Post-Injury Buprenorphine Administration Is Associated with Long-Term Region-Specific Glial Alterations in Rats

Abstract

Traumatic brain injury (TBI) is a major leading cause of death and disability. While previous studies regarding focal pathologies following TBI have been done, there is a lack of information concerning the role of analgesics and their influences on injury pathology. Buprenorphine (Bup), an opioid analgesic, is a commonly used analgesic in experimental TBI models. Our previous studies investigated the acute effects of Buprenorphine-sustained release-Lab (Bup-SR-Lab) on diffuse neuronal/glial pathology, neuroinflammation, cell damage, and systemic physiology. The current study investigated the longer-term chronic outcomes of Bup-SR-Lab treatment at 4 weeks following TBI utilizing a central fluid percussion injury (cFPI) model in adult male rats. Histological assessments of physiological changes, neuronal damage, cortical and thalamic cytokine expression, microglial and astrocyte morphological changes, and myelin alterations were done, as we had done in our acute study. In the current study the Whisker Nuisance Task (WNT) was also performed pre- and 4w post-injury to assess changes in somatosensory sensitivity following saline or Bup-SR-Lab treatment. Bup-SR-Lab treatment had no impact on overall physiology or neuronal damage at 4w post-injury regardless of region or injury, nor did it have any significant effects on somatosensory sensitivity. However, greater IL-4 cytokine expression with Bup-SR-Lab treatment was observed compared to saline treated animals. Microglia and astrocytes also demonstrated region-specific morphological alterations associated with Bup-SR-Lab treatment, in which cortical microglia and thalamic astrocytes were particularly vulnerable to Bup-mediated changes. There were discernable injury-specific and region-specific differences regarding myelin integrity and changes in specific myelin basic protein (MBP) isoform expression following Bup-SR-Lab treatment. This study indicates that use of Bup-SR-Lab could impact TBI-induced glial alterations in a region-specific manner 4w following diffuse brain injury.

The Effects of Cathepsin B Inhibition in the Face of Diffuse Traumatic Brain Injury and Secondary Intracranial Pressure Elevation

“…Neuronal membrane disruption was consistent in all groups (F5,30=0.93 p=0.47; Figure 8; Supplemental Table S2). Sham animals demonstrated levels of neuronal membrane disruption consistent with previous studies [7,20,40] in which the sham injury group infused with 10% DMSO had 7.83% ± 2.16 neurons sustaining membrane disruption and the sham injury group infused with CA-074Me had 12.09% ± 3.91 neurons sustaining membrane disruption (Figure 6 A & D, Figure 8). Rats sustaining CFPI demonstrated membrane disruption in a much lower percentage of neurons than anticipated based on previous findings [7,20,40] in which the CFPI group infused with 10% DMSO had 6.56% ± 1.13 neurons sustaining membrane disruption and the CFPI group infused with CA-074Me had 10.86% ± 3.08 neurons sustaining membrane disruption (Figure 6 B & E; Figure 8).…”

“…Sham animals demonstrated levels of neuronal membrane disruption consistent with previous studies [7,20,40] in which the sham injury group infused with 10% DMSO had 7.83% ± 2.16 neurons sustaining membrane disruption and the sham injury group infused with CA-074Me had 12.09% ± 3.91 neurons sustaining membrane disruption (Figure 6 A & D, Figure 8). Rats sustaining CFPI demonstrated membrane disruption in a much lower percentage of neurons than anticipated based on previous findings [7,20,40] in which the CFPI group infused with 10% DMSO had 6.56% ± 1.13 neurons sustaining membrane disruption and the CFPI group infused with CA-074Me had 10.86% ± 3.08 neurons sustaining membrane disruption (Figure 6 B & E; Figure 8). At percentages similar to those in sham and CFPI groups, animals sustaining CFPI with secondary ICP elevation to 20mmHg also demonstrated minimal neuronal membrane disruption, in which the TBI+ ICP elevation group infused with 10% DMSO had 10.72% ± 2.60 neurons sustaining membrane disruption and the TBI+ ICP elevation group infused with CA-074Me had 6.34% ± 1.28 neurons sustaining membrane disruption (Figure 6 C & F; Figure 8).…”

“…Hypersensitivity in the whisker barrels was assessed using the whisker nuisance task (WNT) [7,39,40]. Briefly, animals were assessed prior to injury and at 2w post sham or CFPI by an investigator blind to animal group.…”

“…To investigate the potential changes in somatosensory sensitivity following CA-074Me infusion, the Whisker Nuisance Task (WNT) [7,39,40] was performed in animals prior to injury and at 2w following sham, CFPI, or CFPI and secondary ICP elevation to 20mmHg for all groups in which a higher score indicated higher somatosensory sensitivity to whisker stimulation. Pre-injury scores were comparable across all groups: Sham injury with 10% DMSO (3.33 ± 0.43; n=11), Sham injury with CA-074Me (3.43 ± 0.45; n=13), TBI with 10% DMSO (4.58 ± 0.66; n=12), TBI with CA-074Me (4.36 ± 0.42; n=13), TBI+ ICP elevation with 10% DMSO (3.79 ± 0.37; n=11), TBI+ ICP elevation with CA-074Me (3.68 ± 0.53; n=12).…”

Aging with TBI vs. Aging: 6-month temporal profiles for neuropathology and astrocyte activation converge in behaviorally relevant thalamocortical circuitry of male and female rats

“…Predominantly, astrocytes are implicated in promoting recovery and regaining homeostasis by promoting cellular homeostasis and mediating neuroplastic events [7, 44, 68]. Along these lines, the astrogliosis may provoke axonal sprouting and new synaptic connections of adaptive and maladaptive reorganization, where maladaptive is implicated in development of behavioral morbidity like late-onset sensory hypersensitivity to whisker stimulation which has been replicated across several labs [14, 27, 28, 43, 69]. It is likely that mechanisms mediating preclinical morbidity are relevant to clinical reports where TBI-induced damage to the thalamus is associated with sensory hypersensitivity and hyperarousal which leads to agitation and aggressive behavior in brain-injured humans [70, 71].…”