back-mechanical-sensitivity-assessment-rat-for-mechanistic

Back Mechanical Sensitivity Assessment in the Rat for Mechanistic Investigation of Chronic Back Pain

Low back pain is the leading cause of disability worldwide, with dramatic personal, economic, and social consequences. To develop novel therapeutics, ...

Université du Québec à Trois-Rivières

Functional magnetic resonance imaging (fMRI) is based on neurovascular coupling, which allows inferring neuronal activity from hemodynamic changes. Spinal fMRI has been used to examine pain processes, although spinal neurovascular coupling has never been investigated. In addition, fluctuations in mean arterial pressure (MAP) occur during nociceptive stimulation and this may affect neurovascular coupling. The objective of this study was to examine neurovascular coupling in the rat spinal cord during nociceptive stimulation while MAP was manipulated by cervical spinal transection, which prevents nociception-related MAP increases. Six male Wistar rats were anesthetized with isoflurane (1.2-1.5%). Local field potentials (LFP) and spinal cord blood flow (SCBF) were recorded concurrently in the lumbar enlargement, where activity was evoked by electrical stimulation of the sciatic nerve. In intact conditions, stimulation of graded intensity produced proportional changes in SCBF and LFP that were paralleled by similar changes in MAP. However, spinal transection almost abolished MAP changes (p<0.001), while SCBF and LFP responses were not significantly affected (p>0.3) and remained similarly coupled before and after spinal transection. This indicates that spinal hemodynamic changes reflect neuronal activity even when large fluctuations in MAP occur. This contrasts with results from previous studies on cerebral neurovascular coupling and suggests that spinal autoregulation might allow better adaptation to sudden MAP changes than cerebral autoregulation. Although assessment of the coupling between spinal neuronal activity and BOLD signal remains to be investigated, this study supports the use of spinal fMRI, based on the tight coupling between SCBF and LFP.

Tight neurovascular coupling in the spinal cord during nociceptive stimulation in intact and spinal rats.

Neurological examination remains the primary clinical investigation in patients with spinal cord injury. However, neuroimaging methods such as functional magnetic resonance imaging (fMRI) are promising tools for following functional changes in the course of injury, disease and rehabilitation. However, the relationship between neuronal activity and blood flow in the spinal cord on which fMRI relies has been largely overlooked. The objective of this study was to examine neurovascular coupling in the spinal cord of decerebrated rats during electrical stimulation of the sciatic nerve with and without isoflurane anesthesia (1.2%). Local field potentials (LFP) and spinal cord blood flow (SCBF) were recorded simultaneously in the lumbosacral enlargement. Isoflurane did not significantly alter LFP (p = 0.53) and SCBF (p = 0.57) amplitude. Accordingly, neurovascular coupling remained comparable with or without isoflurane anesthesia (p = 0.39). These results support the use of isoflurane in rodents to investigate nociceptive functions of the spinal cord using fMRI.

Isoflurane anesthesia does not affect spinal cord neurovascular coupling: evidence from decerebrated rats.

Spinal cord and brain processes underlie pain perception, which produces systemic cardiovascular changes. In turn, the autonomic nervous system regulates vascular function in the spinal cord and brain in order to adapt to these systemic changes, while neuronal activity induces local vascular changes. Thus, autonomic regulation and pain processes in the brain and spinal cord are tightly linked and interrelated. The objective of this topical review is to discuss work on neurovascular coupling during nociceptive processing in order to highlight supporting evidence and limitations for the use of cerebral and spinal fMRI to investigate pain mechanisms and spinal nociceptive processes. Work on functional neuroimaging of pain is presented and discussed in relation to available neurovascular coupling studies and related issues. Perspectives on future work are also discussed with an emphasis on differences between the brain and the spinal cord and on different approaches that may be useful to improve current methods, data analyses and interpretation. In summary, this review highlights the lack of data on neurovascular coupling during nociceptive stimulation and indicates that hemodynamic and BOLD responses measured with fMRI may be biased by nonspecific vascular changes. Future neuroimaging studies on nociceptive and pain-related processes would gain further understanding of neurovascular coupling in the brain and spinal cord and should take into account the effects of systemic vascular changes that may affect hemodynamic responses. Anat Rec, 301:1585-1595, 2018. © 2018 Wiley Periodicals, Inc.

