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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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Hypertonic saline–evoked responses of neurons at the Vi/Vc transition were increased in dry eye disease (DE) rats 14 days after surgery. (A) Example of NaCl concentration–evoked neural activity in a wide dynamic range (WDR) cell in a sham rat. (B) Example of NaCl concentration–evoked neural activity in a WDR cell in a DE rat. Scale bars above each histogram in (A) and (B) indicate stimulus period (30 seconds). Bin size = 1 second. (C) Summary of NaCl-evoked Rmag values for sham and 14d DE rats. *P < 0.05, **P < 0.01 vs 0.15 M; b = P < 0.01 vs sham. Sample sizes: sham, n = 11; DE, n = 14. (D) Recording site (*); scale = 100 μm.
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Figure 2: Hypertonic saline–evoked responses of neurons at the Vi/Vc transition were increased in dry eye disease (DE) rats 14 days after surgery. (A) Example of NaCl concentration–evoked neural activity in a wide dynamic range (WDR) cell in a sham rat. (B) Example of NaCl concentration–evoked neural activity in a WDR cell in a DE rat. Scale bars above each histogram in (A) and (B) indicate stimulus period (30 seconds). Bin size = 1 second. (C) Summary of NaCl-evoked Rmag values for sham and 14d DE rats. *P < 0.05, **P < 0.01 vs 0.15 M; b = P < 0.01 vs sham. Sample sizes: sham, n = 11; DE, n = 14. (D) Recording site (*); scale = 100 μm.

Mentions: Rats were anesthetized initially with pentobarbital sodium (50 mg/kg, i.p., n = 69), and catheters were positioned in the right femoral artery for monitoring blood pressure and jugular vein for drug infusion (gallamine triethiodide, 25 mg·kg−1·h−1, at the time of recording). After tracheotomy, animals were respired artificially with oxygen-enriched room air and anesthesia was maintained with isoflurane (1.2%-2.0%). Expiratory end-tidal CO2 (3.5%-4.5%), mean arterial pressure (MAP, 90-120 mm Hg), and body temperature (37°C) were monitored continuously and kept within normal range. Animals were placed in a stereotaxic frame and portions of the C1 vertebra were removed to expose the lower brainstem and upper cervical dorsal horn. The exposed brainstem surface was bathed in warm mineral oil. Neurons recorded at the ventrolateral trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition were approached at an angle of 28° off vertical and 45° off midline and 1.5 to 2.0 mm below the brainstem surface (Fig. 2D). Single neurons were recorded from superficial (I-II) or deep (V) laminae at the Vc/C1 region (Figs. 3D and 4D) by directing the electrode at an angle of 47° off vertical, 60° off midline. For units recorded in superficial laminae, the depth of recording was within 250 μm of the dorsal brainstem surface. Recording sites were confirmed from the location of an electrolytic lesion (5 μA, 10 seconds) marked at the end of the experiment. Extracellular unit activity was recorded using tungsten microelectrodes (5-9 MΩ; Frederic Haer Inc, Bowdoinham, ME) and amplified, discriminated, stored, and analyzed off-line using a PowerLab interface and LabChart software (AD Instruments).


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)

Hypertonic saline–evoked responses of neurons at the Vi/Vc transition were increased in dry eye disease (DE) rats 14 days after surgery. (A) Example of NaCl concentration–evoked neural activity in a wide dynamic range (WDR) cell in a sham rat. (B) Example of NaCl concentration–evoked neural activity in a WDR cell in a DE rat. Scale bars above each histogram in (A) and (B) indicate stimulus period (30 seconds). Bin size = 1 second. (C) Summary of NaCl-evoked Rmag values for sham and 14d DE rats. *P < 0.05, **P < 0.01 vs 0.15 M; b = P < 0.01 vs sham. Sample sizes: sham, n = 11; DE, n = 14. (D) Recording site (*); scale = 100 μm.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4402282&req=5

Figure 2: Hypertonic saline–evoked responses of neurons at the Vi/Vc transition were increased in dry eye disease (DE) rats 14 days after surgery. (A) Example of NaCl concentration–evoked neural activity in a wide dynamic range (WDR) cell in a sham rat. (B) Example of NaCl concentration–evoked neural activity in a WDR cell in a DE rat. Scale bars above each histogram in (A) and (B) indicate stimulus period (30 seconds). Bin size = 1 second. (C) Summary of NaCl-evoked Rmag values for sham and 14d DE rats. *P < 0.05, **P < 0.01 vs 0.15 M; b = P < 0.01 vs sham. Sample sizes: sham, n = 11; DE, n = 14. (D) Recording site (*); scale = 100 μm.
Mentions: Rats were anesthetized initially with pentobarbital sodium (50 mg/kg, i.p., n = 69), and catheters were positioned in the right femoral artery for monitoring blood pressure and jugular vein for drug infusion (gallamine triethiodide, 25 mg·kg−1·h−1, at the time of recording). After tracheotomy, animals were respired artificially with oxygen-enriched room air and anesthesia was maintained with isoflurane (1.2%-2.0%). Expiratory end-tidal CO2 (3.5%-4.5%), mean arterial pressure (MAP, 90-120 mm Hg), and body temperature (37°C) were monitored continuously and kept within normal range. Animals were placed in a stereotaxic frame and portions of the C1 vertebra were removed to expose the lower brainstem and upper cervical dorsal horn. The exposed brainstem surface was bathed in warm mineral oil. Neurons recorded at the ventrolateral trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition were approached at an angle of 28° off vertical and 45° off midline and 1.5 to 2.0 mm below the brainstem surface (Fig. 2D). Single neurons were recorded from superficial (I-II) or deep (V) laminae at the Vc/C1 region (Figs. 3D and 4D) by directing the electrode at an angle of 47° off vertical, 60° off midline. For units recorded in superficial laminae, the depth of recording was within 250 μm of the dorsal brainstem surface. Recording sites were confirmed from the location of an electrolytic lesion (5 μA, 10 seconds) marked at the end of the experiment. Extracellular unit activity was recorded using tungsten microelectrodes (5-9 MΩ; Frederic Haer Inc, Bowdoinham, ME) and amplified, discriminated, stored, and analyzed off-line using a PowerLab interface and LabChart software (AD Instruments).

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