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Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier.

Beggs S, Liu XJ, Kwan C, Salter MW - Mol Pain (2010)

Bottom Line: As the increase is mimicked by applying capsaicin to the nerve, the most parsimonious explanation for our findings is that the increase in permeability is mediated by activation of TRPV1-expressing primary sensory neurons.Our findings may be relevant to the development of pain and neuroplastic changes in the CNS following nerve injury.In addition, our findings may provide the basis for developing methods to purposefully open the BBB when needed to increase brain penetration of therapeutic agents that might normally be excluded by an intact BBB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Program in Neurosciences & Mental Health, Hospital for Sick Children, Department of Physiology, University of Toronto, and University of Toronto Centre for the Study of Pain, Toronto, ON, Canada.

ABSTRACT

Background: The blood-brain barrier (BBB) plays the crucial role of limiting exposure of the central nervous system (CNS) to damaging molecules and cells. Dysfunction of the BBB is critical in a broad range of CNS disorders including neurodegeneration, inflammatory or traumatic injury to the CNS, and stroke. In peripheral tissues, the vascular-tissue permeability is normally greater than BBB permeability, but vascular leakage can be induced by efferent discharge activity in primary sensory neurons leading to plasma extravasation into the extravascular space. Whether discharge activity of sensory afferents entering the CNS may open the BBB or blood-spinal cord barrier (BSCB) remains an open question.

Results: Here we show that peripheral nerve injury (PNI) produced by either sciatic nerve constriction or transecting two of its main branches causes an increase in BSCB permeability, as assessed by using Evans Blue dye or horseradish peroxidase. The increase in BSCB permeability was not observed 6 hours after the PNI but was apparent 24 hours after the injury. The increase in BSCB permeability was transient, peaking about 24-48 hrs after PNI with BSCB integrity returning to normal levels by 7 days. The increase in BSCB permeability was prevented by administering the local anaesthetic lidocaine at the site of the nerve injury. BSCB permeability was also increased 24 hours after electrical stimulation of the sciatic nerve at intensity sufficient to activate C-fibers, but not when A-fibers only were activated. Likewise, BSCB permeability increased following application of capsaicin to the nerve. The increase in permeability caused by C-fiber stimulation or by PNI was not anatomically limited to the site of central termination of primary afferents from the sciatic nerve in the lumbar cord, but rather extended throughout the spinal cord and into the brain.

Conclusions: We have discovered that injury to a peripheral nerve and electrical stimulation of C-fibers each cause an increase in the permeability of the BSCB and the BBB. The increase in permeability is delayed in onset, peaks at about 24 hours and is dependent upon action potential propagation. As the increase is mimicked by applying capsaicin to the nerve, the most parsimonious explanation for our findings is that the increase in permeability is mediated by activation of TRPV1-expressing primary sensory neurons. Our findings may be relevant to the development of pain and neuroplastic changes in the CNS following nerve injury. In addition, our findings may provide the basis for developing methods to purposefully open the BBB when needed to increase brain penetration of therapeutic agents that might normally be excluded by an intact BBB.

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Peripheral nerve injury (PNI) increases BSCB permeability. A: Increased permeability to Evans Blue of spinal cord from naïve rats, sham operated rats or rats with chronic constriction injury (CCI, left) or spared nerve injury (SNI, right). Inset: Standard curve of Evans blue and the representative reading of naïve rats or CCI rats. B: Increased permeability to horseradish peroxidase (HRP) following PNI. Left, representative spinal cord sections of HRP extravasation 24 hours after SNI, CCI or naïve rats. Right, histogram showing the integrated pixel density of HRP signaling. Data are presented as mean ± SEM; *p < 0.05 compared to naïve; n = 4-6 per group. All measurements are from lumbar spinal cord ipsilateral to PNI stimulation.
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Figure 1: Peripheral nerve injury (PNI) increases BSCB permeability. A: Increased permeability to Evans Blue of spinal cord from naïve rats, sham operated rats or rats with chronic constriction injury (CCI, left) or spared nerve injury (SNI, right). Inset: Standard curve of Evans blue and the representative reading of naïve rats or CCI rats. B: Increased permeability to horseradish peroxidase (HRP) following PNI. Left, representative spinal cord sections of HRP extravasation 24 hours after SNI, CCI or naïve rats. Right, histogram showing the integrated pixel density of HRP signaling. Data are presented as mean ± SEM; *p < 0.05 compared to naïve; n = 4-6 per group. All measurements are from lumbar spinal cord ipsilateral to PNI stimulation.

