Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism: WLB-73502, an analgesic with improved efficacy and safety profile compared to strong opioids.

Opioids are the most effective painkillers, but their benefit-risk balance often hinder their therapeutic use. WLB-73502 is a dual, bispecific compound that binds sigma-1 (S1R) and mu-opioid (MOR) receptors. WLB-73502 is an antagonist at the S1R. It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificant ß-arrestin-2 recruitment, thus demonstrating low intrinsic efficacy on MOR at both signalling pathways. Despite its partial MOR agonism, WLB-73502 exerted full antinociceptive efficacy, with potency superior to morphine and similar to oxycodone against nociceptive, inflammatory and osteoarthritis pain, and superior to both morphine and oxycodone against neuropathic pain. WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect. Contrary to morphine and oxycodone, tolerance to its antinociceptive effect did not develop after repeated 4-week administration. Also, contrary to opioid comparators, WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy, and it was devoid of proemetic effect (retching and vomiting) in ferrets at potentially effective doses. WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

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 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 ±â€¯0.5 mg/kg, i.p.; theoretical ED50 = 3.8 ±â€¯0.4 mg/kg, i.p.) and thermal (experimental ED50 = 2.3 ±â€¯0.5 mg/kg, i.p.; theoretical ED50 = 9.8 ±â€¯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.

Evidence for adenosine- and serotonin-mediated antihyperalgesic effects of cizolirtine in rats suffering from diabetic neuropathy.

Cizolirtine is a novel non-opioid drug which demonstrated antinociceptive activity in numerous pain models in rodents. Yet, its mechanism of action remains unknown. Several lines of evidence support the idea that adenosine (ADO) and serotonin (5-HT) modulate nociceptive signaling. Our study aimed at investigating whether these neuroactive molecules could be implicated in the mechanism of action of cizolirtine. Cizolirtine-induced antihyperalgesia was compared before and after pretreatment with ADO A(1)-A(2A) and 5-HT(1B/1D) receptor ligands in rats rendered diabetic by streptozotocin pretreatment and suffering from neuropathic pain. Cizolirtine alone (30-80 mg/kg, i.p.) significantly increased mechanical nociceptive thresholds. Acute pretreatment with the A(1)-A(2A) receptor antagonist caffeine (5 mg/kg, i.p.) or the 5-HT(1B/1D) receptor antagonist GR-127,935 (3 mg/kg, i.p.) significantly reduced the antihyperalgesic effects of cizolirtine. Conversely, cizolirtine-induced antihyperalgesia was promoted by pretreatment with either the selective A(1) receptor agonist CPA (0.3 mg/kg, i.p.) or the selective 5-HT(1B) receptor agonist CP-94,253 (3mg/kg, i.p.), and this potentiation was totally prevented by acute pretreatment with respective antagonists. Interestingly, A(1) receptor blockade by DPCPX inhibited the promoting effect of CP-94,253 on cizolirtine-induced antihyperalgesia, suggesting that the adenosine A(1)-mediated step takes place downstream the serotonin 5-HT(1B)-mediated step in the neurobiological mechanisms underlying cizolirtine action.

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.

Antihyperalgesic effects of cizolirtine in diabetic rats: behavioral and biochemical studies.

Although clinically well controlled at the metabolic level, type I diabetes resulting from an insufficient insulin secretion remains the cause of severe complications. In particular, diabetes can be associated with neuropathic pain which fails to be treated by classical analgesics. In this study, we investigated the efficacy of a novel non opioid analgesic, cizolirtine, to reduce mechanical hyperalgesia associated with streptozotocin (STZ)-induced diabetes, in the rat. Cizolirtine was compared to paroxetine, an antidepressant drug with proven efficacy to relieve painful diabetic neuropathy. Under acute conditions, cizolirtine (30 and 80 mg/kgi.p.) significantly increased paw withdrawal and vocalization thresholds in the paw pressure test in diabetic rats displaying mechanical hyperalgesia. The antihyperalgesic effects of cizolirtine persisted under chronic treatment conditions, since pre-diabetes thresholds were recovered after a two week-treatment with the drug (3 mg/kg/day, s.c.). In this respect, cizolirtine was as efficient as paroxetine (5 mg/kg per day, s.c.) which, however, was inactive under acute treatment conditions. Measurements of the spinal release of calcitonin gene-related peptide (CGRP) through intrathecal perfusion under halothane-anesthesia showed that acute administration of cizolirtine (80 mg/kg, i.p.) significantly diminished (-36%) the peptide outflow in diabetic rats suffering from neuropathic pain. This effect as well as the antihyperalgesic effect of cizolirtine were prevented by the alpha(2)-adrenoreceptor antagonist idazoxan (2 mg/kg, i.p.). These data suggest that the antihyperalgesic effect of cizolirtine in diabetic rats suffering from neuropathic pain implies an alpha(2)-adrenoceptor-dependent presynaptic inhibition of CGRP-containing primary afferent fibers.

