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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

Chemotherapy-induced neuropathic pain after OX treatment.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 8 after four OX administrations. The repeated administration of drugs was evaluated on day 15 after 7 days of daily administration. The cumulative cold scores in response to acetone were evaluated on days 8, 15 and 16 after the baseline reading (testing days). (B) Time-related course of cold allodynia after OX treatment evaluated as cumulative cold score. (C) Effects of a single i.p. administration of E-52862 (grey and black bars) and gabapentin (diagonal dashed bars) at 40 and 100 mg/kg, respectively, on cold allodynia. (D) Dose-response effects of repeated administration of E-52862 (20, 40 and 80 mg/kg) and response to cold stimulus one day after the last administration (day 16). Each point and vertical line represents the mean ± S.E.M. of the values obtained from 10 animals per group. *p < 0.05; **p < 0.01; ***p < 0.001 vs. each vehicle group (one-way ANOVA followed by Newman–Keuls test).
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f3: Chemotherapy-induced neuropathic pain after OX treatment.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 8 after four OX administrations. The repeated administration of drugs was evaluated on day 15 after 7 days of daily administration. The cumulative cold scores in response to acetone were evaluated on days 8, 15 and 16 after the baseline reading (testing days). (B) Time-related course of cold allodynia after OX treatment evaluated as cumulative cold score. (C) Effects of a single i.p. administration of E-52862 (grey and black bars) and gabapentin (diagonal dashed bars) at 40 and 100 mg/kg, respectively, on cold allodynia. (D) Dose-response effects of repeated administration of E-52862 (20, 40 and 80 mg/kg) and response to cold stimulus one day after the last administration (day 16). Each point and vertical line represents the mean ± S.E.M. of the values obtained from 10 animals per group. *p < 0.05; **p < 0.01; ***p < 0.001 vs. each vehicle group (one-way ANOVA followed by Newman–Keuls test).

Mentions: OX administration (Fig. 3A) induced cold allodynia, i.e., increased cumulative cold score in the acetone test respect to HPMC (vehicle)-treated animals on days 8, 15 and 16 (F3,36 = 10.1, p < 0.001 for the cumulative cold score; Fig. 3B).


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)

Chemotherapy-induced neuropathic pain after OX treatment.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 8 after four OX administrations. The repeated administration of drugs was evaluated on day 15 after 7 days of daily administration. The cumulative cold scores in response to acetone were evaluated on days 8, 15 and 16 after the baseline reading (testing days). (B) Time-related course of cold allodynia after OX treatment evaluated as cumulative cold score. (C) Effects of a single i.p. administration of E-52862 (grey and black bars) and gabapentin (diagonal dashed bars) at 40 and 100 mg/kg, respectively, on cold allodynia. (D) Dose-response effects of repeated administration of E-52862 (20, 40 and 80 mg/kg) and response to cold stimulus one day after the last administration (day 16). Each point and vertical line represents the mean ± S.E.M. of the values obtained from 10 animals per group. *p < 0.05; **p < 0.01; ***p < 0.001 vs. each 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

f3: Chemotherapy-induced neuropathic pain after OX treatment.(A) Experimental protocol. The acute treatment effects of the drugs were evaluated on day 8 after four OX administrations. The repeated administration of drugs was evaluated on day 15 after 7 days of daily administration. The cumulative cold scores in response to acetone were evaluated on days 8, 15 and 16 after the baseline reading (testing days). (B) Time-related course of cold allodynia after OX treatment evaluated as cumulative cold score. (C) Effects of a single i.p. administration of E-52862 (grey and black bars) and gabapentin (diagonal dashed bars) at 40 and 100 mg/kg, respectively, on cold allodynia. (D) Dose-response effects of repeated administration of E-52862 (20, 40 and 80 mg/kg) and response to cold stimulus one day after the last administration (day 16). Each point and vertical line represents the mean ± S.E.M. of the values obtained from 10 animals per group. *p < 0.05; **p < 0.01; ***p < 0.001 vs. each vehicle group (one-way ANOVA followed by Newman–Keuls test).
Mentions: OX administration (Fig. 3A) induced cold allodynia, i.e., increased cumulative cold score in the acetone test respect to HPMC (vehicle)-treated animals on days 8, 15 and 16 (F3,36 = 10.1, p < 0.001 for the cumulative cold score; Fig. 3B).

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