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Comparison of central versus peripheral delivery of pregabalin in neuropathic pain states.

Martinez JA, Kasamatsu M, Rosales-Hernandez A, Hanson LR, Frey WH, Toth CC - Mol Pain (2012)

Bottom Line: Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects.Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect.NeP was associated with upregulation of CACNA2D1 mRNA and CaVα2δ-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Neurosciences and the University of Calgary, Calgary, AB, Canada.

ABSTRACT

Background: Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaVα2δ-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects.

Results: We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation. As well, radiolabelled pregabalin was administered to determine localization with different deliveries. We evaluated tactile allodynia and thermal hyperalgesia at multiple time points, and then analyzed harvested nervous system tissues for molecular and immunohistochemical changes in CaVα2δ-1 protein expression. Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect. NeP was associated with upregulation of CACNA2D1 mRNA and CaVα2δ-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain. Pregabalin's effect was limited to suppression of CaVα2δ-1 protein (but not CACNA2D1 mRNA) expression at the spinal dorsal horn in neuropathic pain states. Dorsal root ligation prevented CaVα2δ-1 protein trafficking anterograde from the dorsal root ganglia to the dorsal horn after neuropathic pain initiation.

Conclusions: Either intranasal or intrathecal pregabalin relieves neuropathic pain behaviours, perhaps due to pregabalin's effect upon anterograde CaVα2δ-1 protein trafficking from the DRG to the dorsal horn. Intranasal delivery of agents such as pregabalin may be an attractive alternative to systemic therapy for management of neuropathic pain states.

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Related in: MedlinePlus

Microglia Assessment. Microglia accumulation was assessed in the dorsal regions of thoracic and lumbar spinal cord for control rat spinal cord (A), and with either spinal nerve ligation (B) or diabetic peripheral neuropathy (C) in rats. Greater immunohistochemically-identified accumulation and activation of microglia in the dorsal spinal cord of rats was seen with spinal nerve ligation or diabetic peripheral neuropathy (D) without impact of pregabalin delivery.* indicates significant differences between control (sham SNL surgery or citrate-injected non-diabetic rat respectively) and all SNL and DPN rat values using individual unmatched ANOVA testing (p < 0.0125 after Bonferroni corrections). Bar = 50 μm.
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Figure 6: Microglia Assessment. Microglia accumulation was assessed in the dorsal regions of thoracic and lumbar spinal cord for control rat spinal cord (A), and with either spinal nerve ligation (B) or diabetic peripheral neuropathy (C) in rats. Greater immunohistochemically-identified accumulation and activation of microglia in the dorsal spinal cord of rats was seen with spinal nerve ligation or diabetic peripheral neuropathy (D) without impact of pregabalin delivery.* indicates significant differences between control (sham SNL surgery or citrate-injected non-diabetic rat respectively) and all SNL and DPN rat values using individual unmatched ANOVA testing (p < 0.0125 after Bonferroni corrections). Bar = 50 μm.

Mentions: Microglial quantification was performed in the dorsal thoracic and lumbar spinal cords in rats subjected to diabetes and spinal nerve ligation. There was an increased density of activated microglia in the dorsal spinal cord regions in rats in either neuropathic pain model when compared to control rat spinal cord specimens (Figure 6). There was no difference in microglial quantification in rats receiving saline or pregabalin with any method of delivery in either model of neuropathic pain.


Comparison of central versus peripheral delivery of pregabalin in neuropathic pain states.

Martinez JA, Kasamatsu M, Rosales-Hernandez A, Hanson LR, Frey WH, Toth CC - Mol Pain (2012)

Microglia Assessment. Microglia accumulation was assessed in the dorsal regions of thoracic and lumbar spinal cord for control rat spinal cord (A), and with either spinal nerve ligation (B) or diabetic peripheral neuropathy (C) in rats. Greater immunohistochemically-identified accumulation and activation of microglia in the dorsal spinal cord of rats was seen with spinal nerve ligation or diabetic peripheral neuropathy (D) without impact of pregabalin delivery.* indicates significant differences between control (sham SNL surgery or citrate-injected non-diabetic rat respectively) and all SNL and DPN rat values using individual unmatched ANOVA testing (p < 0.0125 after Bonferroni corrections). Bar = 50 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3285045&req=5

Figure 6: Microglia Assessment. Microglia accumulation was assessed in the dorsal regions of thoracic and lumbar spinal cord for control rat spinal cord (A), and with either spinal nerve ligation (B) or diabetic peripheral neuropathy (C) in rats. Greater immunohistochemically-identified accumulation and activation of microglia in the dorsal spinal cord of rats was seen with spinal nerve ligation or diabetic peripheral neuropathy (D) without impact of pregabalin delivery.* indicates significant differences between control (sham SNL surgery or citrate-injected non-diabetic rat respectively) and all SNL and DPN rat values using individual unmatched ANOVA testing (p < 0.0125 after Bonferroni corrections). Bar = 50 μm.
Mentions: Microglial quantification was performed in the dorsal thoracic and lumbar spinal cords in rats subjected to diabetes and spinal nerve ligation. There was an increased density of activated microglia in the dorsal spinal cord regions in rats in either neuropathic pain model when compared to control rat spinal cord specimens (Figure 6). There was no difference in microglial quantification in rats receiving saline or pregabalin with any method of delivery in either model of neuropathic pain.

Bottom Line: Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects.Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect.NeP was associated with upregulation of CACNA2D1 mRNA and CaVα2δ-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Clinical Neurosciences and the University of Calgary, Calgary, AB, Canada.

ABSTRACT

Background: Although pregabalin therapy is beneficial for neuropathic pain (NeP) by targeting the CaVα2δ-1 subunit, its site of action is uncertain. Direct targeting of the central nervous system may be beneficial for the avoidance of systemic side effects.

Results: We used intranasal, intrathecal, and near-nerve chamber forms of delivery of varying concentrations of pregabalin or saline delivered over 14 days in rat models of experimental diabetic peripheral neuropathy and spinal nerve ligation. As well, radiolabelled pregabalin was administered to determine localization with different deliveries. We evaluated tactile allodynia and thermal hyperalgesia at multiple time points, and then analyzed harvested nervous system tissues for molecular and immunohistochemical changes in CaVα2δ-1 protein expression. Both intrathecal and intranasal pregabalin administration at high concentrations relieved NeP behaviors, while near-nerve pregabalin delivery had no effect. NeP was associated with upregulation of CACNA2D1 mRNA and CaVα2δ-1 protein within peripheral nerve, dorsal root ganglia (DRG), and dorsal spinal cord, but not brain. Pregabalin's effect was limited to suppression of CaVα2δ-1 protein (but not CACNA2D1 mRNA) expression at the spinal dorsal horn in neuropathic pain states. Dorsal root ligation prevented CaVα2δ-1 protein trafficking anterograde from the dorsal root ganglia to the dorsal horn after neuropathic pain initiation.

Conclusions: Either intranasal or intrathecal pregabalin relieves neuropathic pain behaviours, perhaps due to pregabalin's effect upon anterograde CaVα2δ-1 protein trafficking from the DRG to the dorsal horn. Intranasal delivery of agents such as pregabalin may be an attractive alternative to systemic therapy for management of neuropathic pain states.

Show MeSH
Related in: MedlinePlus