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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

Trigeminal neuropathic pain model of chronic constriction injury of the IoN.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 25 after IoN surgery. The repeated administrations of the drugs were evaluated on day 32 after 7 days of repeated daily administration. (B) Time-related course of mechanical allodynia after IoN ligation. Evaluation was performed one day before surgery (baseline) and on postoperative days 5, 15 and 25 (black circles). (C) Effect of a single i.p. administration of E-52862 (20 and 40 mg/kg, i.p.; grey bars), morphine (5 mg/kg; diagonal dashed bars) and pregabalin (40 mg/kg; horizontal dashed bars) on mechanical allodynia. (D) Effect of repeated i.p. administration of E-52862 (20 and 40 mg/kg; grey bars) and morphine (5 mg/kg; diagonal dashed bars) on mechanical allodynia. Each point and vertical line represent the mean ± S.E.M. of the values obtained in at least 10 rats per treatment and baseline groups. ***p < 0.001 vs. pre-surgery in (B). **p < 0.01; ***p < 0.001 vs. vehicle group in (C) and (D) (one-way ANOVA followed by Newman–Keuls test).
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f1: Trigeminal neuropathic pain model of chronic constriction injury of the IoN.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 25 after IoN surgery. The repeated administrations of the drugs were evaluated on day 32 after 7 days of repeated daily administration. (B) Time-related course of mechanical allodynia after IoN ligation. Evaluation was performed one day before surgery (baseline) and on postoperative days 5, 15 and 25 (black circles). (C) Effect of a single i.p. administration of E-52862 (20 and 40 mg/kg, i.p.; grey bars), morphine (5 mg/kg; diagonal dashed bars) and pregabalin (40 mg/kg; horizontal dashed bars) on mechanical allodynia. (D) Effect of repeated i.p. administration of E-52862 (20 and 40 mg/kg; grey bars) and morphine (5 mg/kg; diagonal dashed bars) on mechanical allodynia. Each point and vertical line represent the mean ± S.E.M. of the values obtained in at least 10 rats per treatment and baseline groups. ***p < 0.001 vs. pre-surgery in (B). **p < 0.01; ***p < 0.001 vs. vehicle group in (C) and (D) (one-way ANOVA followed by Newman–Keuls test).

Mentions: Baseline values were obtained one day before surgery, setting the normal response to von Frey filaments (Fig. 1A). Chronic constriction of the IoN induced significant changes in response to mechanical stimulation of the territory innervated by the ligated ipsilateral IoN (Fig. 1B). Initially, 5 days after surgery, the response score dropped significantly, indicating hyposensitivity, but this was followed by a robust hypersensitivity to von Frey filament stimulation on days 15 and 25 after IoN surgery, and hypersensitivity was maintained at least for 32 days after IoN constriction (F4,233 = 533.7, p < 0.001, ANOVA; p < 0.001 for days 5, 15, 25 and 32 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)

Trigeminal neuropathic pain model of chronic constriction injury of the IoN.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 25 after IoN surgery. The repeated administrations of the drugs were evaluated on day 32 after 7 days of repeated daily administration. (B) Time-related course of mechanical allodynia after IoN ligation. Evaluation was performed one day before surgery (baseline) and on postoperative days 5, 15 and 25 (black circles). (C) Effect of a single i.p. administration of E-52862 (20 and 40 mg/kg, i.p.; grey bars), morphine (5 mg/kg; diagonal dashed bars) and pregabalin (40 mg/kg; horizontal dashed bars) on mechanical allodynia. (D) Effect of repeated i.p. administration of E-52862 (20 and 40 mg/kg; grey bars) and morphine (5 mg/kg; diagonal dashed bars) on mechanical allodynia. Each point and vertical line represent the mean ± S.E.M. of the values obtained in at least 10 rats per treatment and baseline groups. ***p < 0.001 vs. pre-surgery in (B). **p < 0.01; ***p < 0.001 vs. vehicle group in (C) and (D) (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

f1: Trigeminal neuropathic pain model of chronic constriction injury of the IoN.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 25 after IoN surgery. The repeated administrations of the drugs were evaluated on day 32 after 7 days of repeated daily administration. (B) Time-related course of mechanical allodynia after IoN ligation. Evaluation was performed one day before surgery (baseline) and on postoperative days 5, 15 and 25 (black circles). (C) Effect of a single i.p. administration of E-52862 (20 and 40 mg/kg, i.p.; grey bars), morphine (5 mg/kg; diagonal dashed bars) and pregabalin (40 mg/kg; horizontal dashed bars) on mechanical allodynia. (D) Effect of repeated i.p. administration of E-52862 (20 and 40 mg/kg; grey bars) and morphine (5 mg/kg; diagonal dashed bars) on mechanical allodynia. Each point and vertical line represent the mean ± S.E.M. of the values obtained in at least 10 rats per treatment and baseline groups. ***p < 0.001 vs. pre-surgery in (B). **p < 0.01; ***p < 0.001 vs. vehicle group in (C) and (D) (one-way ANOVA followed by Newman–Keuls test).
Mentions: Baseline values were obtained one day before surgery, setting the normal response to von Frey filaments (Fig. 1A). Chronic constriction of the IoN induced significant changes in response to mechanical stimulation of the territory innervated by the ligated ipsilateral IoN (Fig. 1B). Initially, 5 days after surgery, the response score dropped significantly, indicating hyposensitivity, but this was followed by a robust hypersensitivity to von Frey filament stimulation on days 15 and 25 after IoN surgery, and hypersensitivity was maintained at least for 32 days after IoN constriction (F4,233 = 533.7, p < 0.001, ANOVA; p < 0.001 for days 5, 15, 25 and 32 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