Functional Neuroimaging of Nociceptive and Pain-Related Activity in the Spinal Cord and Brain: Insights From Neurovascular Coupling Studies.

Cerebral blood flow (CBF) is essential for neuronal metabolic functions. CBF is partly regulated by cholinergic projections from the nucleus basalis of Meynert (NBM) during cortical processing of sensory information. During pain-related processing, however, this mechanism may be altered by large fluctuations in systemic mean arterial pressure (MAP). The objective of this study was to investigate the contribution of NBM to CBF responses evoked by nociceptive electrical stimuli and how it may be affected by systemic MAP. CBF was recorded in isoflurane-anesthetized rats (n = 8) using laser speckle contrast imaging, in two conditions (intact vs left NBM lesion). Electrical stimulation was applied to the sciatic nerve. Sciatic stimulation produced intensity dependent increases in MAP (p < 0.001) that were almost identical between conditions (intact vs left NBM lesion; p = 0.96). In both conditions, sciatic stimulation produced intensity dependent CBF increases (p < 0.001). After NBM lesion, CBF responses were decreased in the left somatosensory cortex ipsilateral to NBM lesion (p = 0.02) but not in the right somatosensory cortex (p = 0.46). These results indicate that NBM contributes to CBF responses to nociceptive stimulation in the ipsilateral, but not contralateral somatosensory cortex and that CBF response attenuation by NBM lesion is not compensated passively by systemic MAP changes. This highlights the importance of NBM's integrity for pain-related hemodynamic responses in the somatosensory cortex.

Regulation of cortical blood flow responses by the nucleus basalis of Meynert during nociceptive processing.

Functional magnetic resonance imaging (fMRI) of the spinal cord relies on the integrity of neurovascular coupling (NVC) to infer neuronal activity from hemodynamic changes. Astrocytes are a key component of cerebral NVC, but their role in spinal NVC is unclear. The objective of this study was to examine whether inhibition of astrocyte metabolism by fluorocitrate alters spinal NVC. In 14 rats, local field potential (LFP) and spinal cord blood flow (SCBF) were recorded simultaneously in the lumbosacral enlargement during noxious stimulation of the sciatic nerve before and after a local administration of fluorocitrate (N  = 7) or saline (N  = 7). Fluorocitrate significantly reduced SCBF responses (p  < 0.001) but not LFP amplitude (p  = 0.22) compared with saline. Accordingly, NVC was altered by fluorocitrate compared with saline (p  < 0.01). These results support the role of astrocytes in spinal NVC and have implications for spinal cord imaging with fMRI for conditions in which astrocyte metabolism may be altered.

Contribution of astrocytes to neurovascular coupling in the spinal cord of the rat.

Medetomidine and isoflurane are commonly used for general anaesthesia in fMRI studies, but they alter cerebral blood flow (CBF) regulation and neurovascular coupling (NVC). In addition, medetomidine induces hypoinsulinemia and hyperglycaemia, which also alter CBF regulation and NVC. Furthermore, sudden changes in arterial pressure induced by noxious stimulation may affect NVC differently under medetomidine and isoflurane anaesthesia, considering their different effects on vascular functions. The first objective of this study was to compare NVC under medetomidine and isoflurane anaesthesia during noxious stimulation. The second objective was to examine whether fasting may improve NVC by reducing medetomidine-induced hyperglycaemia. In male Wister rats, noxious electrical stimulation was applied to the sciatic nerve in fasted or non-fasted animals. CBF and local field potentials (LFP) were recorded in the somatosensory cortex to assess NVC (CBF/LFP ratio). The CBF/LFP ratio was increased by medetomidine compared with isoflurane (p = 0.004), but this effect was abolished by fasting (p = 0.8). Accordingly, medetomidine produced a threefold increase in blood glucose (p < 0.001), but this effect was also abolished by fasting (p = 0.3). This indicates that isoflurane and medetomidine anaesthesia alter NVC differently, but the undesirable glucose dependent effects of medetomidine on NVC can be prevented by fasting.