Mentions: We assessed the integrity of the BSCB with intravenously administered Evans Blue dye. Evans Blue binds to albumin in the circulation producing a molecular complex of sufficient molecular size that it does not cross the intact BSCB or BBB. Thus, there is minimal accumulation of Evans Blue in the spinal cord, or brain, under basal conditions in naïve animals (Figure 1). To investigate whether BSCB permeability might be altered by CCI we administered Evans Blue at varying times after the nerve injury, induced by placing a polythene cuff around the nerve, and quantified the amount of Evans Blue in the dorsal spinal cord ipsilateral to the injury. We found that 6 hours after the CCI surgery, the level of Evans Blue accumulating was not different from that of the dorsal horn of naïve animals, or animals that we subjected to sham surgery (Figure 1A left). In contrast, 24 hours after surgery there was a significant increase in Evans Blue in the ipsilateral dorsal horn of nerve-injured animals as compared with sham controls (Figure 1A left). Evans Blue accumulation in the dorsal horn of nerve-injured animals was also significantly increased when the dye was administered 3 days after surgery. However, when Evans Blue was administered 7 days after surgery the dye accumulation in the dorsal horn of nerve-injured animals was not different from that of sham controls or naïve animals.


Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier.

Beggs S, Liu XJ, Kwan C, Salter MW - Mol Pain (2010)

Peripheral nerve injury (PNI) increases BSCB permeability. A: Increased permeability to Evans Blue of spinal cord from naïve rats, sham operated rats or rats with chronic constriction injury (CCI, left) or spared nerve injury (SNI, right). Inset: Standard curve of Evans blue and the representative reading of naïve rats or CCI rats. B: Increased permeability to horseradish peroxidase (HRP) following PNI. Left, representative spinal cord sections of HRP extravasation 24 hours after SNI, CCI or naïve rats. Right, histogram showing the integrated pixel density of HRP signaling. Data are presented as mean ± SEM; *p < 0.05 compared to naïve; n = 4-6 per group. All measurements are from lumbar spinal cord ipsilateral to PNI stimulation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2984489&req=5

Figure 1: Peripheral nerve injury (PNI) increases BSCB permeability. A: Increased permeability to Evans Blue of spinal cord from naïve rats, sham operated rats or rats with chronic constriction injury (CCI, left) or spared nerve injury (SNI, right). Inset: Standard curve of Evans blue and the representative reading of naïve rats or CCI rats. B: Increased permeability to horseradish peroxidase (HRP) following PNI. Left, representative spinal cord sections of HRP extravasation 24 hours after SNI, CCI or naïve rats. Right, histogram showing the integrated pixel density of HRP signaling. Data are presented as mean ± SEM; *p < 0.05 compared to naïve; n = 4-6 per group. All measurements are from lumbar spinal cord ipsilateral to PNI stimulation.
Mentions: We assessed the integrity of the BSCB with intravenously administered Evans Blue dye. Evans Blue binds to albumin in the circulation producing a molecular complex of sufficient molecular size that it does not cross the intact BSCB or BBB. Thus, there is minimal accumulation of Evans Blue in the spinal cord, or brain, under basal conditions in naïve animals (Figure 1). To investigate whether BSCB permeability might be altered by CCI we administered Evans Blue at varying times after the nerve injury, induced by placing a polythene cuff around the nerve, and quantified the amount of Evans Blue in the dorsal spinal cord ipsilateral to the injury. We found that 6 hours after the CCI surgery, the level of Evans Blue accumulating was not different from that of the dorsal horn of naïve animals, or animals that we subjected to sham surgery (Figure 1A left). In contrast, 24 hours after surgery there was a significant increase in Evans Blue in the ipsilateral dorsal horn of nerve-injured animals as compared with sham controls (Figure 1A left). Evans Blue accumulation in the dorsal horn of nerve-injured animals was also significantly increased when the dye was administered 3 days after surgery. However, when Evans Blue was administered 7 days after surgery the dye accumulation in the dorsal horn of nerve-injured animals was not different from that of sham controls or naïve animals.

