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Role of anoctamin-1 and bestrophin-1 in spinal nerve ligation-induced neuropathic pain in rats.

Pineda-Farias JB, Barragán-Iglesias P, Loeza-Alcocer E, Torres-López JE, Rocha-González HI, Pérez-Severiano F, Delgado-Lezama R, Granados-Soto V - Mol Pain (2015)

Bottom Line: Intrathecal administration of non-selective CaCCs inhibitors (NPPB, 9-AC and NFA) dose-dependently reduced tactile allodynia.Blockade of these CaCCs suppresses compound action potential generation in putative C fibers and lessens established tactile allodynia.As CaCCs activity contributes to neuropathic pain maintenance, selective inhibition of their activity may function as a tool to generate analgesia in nerve injury pain states.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Sede Sur, Calzada de los Tenorios 235, Colonia Granjas Coapa, 14330, México, D.F., México. jorgepinedafarias@yahoo.com.mx.

ABSTRACT

Background: Calcium-activated chloride channels (CaCCs) activation induces membrane depolarization by increasing chloride efflux in primary sensory neurons that can facilitate action potential generation. Previous studies suggest that CaCCs family members bestrophin-1 and anoctamin-1 are involved in inflammatory pain. However, their role in neuropathic pain is unclear. In this investigation we assessed the involvement of these CaCCs family members in rats subjected to the L5/L6 spinal nerve ligation. In addition, anoctamin-1 and bestrophin-1 mRNA and protein expression in dorsal root ganglion (DRG) and spinal cord was also determined in the presence and absence of selective inhibitors.

Results: L5/L6 spinal nerve ligation induced mechanical tactile allodynia. Intrathecal administration of non-selective CaCCs inhibitors (NPPB, 9-AC and NFA) dose-dependently reduced tactile allodynia. Intrathecal administration of selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) also dose-dependently diminished tactile allodynia and thermal hyperalgesia. Anoctamin-1 and bestrophin-1 mRNA and protein were expressed in the dorsal spinal cord and DRG of naïve, sham and neuropathic rats. L5/L6 spinal nerve ligation rose mRNA and protein expression of anoctamin-1, but not bestrophin-1, in the dorsal spinal cord and DRG from day 1 to day 14 after nerve ligation. In addition, repeated administration of CaCCs inhibitors (T16Ainh-A01, CaCCinh-A01 or NFA) or anti-anoctamin-1 antibody prevented spinal nerve ligation-induced rises in anoctamin-1 mRNA and protein expression. Following spinal nerve ligation, the compound action potential generation of putative C fibers increased while selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) attenuated such increase.

Conclusions: There is functional anoctamin-1 and bestrophin-1 expression in rats at sites related to nociceptive processing. Blockade of these CaCCs suppresses compound action potential generation in putative C fibers and lessens established tactile allodynia. As CaCCs activity contributes to neuropathic pain maintenance, selective inhibition of their activity may function as a tool to generate analgesia in nerve injury pain states.

No MeSH data available.


Related in: MedlinePlus

Intrathecal injection of non-selective and selective CaCCs inhibitors reduces thermal hyperalgesia. Time-course of the antihyperalgesic effect of NFA (300 μg), T16Ainh-A01 (10 μg) and CaCCinh-A01 (10 μg) in rats subjected to L5/L6 spinal nerve injury compared to naïve, sham and vehicle groups. Withdrawal latency was assessed 14 days after spinal nerve injury. Data are presented as the mean ± SEM for six animals determined by the mean of three trials for each rat at each time. Note that CaCCs inhibitors increased withdrawal latency. *Significantly different from the vehicle group (p < 0.05), as determined by repeated measures two-way ANOVA followed by the Bonferroni test.
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Fig3: Intrathecal injection of non-selective and selective CaCCs inhibitors reduces thermal hyperalgesia. Time-course of the antihyperalgesic effect of NFA (300 μg), T16Ainh-A01 (10 μg) and CaCCinh-A01 (10 μg) in rats subjected to L5/L6 spinal nerve injury compared to naïve, sham and vehicle groups. Withdrawal latency was assessed 14 days after spinal nerve injury. Data are presented as the mean ± SEM for six animals determined by the mean of three trials for each rat at each time. Note that CaCCs inhibitors increased withdrawal latency. *Significantly different from the vehicle group (p < 0.05), as determined by repeated measures two-way ANOVA followed by the Bonferroni test.

Mentions: Besides tactile allodynia, ligation of L5/L6 spinal nerves caused a significant decrease in the withdrawal latency time produced by a thermal stress in the ipsilateral, but not contralateral (data not shown), paw of all rats as compared to the naïve or sham-operated animals. On the other hand, intrathecal administration (on day 14th) of either NFA (300 µg), T16Ainh-A01 (10 µg) or CaCCinh-A01 (10 µg), but not vehicle, significantly increased the withdrawal latency time in the ligated animals (Figure 3). The maximal antihyperalgesic effect in all cases occurred in approximately 2 h after drug administration and then decayed gradually in about 8 h.Figure 3


Role of anoctamin-1 and bestrophin-1 in spinal nerve ligation-induced neuropathic pain in rats.

