering the selective 5‐HT7 receptor antagonist SB‐258719. Interestingly, blocking of 5‐HT7 receptors with SB‐258719 (2.5 and 10 mg/kg) enhanced mechanical (but not thermal) hypersensitivity in nerve‐injured mice and induced mechanical hypersensitivity in sham‐operated mice. Effectiveness of the treatment with a 5‐HT7 receptor agonist was maintained after repeated systemic administration: no tolerance to the antiallodynic and antihyperalgesic effects was developed following treatment with the selective 5‐HT7 receptor agonist E‐57431 (10 mg/kg) twice daily for 11 days. The 5‐HT7 receptor co‐localized with GABAergic cells in the dorsal horn of the spinal cord, suggesting that the activation of spinal inhibitory GABAergic interneurons could contribute to the analgesic effects of 5‐HT7 receptor agonists. In addition, a significant increase of 5‐HT7 receptors was found by immunohistochemistry in the ipsilateral dorsal horn of the spinal cord after nerve injury, suggesting a “pain”‐triggered regulation of receptor expression. These results support the idea that the 5‐HT7 receptor subtype is involved in the control of pain and point to a new potential use of 5‐HT7 receptor agonists for the treatment 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 (&sgr;1R) 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)=35.9 and 42.1 mg/kg for CARR-induced and CFA-induced pain, respectively] and thermal (ED50=27.9 mg/kg, CARR) hypersensitivity, whereas ibuprofen (CARR, mechanical allodynia) and celecoxib (CARR, thermal hyperalgesia; CFA, mechanical allodynia) failed to reach maximum efficacy. Morphine also showed maximum efficacy in all tests. Unlike celecoxib and ibuprofen, which decreased paw volume significantly, CARR-induced paw oedema was not reduced by S1RA and morphine, thus suggesting that the antinociceptive effect of S1RA does not involve a major anti-inflammatory (antioedema) action. S1RA was devoid of efficacy when administered to &sgr;1R knockout mice, thus suggesting the involvement of &sgr;1R in the antinociceptive effects exerted by S1RA. We conclude that S1RA represents a promising novel analgesic therapy for inflammatory pain.

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. In the OX model, single administration of E-52862 reversed the hypersensitivity to cold stimuli similarly to 100 mg/kg of gabapentin. Interestingly, repeated E-52862 administration twice daily over 7 days did not induce pharmacodynamic tolerance but an increased antinociceptive effect in all three models. Additionally, as shown in the STZ and OX models, repeated daily treatment with E-52862 attenuated baseline pain behaviours, which supports a sustained modifying effect on underlying pain-generating mechanisms. These preclinical findings support a role for σ1R in neuropathic pain and extend the potential for the use of selective σ1R antagonists (e.g., E-52862) to the chronic treatment of cephalic and extra-cephalic neuropathic pain.

Predicting the Antinociceptive Efficacy of σ1 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. This tool may assist in predicting the antinociceptive efficacy of σ1 receptor ligands.

Sigma-1 receptor and inflammatory pain

IntroductionThe 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.DiscussionRecent studies using pharmacological and genetic tools have explored the role of Sig-1R in inflammatory pain conditions. Mice lacking the Sig-1R have shown different patterns of phenotypic responses to inflammatory injury. Systemic or peripheral administration of several Sig-1R antagonists, including the selective Sig-1R antagonist S1RA, inhibited both mechanical and thermal hypersensitivity in several preclinical models of inflammatory pain. These recent studies are summarized in the present commentary.ConclusionCentral and peripheral pharmacological blockade of Sig-1R could be an effective option to treat inflammatory pain.

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. Here, we characterized and compared the effect of the analgesic ibuprofen (Ibu) and the stimulant, caffeine, in assays of acute pain-stimulated and pain-depressed behavior. Intraperitoneal injection of acetic acid (AA) served as a noxious stimulus to stimulate a writhing response or depress saccharin preference and locomotor activity (LMA) in mice. AA injection caused the maximum number of writhes between 5 and 20 minutes after administration, and writhing almost disappeared 1 hour later. AA-treated mice showed signs of depression-like behaviors after writhing resolution, as evidenced by reduced locomotion and saccharin preference for at least 4 and 6 hours, respectively. Depression-like behaviors resolved within 24 hours after AA administration. A dose of Ibu (40 mg/kg) – inactive to reduce AA-induced abdominal writhing – administered before or after AA injection significantly reverted pain-induced saccharin preference deficit. The same dose of Ibu also significantly reverted the AA-depressed LMA, but only when it was administered after AA injection. Caffeine restored locomotion – but not saccharin preference – in AA-treated mice, thus suggesting that the reduction in saccharin preference – but not in locomotion – was specifically sensitive to analgesics. In conclusion, AA-induced acute pain attenuated saccharin preference and LMA beyond the resolution of writhing behavior, and the changes in the expression of hedonic behavior, such as sweet taste preference, can be used as a more sensitive and translational model to evaluate analgesics.

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 (σ1R) in nociception, mainly based on the pain-attenuated phenotype of σ1R knockout mice and on the antinociceptive effect exerted by σ1R antagonists on pains of different etiologies. σ1R 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 antagonism of σ1R leads to decreased amplification of pain signaling within the spinal cord (central sensitization), but recent data also support a role at the periphery. σ1R antagonists have consistently demonstrated efficacy in neuropathic pain , but also in other types of pain including inflammatory, orofacial, visceral, and post-operative pain. Apart from acting alone, when combined with opioids, σ1R antagonists enhance opioid analgesia but not opioid-induced unwanted effects. Interestingly, unlike opioids, σ1R antagonists do not modify normal sensory mechanical and thermal sensitivity thresholds but they exert antihypersensitive effects in sensitizing conditions, enabling the reversal of nociceptive thresholds back to normal values. Accordingly, σ1R antagonists are not strictly analgesics; they are antiallodynic and antihyperalgesic drugs acting when the system is sensitized following prolonged noxious stimulation or persistent abnormal afferent input (e.g., secondary to nerve injury). These are distinctive features allowing σ1R antagonists to exert a modulatory effect specifically in pathophysiological conditions such as chronic pain .

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

Abstract 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 ctcsusp) was compared with both tramadol and celecoxib alone in a rat plantar incision postoperative pain model. For comparison, the strong opioids morphine and oxycodone, and a tramadol plus acetaminophen combination at a molecular ratio of 1:17 were also tested. Isobolographic analyses showed that ctcsusp exerted synergistic mechanical antiallodynic (experimental ED50 = 2.0 ± 0.5 mg/kg, i.p.; theoretical ED50 = 3.8 ± 0.4 mg/kg, i.p.) and thermal (experimental ED50 = 2.3 ± 0.5 mg/kg, i.p.; theoretical ED50 = 9.8 ± 0.8 mg/kg, i.p.) antihyperalgesic effects in the postoperative pain model. In contrast, the tramadol and acetaminophen combination showed antagonistic effects on both mechanical allodynia and thermal hyperalgesia. No synergies between tramadol and celecoxib on locomotor activity, motor coordination, ulceration potential and gastrointestinal transit were observed after the administration of ctcsusp. Overall, rat efficacy and safety data revealed that ctcsusp provided synergistic analgesic effects compared with each API alone, without enhancing adverse effects. Moreover, ctcsusp showed similar efficacy but improved safety ratio (80, measured as gastrointestinal transit vs postoperative pain ED50 ratios) compared with the strong opioids morphine (2.5) and oxycodone (5.8). The overall in vivo profile of ctcsusp supports the further investigation of CTC in the clinical management of moderate‐to‐severe acute pain as an alternative to strong opioids.