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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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Increased BSCB permeability extends throughout the spinal cord. A: left panel, representative spinal cord from naïve rats, rats 24 hours post C-fiber stimulation or rats with lidocaine block before C-fiber stimulation. Middle and right panels, C-fiber stimulation (middle) or local application of capsaicin onto sciatic nerve (right) increases contralateral spinal cord Evans Blue permeability 24 hours post treatment. B: Increased permeability to Evans Blue in the lumbar spinal cord contralateral to CCI (left panel) or SNI (middle) and in thoracic spinal cord (right). Upper picture: representative spinal cord and brain from naïve rats, or rats 24 hours post PNI. Data are presented as mean ± SEM; *P < 0.05, **p < 0.01, **P < 0.001 compared to respective naïve groups, n = 6-9 per group.
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Figure 5: Increased BSCB permeability extends throughout the spinal cord. A: left panel, representative spinal cord from naïve rats, rats 24 hours post C-fiber stimulation or rats with lidocaine block before C-fiber stimulation. Middle and right panels, C-fiber stimulation (middle) or local application of capsaicin onto sciatic nerve (right) increases contralateral spinal cord Evans Blue permeability 24 hours post treatment. B: Increased permeability to Evans Blue in the lumbar spinal cord contralateral to CCI (left panel) or SNI (middle) and in thoracic spinal cord (right). Upper picture: representative spinal cord and brain from naïve rats, or rats 24 hours post PNI. Data are presented as mean ± SEM; *P < 0.05, **p < 0.01, **P < 0.001 compared to respective naïve groups, n = 6-9 per group.

Mentions: In investigating the effects of electrical C-fiber stimulation we examined the contralateral as well as the ipsilateral lumbar dorsal spinal cord and found that the increase in Evans Blue accumulation 24 hrs after stimulation was produced in the contralateral, as well as the ipsilateral dorsal spinal cord (Figure 5A). Moreover the level of Evans Blue in the contralateral side was not different from on the side ipsilateral to the nerve stimulation. Increased Evans Blue accumulation in the contralateral dorsal cord was mimicked by applying capsaicin to the sciatic nerve (Figure 5A). The increases in Evans Blue accumulation in spinal cord was prevented by applying lidocaine to the sciatic nerve just prior to electrical stimulation (Figure 5A). Taking these findings together we conclude that the increase in BSCB permeability triggered by short-duration electrical stimulation of C-fibers was not restricted to the ipisilateral spinal dorsal horn but was widespread in the spinal cord.


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)

Increased BSCB permeability extends throughout the spinal cord. A: left panel, representative spinal cord from naïve rats, rats 24 hours post C-fiber stimulation or rats with lidocaine block before C-fiber stimulation. Middle and right panels, C-fiber stimulation (middle) or local application of capsaicin onto sciatic nerve (right) increases contralateral spinal cord Evans Blue permeability 24 hours post treatment. B: Increased permeability to Evans Blue in the lumbar spinal cord contralateral to CCI (left panel) or SNI (middle) and in thoracic spinal cord (right). Upper picture: representative spinal cord and brain from naïve rats, or rats 24 hours post PNI. Data are presented as mean ± SEM; *P < 0.05, **p < 0.01, **P < 0.001 compared to respective naïve groups, n = 6-9 per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: Increased BSCB permeability extends throughout the spinal cord. A: left panel, representative spinal cord from naïve rats, rats 24 hours post C-fiber stimulation or rats with lidocaine block before C-fiber stimulation. Middle and right panels, C-fiber stimulation (middle) or local application of capsaicin onto sciatic nerve (right) increases contralateral spinal cord Evans Blue permeability 24 hours post treatment. B: Increased permeability to Evans Blue in the lumbar spinal cord contralateral to CCI (left panel) or SNI (middle) and in thoracic spinal cord (right). Upper picture: representative spinal cord and brain from naïve rats, or rats 24 hours post PNI. Data are presented as mean ± SEM; *P < 0.05, **p < 0.01, **P < 0.001 compared to respective naïve groups, n = 6-9 per group.
Mentions: In investigating the effects of electrical C-fiber stimulation we examined the contralateral as well as the ipsilateral lumbar dorsal spinal cord and found that the increase in Evans Blue accumulation 24 hrs after stimulation was produced in the contralateral, as well as the ipsilateral dorsal spinal cord (Figure 5A). Moreover the level of Evans Blue in the contralateral side was not different from on the side ipsilateral to the nerve stimulation. Increased Evans Blue accumulation in the contralateral dorsal cord was mimicked by applying capsaicin to the sciatic nerve (Figure 5A). The increases in Evans Blue accumulation in spinal cord was prevented by applying lidocaine to the sciatic nerve just prior to electrical stimulation (Figure 5A). Taking these findings together we conclude that the increase in BSCB permeability triggered by short-duration electrical stimulation of C-fibers was not restricted to the ipisilateral spinal dorsal horn but was widespread in the spinal cord.

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