Fasting prevents medetomidine-induced hyperglycaemia and alterations of neurovascular coupling in the somatosensory cortex of the rat during noxious stimulation.

Visual deprivation leads to behavioural adaptations. Early visual deprivation has greater effects on sensory systems compared with late visual deprivation. Although this has been well studied, the impact of visual deprivation on pain sensitivity has scarcely been investigated. In humans, one study indicates that pain sensitivity is increased in early, but not late-onset blindness. In animals, one study indicates that sensitivity to noxious stimulation is increased in anophthalmic mice, but the impact of late visual deprivation on sensitivity remains unknown. The aim of this behavioural study was to examine sensitivity to noxious stimulation in mice with early and late visual deprivation. We hypothesized that visual deprivation would have different effects on sensitivity to noxious stimulation depending on its onset.

Early and late visual deprivation induce hypersensitivity to mechanical and thermal noxious stimuli in the ZRDBA mouse.

Functional magnetic resonance imaging (fMRI) has been used to investigate nociceptive processes in patients with chronic pain. However, the results may be confounded with changes in neurovascular coupling induced by chronic pain. The objective of the present study was to examine spinal neurovascular coupling in a rat model of chronic back pain induced by muscle inflammation. Rats received 150 µl intramuscular injections of either complete Freund's adjuvant (CFA: n=18) or saline (CTL: n=18) in L5-L6 paravertebral muscles. Under 1.2 % isoflurane anesthesia, spinal cord blood flow (SCBF) and local field potentials (LFP) evoked by electrical stimulation of the sciatic nerve were recorded simultaneously in the lumbar enlargement of the spinal cord, 14 or 28 days after the injections. Mechanical hypersensitivity was observed in CFA compared with CTL rats for the back (p<0.001) and hind paws (p<0.01). SCBF response amplitude and LFP amplitude were not significantly different between groups (day 14: p>0.5; day 28: p>0.6). However, the time course of SCBF responses was different between groups on day 14 (p<0.001) and day 28 (p<0.001). Nevertheless, neurovascular coupling was comparable between groups on days 14 and 28, whether NVC was calculated with the amplitude or the area under the curve of SCBF responses (all p>0.2). These results indicate that spinal hemodynamic changes reflect neuronal activity in this animal model, although the time course of SCBF responses is affected by chronic inflammatory back pain. This warrants careful use of spinal fMRI in animal models and patients with chronic back pain.

Spinal neurovascular coupling is preserved despite time dependent alterations of spinal cord blood flow responses in a rat model of chronic back pain: implications for functional spinal cord imaging.

Article	Year
Tight neurovascular coupling in the spinal cord during nociceptive stimulation in intact and spinal rats. Neuroscience\| PubMed ID: 28479402	2017
Isoflurane anesthesia does not affect spinal cord neurovascular coupling: evidence from decerebrated rats. The journal of physiological sciences : JPS\| PubMed ID: 29600499	2019
Functional Neuroimaging of Nociceptive and Pain-Related Activity in the Spinal Cord and Brain: Insights From Neurovascular Coupling Studies. Anatomical record (Hoboken, N.J. : 2007)\| PubMed ID: 29752872	2018
Regulation of cortical blood flow responses by the nucleus basalis of Meynert during nociceptive processing. Neuroscience research\| PubMed ID: 30711380	2019
Contribution of astrocytes to neurovascular coupling in the spinal cord of the rat. The journal of physiological sciences : JPS\| PubMed ID: 34049480	2021
Fasting prevents medetomidine-induced hyperglycaemia and alterations of neurovascular coupling in the somatosensory cortex of the rat during noxious stimulation. The European journal of neuroscience\| PubMed ID: 34137097	2021
Early and late visual deprivation induce hypersensitivity to mechanical and thermal noxious stimuli in the ZRDBA mouse. European journal of pain (London, England)\| PubMed ID: 34260794	2021
Spinal neurovascular coupling is preserved despite time dependent alterations of spinal cord blood flow responses in a rat model of chronic back pain: implications for functional spinal cord... Pain\| PubMed ID: 36036900	2022

Thierry Paquette

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