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

Gris G, Portillo-Salido E, Aubel B, Darbaky Y, Deseure K, Vela JM, Merlos M, Zamanillo D - Sci Rep (2016)

Bottom Line: Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Drug Discovery &Preclinical Development, ESTEVE, Barcelona, Spain.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Effect of repeated administration of E-52862 on cold allodynia in a preventive paradigm in OX-induced neuropathy in rats.(A) Experimental preventive protocol. In this case, the administration of E-52862 started two days before the first OX injection. The preventive effect was evaluated on days 8, 15 and 16 after the first injection of OX (testing days). The evaluation on day 16 was performed one day after the last administration of E-52862. (B) Effects of the repeated administration of E-52862 at 40 mg/kg (grey bars) in the preventive protocol on cold allodynia evaluated as cumulative cold score. Each point and vertical line represents the mean ± S.E.M. of the values obtained from 10 animals per group. **p < 0.01; ***p < 0.001 vs. vehicle group (one-way ANOVA followed by Newman–Keuls test).
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f4: Effect of repeated administration of E-52862 on cold allodynia in a preventive paradigm in OX-induced neuropathy in rats.(A) Experimental preventive protocol. In this case, the administration of E-52862 started two days before the first OX injection. The preventive effect was evaluated on days 8, 15 and 16 after the first injection of OX (testing days). The evaluation on day 16 was performed one day after the last administration of E-52862. (B) Effects of the repeated administration of E-52862 at 40 mg/kg (grey bars) in the preventive protocol on cold allodynia evaluated as cumulative cold score. Each point and vertical line represents the mean ± S.E.M. of the values obtained from 10 animals per group. **p < 0.01; ***p < 0.001 vs. vehicle group (one-way ANOVA followed by Newman–Keuls test).

Mentions: Therefore, given the potential benefit of co-administering patients with antineoplastic drugs and drugs counteracting antineoplastic’s undesired effects, the possible preventive effect of E-52862 on the development of OX-induced neuropathic pain (i.e., cold allodynia) was also investigated. For this purpose, E-52862 was administered i.p. b.i.d at 40 mg/kg starting 2 days before the first injection of OX and throughout the OX treatment period (last OX injection on day 14) (Fig. 4A). On day 8, rats co-treated with OX and E-52862 b.i.d. at 40 mg/kg exhibited significantly lower cumulative cold scores as compared to the OX + vehicle group (p < 0.01 for comparisons between E-52862 40 mg/kg vs. vehicle; Fig. 4B). One week later, on day 15, the antiallodynic effect of the treatment was maintained (F2,25 = 13.5, p < 0.001, ANOVA; p < 0.01 E-52862 40 mg/kg vs. vehicle). Interestingly, 24 hours after E-52862 treatment completion (day 16) animals showed reduced cold allodynia (F2,25 = 16.4, p < 0.001, ANOVA; p < 0.01 E-52862 40 mg/kg vs. vehicle) compared to the vehicle-treated OX-treated group (3.5 ± 0.7 vs. 6.7 ± 0.9), although cumulative pain scores were higher than baseline values in non-neuropathic animals that did not receive OX (F2,25 = 16.4, p < 0.001, ANOVA; p < 0.05 for comparisons between E-52862 40 mg/kg vs. baseline).


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

Gris G, Portillo-Salido E, Aubel B, Darbaky Y, Deseure K, Vela JM, Merlos M, Zamanillo D - Sci Rep (2016)

Effect of repeated administration of E-52862 on cold allodynia in a preventive paradigm in OX-induced neuropathy in rats.(A) Experimental preventive protocol. In this case, the administration of E-52862 started two days before the first OX injection. The preventive effect was evaluated on days 8, 15 and 16 after the first injection of OX (testing days). The evaluation on day 16 was performed one day after the last administration of E-52862. (B) Effects of the repeated administration of E-52862 at 40 mg/kg (grey bars) in the preventive protocol on cold allodynia evaluated as cumulative cold score. Each point and vertical line represents the mean ± S.E.M. of the values obtained from 10 animals per group. **p < 0.01; ***p < 0.001 vs. vehicle group (one-way ANOVA followed by Newman–Keuls test).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4834548&req=5

f4: Effect of repeated administration of E-52862 on cold allodynia in a preventive paradigm in OX-induced neuropathy in rats.(A) Experimental preventive protocol. In this case, the administration of E-52862 started two days before the first OX injection. The preventive effect was evaluated on days 8, 15 and 16 after the first injection of OX (testing days). The evaluation on day 16 was performed one day after the last administration of E-52862. (B) Effects of the repeated administration of E-52862 at 40 mg/kg (grey bars) in the preventive protocol on cold allodynia evaluated as cumulative cold score. Each point and vertical line represents the mean ± S.E.M. of the values obtained from 10 animals per group. **p < 0.01; ***p < 0.001 vs. vehicle group (one-way ANOVA followed by Newman–Keuls test).
Mentions: Therefore, given the potential benefit of co-administering patients with antineoplastic drugs and drugs counteracting antineoplastic’s undesired effects, the possible preventive effect of E-52862 on the development of OX-induced neuropathic pain (i.e., cold allodynia) was also investigated. For this purpose, E-52862 was administered i.p. b.i.d at 40 mg/kg starting 2 days before the first injection of OX and throughout the OX treatment period (last OX injection on day 14) (Fig. 4A). On day 8, rats co-treated with OX and E-52862 b.i.d. at 40 mg/kg exhibited significantly lower cumulative cold scores as compared to the OX + vehicle group (p < 0.01 for comparisons between E-52862 40 mg/kg vs. vehicle; Fig. 4B). One week later, on day 15, the antiallodynic effect of the treatment was maintained (F2,25 = 13.5, p < 0.001, ANOVA; p < 0.01 E-52862 40 mg/kg vs. vehicle). Interestingly, 24 hours after E-52862 treatment completion (day 16) animals showed reduced cold allodynia (F2,25 = 16.4, p < 0.001, ANOVA; p < 0.01 E-52862 40 mg/kg vs. vehicle) compared to the vehicle-treated OX-treated group (3.5 ± 0.7 vs. 6.7 ± 0.9), although cumulative pain scores were higher than baseline values in non-neuropathic animals that did not receive OX (F2,25 = 16.4, p < 0.001, ANOVA; p < 0.05 for comparisons between E-52862 40 mg/kg vs. baseline).

Bottom Line: Mechanical hypersensitivity induced after IoN surgery or STZ administration was reduced by acute treatment with E-52862 and morphine, but not by pregabalin.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Drug Discovery &Preclinical Development, ESTEVE, Barcelona, Spain.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus