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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

Diabetic neuropathic pain model after STZ injection.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 21 after the STZ injection. The repeated administrations of the drugs were evaluated on day 28 after 7 days of daily administration. (B) Time-related course of mechanical hyperalgesia after STZ injection (black triangles) and blood glucose levels (white bars) evaluated 4 days post-STZ injection. (C) Effects of a single i.p. administration of E-52862 (40 and 80 mg/kg; grey and black bars), morphine (10 and 20 mg/kg; diagonal dashed bars) and pregabalin (80 mg/kg; horizontal dashed bars) on mechanical hyperalgesia. (D) Effect of repeated i.p. administration of E-52862 (40 mg/kg; grey bars) on mechanical hyperalgesia. Rats were evaluated before and 15 min after the last administration. Each point and vertical line represents the mean ± S.E.M. of the values obtained from at least 8 animals per treatment group. Difference between pre- and post-STZ in glucose levels and mechanical hyperalgesia: ***p < 0.001 (Student’s t-test for glucose values and one-way ANOVA followed by Newman–Keuls test for hyperalgesia development of); ***p < 0.001 vs. vehicle group (HPMC 0.5%) (one-way ANOVA followed by Newman–Keuls test).
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f2: Diabetic neuropathic pain model after STZ injection.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 21 after the STZ injection. The repeated administrations of the drugs were evaluated on day 28 after 7 days of daily administration. (B) Time-related course of mechanical hyperalgesia after STZ injection (black triangles) and blood glucose levels (white bars) evaluated 4 days post-STZ injection. (C) Effects of a single i.p. administration of E-52862 (40 and 80 mg/kg; grey and black bars), morphine (10 and 20 mg/kg; diagonal dashed bars) and pregabalin (80 mg/kg; horizontal dashed bars) on mechanical hyperalgesia. (D) Effect of repeated i.p. administration of E-52862 (40 mg/kg; grey bars) on mechanical hyperalgesia. Rats were evaluated before and 15 min after the last administration. Each point and vertical line represents the mean ± S.E.M. of the values obtained from at least 8 animals per treatment group. Difference between pre- and post-STZ in glucose levels and mechanical hyperalgesia: ***p < 0.001 (Student’s t-test for glucose values and one-way ANOVA followed by Newman–Keuls test for hyperalgesia development of); ***p < 0.001 vs. vehicle group (HPMC 0.5%) (one-way ANOVA followed by Newman–Keuls test).

Mentions: Rats showed increased glucose levels 4 days after STZ injection (453.3 ± 9.0 mg/dl vs. 115.7 ± 1.8 mg/dl, p < 0.001; Fig. 2B) and exhibited a robust reduction of paw withdrawal thresholds in response to noxious pressure stimulation (mechanical hyperalgesia) by 3-4 weeks after the injection of STZ (from 418.9 ± 5.4 to 220 ± 5.6 grams, F2,162 = 354.4, p < 0.001, ANOVA; p < 0.001 for days 21 and 28 post-STZ vs. baseline) (Fig. 2B).


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)

Diabetic neuropathic pain model after STZ injection.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 21 after the STZ injection. The repeated administrations of the drugs were evaluated on day 28 after 7 days of daily administration. (B) Time-related course of mechanical hyperalgesia after STZ injection (black triangles) and blood glucose levels (white bars) evaluated 4 days post-STZ injection. (C) Effects of a single i.p. administration of E-52862 (40 and 80 mg/kg; grey and black bars), morphine (10 and 20 mg/kg; diagonal dashed bars) and pregabalin (80 mg/kg; horizontal dashed bars) on mechanical hyperalgesia. (D) Effect of repeated i.p. administration of E-52862 (40 mg/kg; grey bars) on mechanical hyperalgesia. Rats were evaluated before and 15 min after the last administration. Each point and vertical line represents the mean ± S.E.M. of the values obtained from at least 8 animals per treatment group. Difference between pre- and post-STZ in glucose levels and mechanical hyperalgesia: ***p < 0.001 (Student’s t-test for glucose values and one-way ANOVA followed by Newman–Keuls test for hyperalgesia development of); ***p < 0.001 vs. vehicle group (HPMC 0.5%) (one-way ANOVA followed by Newman–Keuls test).
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getmorefigures.php?uid=PMC4834548&req=5

f2: Diabetic neuropathic pain model after STZ injection.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 21 after the STZ injection. The repeated administrations of the drugs were evaluated on day 28 after 7 days of daily administration. (B) Time-related course of mechanical hyperalgesia after STZ injection (black triangles) and blood glucose levels (white bars) evaluated 4 days post-STZ injection. (C) Effects of a single i.p. administration of E-52862 (40 and 80 mg/kg; grey and black bars), morphine (10 and 20 mg/kg; diagonal dashed bars) and pregabalin (80 mg/kg; horizontal dashed bars) on mechanical hyperalgesia. (D) Effect of repeated i.p. administration of E-52862 (40 mg/kg; grey bars) on mechanical hyperalgesia. Rats were evaluated before and 15 min after the last administration. Each point and vertical line represents the mean ± S.E.M. of the values obtained from at least 8 animals per treatment group. Difference between pre- and post-STZ in glucose levels and mechanical hyperalgesia: ***p < 0.001 (Student’s t-test for glucose values and one-way ANOVA followed by Newman–Keuls test for hyperalgesia development of); ***p < 0.001 vs. vehicle group (HPMC 0.5%) (one-way ANOVA followed by Newman–Keuls test).
Mentions: Rats showed increased glucose levels 4 days after STZ injection (453.3 ± 9.0 mg/dl vs. 115.7 ± 1.8 mg/dl, p < 0.001; Fig. 2B) and exhibited a robust reduction of paw withdrawal thresholds in response to noxious pressure stimulation (mechanical hyperalgesia) by 3-4 weeks after the injection of STZ (from 418.9 ± 5.4 to 220 ± 5.6 grams, F2,162 = 354.4, p < 0.001, ANOVA; p < 0.001 for days 21 and 28 post-STZ vs. baseline) (Fig. 2B).

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