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Sensitization of trigeminal brainstem pathways in a model for tear deficient dry eye.

Rahman M, Okamoto K, Thompson R, Katagiri A, Bereiter DA - Pain (2015)

Bottom Line: Spontaneous tear volume was reduced by ∼50% at 14 days after exorbital gland removal.These results indicated that persistent tear deficiency caused sensitization of ocular-responsive neurons at multiple regions of the caudal trigeminal brainstem and enhanced OOemg activity.Central sensitization of ocular-related brainstem circuits is a significant factor in DE and likely contributes to the apparent weak correlation between peripheral signs of tear dysfunction and symptoms of irritation.

View Article: PubMed Central - PubMed

Affiliation: Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, MN, USA.

ABSTRACT
Chronic dry eye disease (DE) is associated with an unstable tear film and symptoms of ocular discomfort. The characteristics of symptoms suggest a key role for central neural processing; however, little is known about central neuroplasticity and DE. We used a model for tear deficient DE and assessed effects on eye blink behavior, orbicularis oculi muscle activity (OOemg), and trigeminal brainstem neural activity in male rats. Ocular-responsive neurons were recorded at the interpolaris/caudalis transition (Vi/Vc) and Vc/upper cervical cord (Vc/C1) regions under isoflurane, whereas OOemg activity was recorded under urethane. Spontaneous tear volume was reduced by ∼50% at 14 days after exorbital gland removal. Hypertonic saline-evoked eye blink behavior in awake rats was enhanced throughout the 14 days after surgery. Saline-evoked neural activity at the Vi/Vc transition and in superficial and deep laminae at the Vc/C1 region was greatly enhanced in DE rats. Neurons from DE rats classified as wide dynamic range displayed enlarged convergent periorbital receptive fields consistent with central sensitization. Saline-evoked OOemg activity was markedly enhanced in DE rats compared with controls. Synaptic blockade at the Vi/Vc transition or the Vc/C1 region greatly reduced hypertonic saline-evoked OOemg activity in DE and sham rats. These results indicated that persistent tear deficiency caused sensitization of ocular-responsive neurons at multiple regions of the caudal trigeminal brainstem and enhanced OOemg activity. Central sensitization of ocular-related brainstem circuits is a significant factor in DE and likely contributes to the apparent weak correlation between peripheral signs of tear dysfunction and symptoms of irritation.

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Inhibition of hypertonic saline–evoked OOemg responses after synaptic blockade at the Vi/Vc transition or the Vc/C1 region. (A) Examples of inhibition of hypertonic saline–evoked OOemg activity in dry eye disease (DE) rats after CoCl2 (0.3 μL, 100 mM) injection into the Vi/Vc transition (upper trace) or into the Vc/C1 region (lower trace). Scale bar = 30 seconds. (B) Summary of integrated OOemg responses to hypertonic saline in sham and 14d DE rats after synaptic blockade at the Vi/Vc transition (left panel) or at the Vc/C1 region (right panel). **P < 0.01 vs preinjection value; b = P < 0.01 vs sham. Sample sizes for Vi/Vc transition injections: sham-PBS, n = 5; sham-CoCl2, n = 4; DE-PBS, n = 4, DE-CoCl2, n = 5. Sample sizes for Vc/C1 region injections: sham-PBS, n = 4; sham-CoCl2, n = 5; DE-PBS, n = 4, DE-CoCl2, n = 5.
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Figure 7: Inhibition of hypertonic saline–evoked OOemg responses after synaptic blockade at the Vi/Vc transition or the Vc/C1 region. (A) Examples of inhibition of hypertonic saline–evoked OOemg activity in dry eye disease (DE) rats after CoCl2 (0.3 μL, 100 mM) injection into the Vi/Vc transition (upper trace) or into the Vc/C1 region (lower trace). Scale bar = 30 seconds. (B) Summary of integrated OOemg responses to hypertonic saline in sham and 14d DE rats after synaptic blockade at the Vi/Vc transition (left panel) or at the Vc/C1 region (right panel). **P < 0.01 vs preinjection value; b = P < 0.01 vs sham. Sample sizes for Vi/Vc transition injections: sham-PBS, n = 5; sham-CoCl2, n = 4; DE-PBS, n = 4, DE-CoCl2, n = 5. Sample sizes for Vc/C1 region injections: sham-PBS, n = 4; sham-CoCl2, n = 5; DE-PBS, n = 4, DE-CoCl2, n = 5.

Mentions: Microinjection of the nonselective synaptic blocking agent, CoCl2 (100 mM, 0.3 μL), into the Vi/Vc transition (Fig. 7A, upper trace) or the Vc/C1 region (Fig. 7A, lower trace) significantly reduced the OOemg response to repeated application of 2.5M NaCl to the ocular surface. As summarized in Figure 7B (left panel), blockade at the Vi/Vc transition caused a marked inhibition of the NaCl-evoked OOemg response at 10 minutes in both DE and sham rats with only minor recovery by 50 minutes compared with vehicle injection (F3,40 = 54.5, P < 0.001). CoCl2 blockade at the Vc/C1 region also reduced the NaCl-evoked OOemg responses compared with vehicle injections in DE and sham rats (Fig. 7B, right panel, F3,42 = 17.1, P < 0.001). However, in contrast to Vi/Vc injections, blockade at Vc/C1 caused only a transient decrease in evoked OOemg response in sham rats at 10 minutes (F3,42 = 6.4, P < 0.005) and a trend towards preinjection values by 50 minutes in DE rats (F3,42 = 27.1, P < 0.001).


Sensitization of trigeminal brainstem pathways in a model for tear deficient dry eye.