Pineda-Farias JB, Barragán-Iglesias P, Loeza-Alcocer E, Torres-López JE, Rocha-González HI, Pérez-Severiano F, Delgado-Lezama R, Granados-Soto V - Mol Pain (2015)

Intrathecal injection of non-selective and selective CaCCs inhibitors reduces thermal hyperalgesia. Time-course of the antihyperalgesic effect of NFA (300 μg), T16Ainh-A01 (10 μg) and CaCCinh-A01 (10 μg) in rats subjected to L5/L6 spinal nerve injury compared to naïve, sham and vehicle groups. Withdrawal latency was assessed 14 days after spinal nerve injury. Data are presented as the mean ± SEM for six animals determined by the mean of three trials for each rat at each time. Note that CaCCs inhibitors increased withdrawal latency. *Significantly different from the vehicle group (p < 0.05), as determined by repeated measures two-way ANOVA followed by the Bonferroni test.
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4487556&req=5

Fig3: Intrathecal injection of non-selective and selective CaCCs inhibitors reduces thermal hyperalgesia. Time-course of the antihyperalgesic effect of NFA (300 μg), T16Ainh-A01 (10 μg) and CaCCinh-A01 (10 μg) in rats subjected to L5/L6 spinal nerve injury compared to naïve, sham and vehicle groups. Withdrawal latency was assessed 14 days after spinal nerve injury. Data are presented as the mean ± SEM for six animals determined by the mean of three trials for each rat at each time. Note that CaCCs inhibitors increased withdrawal latency. *Significantly different from the vehicle group (p < 0.05), as determined by repeated measures two-way ANOVA followed by the Bonferroni test.
Mentions: Besides tactile allodynia, ligation of L5/L6 spinal nerves caused a significant decrease in the withdrawal latency time produced by a thermal stress in the ipsilateral, but not contralateral (data not shown), paw of all rats as compared to the naïve or sham-operated animals. On the other hand, intrathecal administration (on day 14th) of either NFA (300 µg), T16Ainh-A01 (10 µg) or CaCCinh-A01 (10 µg), but not vehicle, significantly increased the withdrawal latency time in the ligated animals (Figure 3). The maximal antihyperalgesic effect in all cases occurred in approximately 2 h after drug administration and then decayed gradually in about 8 h.Figure 3

Bottom Line: Intrathecal administration of non-selective CaCCs inhibitors (NPPB, 9-AC and NFA) dose-dependently reduced tactile allodynia.Blockade of these CaCCs suppresses compound action potential generation in putative C fibers and lessens established tactile allodynia.As CaCCs activity contributes to neuropathic pain maintenance, selective inhibition of their activity may function as a tool to generate analgesia in nerve injury pain states.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology of Pain Laboratory, Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados (Cinvestav), Sede Sur, Calzada de los Tenorios 235, Colonia Granjas Coapa, 14330, México, D.F., México. jorgepinedafarias@yahoo.com.mx.

ABSTRACT

Background: Calcium-activated chloride channels (CaCCs) activation induces membrane depolarization by increasing chloride efflux in primary sensory neurons that can facilitate action potential generation. Previous studies suggest that CaCCs family members bestrophin-1 and anoctamin-1 are involved in inflammatory pain. However, their role in neuropathic pain is unclear. In this investigation we assessed the involvement of these CaCCs family members in rats subjected to the L5/L6 spinal nerve ligation. In addition, anoctamin-1 and bestrophin-1 mRNA and protein expression in dorsal root ganglion (DRG) and spinal cord was also determined in the presence and absence of selective inhibitors.

Results: L5/L6 spinal nerve ligation induced mechanical tactile allodynia. Intrathecal administration of non-selective CaCCs inhibitors (NPPB, 9-AC and NFA) dose-dependently reduced tactile allodynia. Intrathecal administration of selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) also dose-dependently diminished tactile allodynia and thermal hyperalgesia. Anoctamin-1 and bestrophin-1 mRNA and protein were expressed in the dorsal spinal cord and DRG of naïve, sham and neuropathic rats. L5/L6 spinal nerve ligation rose mRNA and protein expression of anoctamin-1, but not bestrophin-1, in the dorsal spinal cord and DRG from day 1 to day 14 after nerve ligation. In addition, repeated administration of CaCCs inhibitors (T16Ainh-A01, CaCCinh-A01 or NFA) or anti-anoctamin-1 antibody prevented spinal nerve ligation-induced rises in anoctamin-1 mRNA and protein expression. Following spinal nerve ligation, the compound action potential generation of putative C fibers increased while selective CaCCs inhibitors (T16Ainh-A01 and CaCCinh-A01) attenuated such increase.

Conclusions: There is functional anoctamin-1 and bestrophin-1 expression in rats at sites related to nociceptive processing. Blockade of these CaCCs suppresses compound action potential generation in putative C fibers and lessens established tactile allodynia. As CaCCs activity contributes to neuropathic pain maintenance, selective inhibition of their activity may function as a tool to generate analgesia in nerve injury pain states.

No MeSH data available.


Related in: MedlinePlus