The antimigraine 5-HT 1B/1D receptor agonists, sumatriptan, zolmitriptan and dihydroergotamine, attenuate pain-related behaviour in a rat model of trigeminal neuropathic pain.

1. Peripheral lesion to the trigeminal nerve may induce severe pain states. Several lines of evidence have suggested that the antimigraine effect of the triptans with 5-HT(1B/1D) receptor agonist properties may result from inhibition of nociceptive transmission in the spinal nucleus of the trigeminal nerve by these drugs. On this basis, we have assessed the potential antinociceptive effects of sumatriptan and zolmitriptan, compared to dihydroergotamine (DHE), in a rat model of trigeminal neuropathic pain. 2. Chronic constriction injury was produced by two loose ligatures of the infraorbital nerve on the right side. Responsiveness to von Frey filament stimulation of the vibrissal pad was used to evaluate allodynia. 3. Two weeks after ligatures, rats with a chronic constriction of the right infraorbital nerve displayed bilateral mechanical hyper-responsiveness to von Frey filament stimulation of the vibrissal pad with a mean threshold of 0.38+/-0.04 g on the injured side and of 0.43+/-0.04 g on the contralateral (left) side (versus > or =12.5 g on both sides in the same rats prior to nerve constriction injury). 4. Sumatriptan at a clinically relevant dose (100 microg kg(-1), s.c.) led to a significant reduction of the mechanical allodynia-like behaviour on both the injured and the contralateral sides (peak-effects 6.3+/-1.1 g and 4.4+/-0.7 g, respectively). A more pronounced effect was obtained with zolmitriptan (100 microg kg(-1), s.c.) (peak-effects: 7.4+/-0.9 g and 3.2+/-1.3 g) whereas DHE (50-100 microg kg(-1), i.v.) was less active (peak-effect approximately 1.5 g). 5. Subcutaneous pretreatment with the 5-HT(1B/1D) receptor antagonist, GR 127935 (3 mg kg(-1)), prevented the anti-allodynia-like effects of triptans and DHE. Pretreatment with the 5-HT(1A) receptor antagonist, WAY 100635 (2 mg kg(-1), s.c.), did not alter the effect of triptans but significantly enhanced that of DHE (peak effect 4.3+/-0.5 g). 6. In a rat model of peripheral neuropathic pain, which consisted of a unilateral loose constriction of the sciatic nerve, neither sumatriptan (50-300 microg kg(-1)) nor zolmitriptan (50-300 microg kg(-1)) modified the thresholds for paw withdrawal and vocalization in response to noxious mechanical stimulation. 7. These results support the rationale for exploring the clinical efficacy of brain penetrant 5-HT(1B/1D) receptor agonists as analgesics to reduce certain types of trigeminal neuropathic pain in humans.

Mechanical, thermal and formalin-induced nociception is differentially altered in 5-HT1A-/-, 5-HT1B-/-, 5-HT2A-/-, 5-HT3A-/- and 5-HTT-/- knock-out male mice.

Extensive studies in rodents suggest that serotonin (5-HT) modulates nociceptive responses through the stimulation of several receptor types. However, it remains to demonstrate that these receptors participate in the control of nociception under physiological conditions. Pain behaviors of mutants which do not express 5-HT1A, 5-HT1B, 5-HT2A or 5-HT3A receptors, or lacking the 5-HT transporter, compared to paired wild-type mice of the same genetic background, were examined using validated tests based on different sensory modalities. Mechanical (von Frey filaments, tail pressure, tail clip tests), thermal (radiant heat, 46 degrees C water bath, hot-plate test) and formalin-induced nociception were determined in 2- to 3-month-old males. 5-HT1A knock-out mice differed from wild-types by higher thermal sensitivity (hot-plate test only), and 5-HT1B knock-out mice by higher thermal and formalin sensitivity. Both 5-HT2A and 5-HT3A knock-out mice differed from wild-types by a dramatic decrease in the formalin-induced nociceptive responses for phase II (16-45 min after injection/inflammatory phase). In contrast, neither mechanical, thermal nor formalin-induced nociception differed between mutants lacking the 5-HT transporter and paired wild-type mice. Although differences in spontaneous locomotor activity in 5-HT1B-/- (increase) and 5-HT3A-/- (decrease) knock-out mice versus paired wild-types might have confounded differences in nociception, acute 5-HT receptor blockade by selective antagonists was found to replicate in wild-type mice the effects on pain behavior, but not on locomotor activity, of the respective gene knock-out in mutants. These results support the conclusion that the complex control of pain mechanisms by 5-HT, acting at multiple receptors, is physiologically relevant in mice.