Rahman M, Okamoto K, Thompson R, Katagiri A, Bereiter DA - Pain (2015)

Inhibition of hypertonic saline–evoked OOemg responses after synaptic blockade at the Vi/Vc transition or the Vc/C1 region. (A) Examples of inhibition of hypertonic saline–evoked OOemg activity in dry eye disease (DE) rats after CoCl2 (0.3 μL, 100 mM) injection into the Vi/Vc transition (upper trace) or into the Vc/C1 region (lower trace). Scale bar = 30 seconds. (B) Summary of integrated OOemg responses to hypertonic saline in sham and 14d DE rats after synaptic blockade at the Vi/Vc transition (left panel) or at the Vc/C1 region (right panel). **P < 0.01 vs preinjection value; b = P < 0.01 vs sham. Sample sizes for Vi/Vc transition injections: sham-PBS, n = 5; sham-CoCl2, n = 4; DE-PBS, n = 4, DE-CoCl2, n = 5. Sample sizes for Vc/C1 region injections: sham-PBS, n = 4; sham-CoCl2, n = 5; DE-PBS, n = 4, DE-CoCl2, n = 5.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 7: Inhibition of hypertonic saline–evoked OOemg responses after synaptic blockade at the Vi/Vc transition or the Vc/C1 region. (A) Examples of inhibition of hypertonic saline–evoked OOemg activity in dry eye disease (DE) rats after CoCl2 (0.3 μL, 100 mM) injection into the Vi/Vc transition (upper trace) or into the Vc/C1 region (lower trace). Scale bar = 30 seconds. (B) Summary of integrated OOemg responses to hypertonic saline in sham and 14d DE rats after synaptic blockade at the Vi/Vc transition (left panel) or at the Vc/C1 region (right panel). **P < 0.01 vs preinjection value; b = P < 0.01 vs sham. Sample sizes for Vi/Vc transition injections: sham-PBS, n = 5; sham-CoCl2, n = 4; DE-PBS, n = 4, DE-CoCl2, n = 5. Sample sizes for Vc/C1 region injections: sham-PBS, n = 4; sham-CoCl2, n = 5; DE-PBS, n = 4, DE-CoCl2, n = 5.
Mentions: Microinjection of the nonselective synaptic blocking agent, CoCl2 (100 mM, 0.3 μL), into the Vi/Vc transition (Fig. 7A, upper trace) or the Vc/C1 region (Fig. 7A, lower trace) significantly reduced the OOemg response to repeated application of 2.5M NaCl to the ocular surface. As summarized in Figure 7B (left panel), blockade at the Vi/Vc transition caused a marked inhibition of the NaCl-evoked OOemg response at 10 minutes in both DE and sham rats with only minor recovery by 50 minutes compared with vehicle injection (F3,40 = 54.5, P < 0.001). CoCl2 blockade at the Vc/C1 region also reduced the NaCl-evoked OOemg responses compared with vehicle injections in DE and sham rats (Fig. 7B, right panel, F3,42 = 17.1, P < 0.001). However, in contrast to Vi/Vc injections, blockade at Vc/C1 caused only a transient decrease in evoked OOemg response in sham rats at 10 minutes (F3,42 = 6.4, P < 0.005) and a trend towards preinjection values by 50 minutes in DE rats (F3,42 = 27.1, P < 0.001).

Bottom Line: Spontaneous tear volume was reduced by ∼50% at 14 days after exorbital gland removal.These results indicated that persistent tear deficiency caused sensitization of ocular-responsive neurons at multiple regions of the caudal trigeminal brainstem and enhanced OOemg activity.Central sensitization of ocular-related brainstem circuits is a significant factor in DE and likely contributes to the apparent weak correlation between peripheral signs of tear dysfunction and symptoms of irritation.

View Article: PubMed Central - PubMed

Affiliation: Department of Diagnostic and Biological Sciences, University of Minnesota School of Dentistry, Minneapolis, MN, USA.

ABSTRACT
Chronic dry eye disease (DE) is associated with an unstable tear film and symptoms of ocular discomfort. The characteristics of symptoms suggest a key role for central neural processing; however, little is known about central neuroplasticity and DE. We used a model for tear deficient DE and assessed effects on eye blink behavior, orbicularis oculi muscle activity (OOemg), and trigeminal brainstem neural activity in male rats. Ocular-responsive neurons were recorded at the interpolaris/caudalis transition (Vi/Vc) and Vc/upper cervical cord (Vc/C1) regions under isoflurane, whereas OOemg activity was recorded under urethane. Spontaneous tear volume was reduced by ∼50% at 14 days after exorbital gland removal. Hypertonic saline-evoked eye blink behavior in awake rats was enhanced throughout the 14 days after surgery. Saline-evoked neural activity at the Vi/Vc transition and in superficial and deep laminae at the Vc/C1 region was greatly enhanced in DE rats. Neurons from DE rats classified as wide dynamic range displayed enlarged convergent periorbital receptive fields consistent with central sensitization. Saline-evoked OOemg activity was markedly enhanced in DE rats compared with controls. Synaptic blockade at the Vi/Vc transition or the Vc/C1 region greatly reduced hypertonic saline-evoked OOemg activity in DE and sham rats. These results indicated that persistent tear deficiency caused sensitization of ocular-responsive neurons at multiple regions of the caudal trigeminal brainstem and enhanced OOemg activity. Central sensitization of ocular-related brainstem circuits is a significant factor in DE and likely contributes to the apparent weak correlation between peripheral signs of tear dysfunction and symptoms of irritation.

Show MeSH
Related in: MedlinePlus