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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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Local application of capsaicin increases BSCB permeability. A: 1% Capsaicin or vehicle was applied onto the sciatic nerve and Evans Blue extravasation was measured 24 hours later. All readings are from lumbar spinal cord ipsilateral to capsaicin or vehicle. Data are presented as mean ± SEM; **p < 0.01 compared to naïve, n = 5-9 per group.B: 1% Capsaicin was applied to the sciatic nerve and Evans Blue was injected immediately after capsaicin. Ipsilateral and contralateral paw images were captured 45 minutes after capsaicin treatment.
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Figure 4: Local application of capsaicin increases BSCB permeability. A: 1% Capsaicin or vehicle was applied onto the sciatic nerve and Evans Blue extravasation was measured 24 hours later. All readings are from lumbar spinal cord ipsilateral to capsaicin or vehicle. Data are presented as mean ± SEM; **p < 0.01 compared to naïve, n = 5-9 per group.B: 1% Capsaicin was applied to the sciatic nerve and Evans Blue was injected immediately after capsaicin. Ipsilateral and contralateral paw images were captured 45 minutes after capsaicin treatment.

Mentions: Neurogenic plasma extravasation is mediated through activating primary afferent C-fibers that express TRPV1 and are hence activated by capsaicin [9,22]. To determine whether activating this class of primary afferent might increase BSCB permeability we applied capsaicin to the sciatic nerve and measured Evans Blue in the dorsal spinal cord 24 hrs later. We found that capsaicin, but not vehicle control, caused an increase in Evans Blue at 24 hrs (Figure 4A). In contrast applying capsaicin to the sciatic nerve led to peripheral plasma extravasation that was apparent within 45 min (Figure 4B) Thus, we conclude that activating TRPV1-expressing C-fibers is sufficient to cause an increase in BSCB permeability.


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)

Local application of capsaicin increases BSCB permeability. A: 1% Capsaicin or vehicle was applied onto the sciatic nerve and Evans Blue extravasation was measured 24 hours later. All readings are from lumbar spinal cord ipsilateral to capsaicin or vehicle. Data are presented as mean ± SEM; **p < 0.01 compared to naïve, n = 5-9 per group.B: 1% Capsaicin was applied to the sciatic nerve and Evans Blue was injected immediately after capsaicin. Ipsilateral and contralateral paw images were captured 45 minutes after capsaicin treatment.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Local application of capsaicin increases BSCB permeability. A: 1% Capsaicin or vehicle was applied onto the sciatic nerve and Evans Blue extravasation was measured 24 hours later. All readings are from lumbar spinal cord ipsilateral to capsaicin or vehicle. Data are presented as mean ± SEM; **p < 0.01 compared to naïve, n = 5-9 per group.B: 1% Capsaicin was applied to the sciatic nerve and Evans Blue was injected immediately after capsaicin. Ipsilateral and contralateral paw images were captured 45 minutes after capsaicin treatment.
Mentions: Neurogenic plasma extravasation is mediated through activating primary afferent C-fibers that express TRPV1 and are hence activated by capsaicin [9,22]. To determine whether activating this class of primary afferent might increase BSCB permeability we applied capsaicin to the sciatic nerve and measured Evans Blue in the dorsal spinal cord 24 hrs later. We found that capsaicin, but not vehicle control, caused an increase in Evans Blue at 24 hrs (Figure 4A). In contrast applying capsaicin to the sciatic nerve led to peripheral plasma extravasation that was apparent within 45 min (Figure 4B) Thus, we conclude that activating TRPV1-expressing C-fibers is sufficient to cause an increase in BSCB permeability.

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