Bottom Line: As the increase is mimicked by applying capsaicin to the nerve, the most parsimonious explanation for our findings is that the increase in permeability is mediated by activation of TRPV1-expressing primary sensory neurons.Our findings may be relevant to the development of pain and neuroplastic changes in the CNS following nerve injury.In addition, our findings may provide the basis for developing methods to purposefully open the BBB when needed to increase brain penetration of therapeutic agents that might normally be excluded by an intact BBB.

View Article: PubMed Central - HTML - PubMed

Affiliation: Program in Neurosciences & Mental Health, Hospital for Sick Children, Department of Physiology, University of Toronto, and University of Toronto Centre for the Study of Pain, Toronto, ON, Canada.

ABSTRACT

Background: The blood-brain barrier (BBB) plays the crucial role of limiting exposure of the central nervous system (CNS) to damaging molecules and cells. Dysfunction of the BBB is critical in a broad range of CNS disorders including neurodegeneration, inflammatory or traumatic injury to the CNS, and stroke. In peripheral tissues, the vascular-tissue permeability is normally greater than BBB permeability, but vascular leakage can be induced by efferent discharge activity in primary sensory neurons leading to plasma extravasation into the extravascular space. Whether discharge activity of sensory afferents entering the CNS may open the BBB or blood-spinal cord barrier (BSCB) remains an open question.

Results: Here we show that peripheral nerve injury (PNI) produced by either sciatic nerve constriction or transecting two of its main branches causes an increase in BSCB permeability, as assessed by using Evans Blue dye or horseradish peroxidase. The increase in BSCB permeability was not observed 6 hours after the PNI but was apparent 24 hours after the injury. The increase in BSCB permeability was transient, peaking about 24-48 hrs after PNI with BSCB integrity returning to normal levels by 7 days. The increase in BSCB permeability was prevented by administering the local anaesthetic lidocaine at the site of the nerve injury. BSCB permeability was also increased 24 hours after electrical stimulation of the sciatic nerve at intensity sufficient to activate C-fibers, but not when A-fibers only were activated. Likewise, BSCB permeability increased following application of capsaicin to the nerve. The increase in permeability caused by C-fiber stimulation or by PNI was not anatomically limited to the site of central termination of primary afferents from the sciatic nerve in the lumbar cord, but rather extended throughout the spinal cord and into the brain.

Conclusions: We have discovered that injury to a peripheral nerve and electrical stimulation of C-fibers each cause an increase in the permeability of the BSCB and the BBB. The increase in permeability is delayed in onset, peaks at about 24 hours and is dependent upon action potential propagation. As the increase is mimicked by applying capsaicin to the nerve, the most parsimonious explanation for our findings is that the increase in permeability is mediated by activation of TRPV1-expressing primary sensory neurons. Our findings may be relevant to the development of pain and neuroplastic changes in the CNS following nerve injury. In addition, our findings may provide the basis for developing methods to purposefully open the BBB when needed to increase brain penetration of therapeutic agents that might normally be excluded by an intact BBB.

Show MeSH
Related in: MedlinePlus