Buprenorphine alters microglia and astrocytes acutely following diffuse traumatic brain injury

Abstract

Traumatic brain injury (TBI) is a common phenomenon, accounting for significant cost and adverse health effects. While there is information about focal pathologies following TBI, knowledge of more diffuse processes is lacking, particularly regarding how analgesics affect this pathology. As buprenorphine is the most commonly used analgesic in experimental TBI models, this study investigated the acute effects of the opioid analgesic buprenorphine (Bup-SR-Lab) on diffuse neuronal/glial pathology, neuroinflammation, cell damage, and systemic physiology. We utilized a model of central fluid percussion injury (CFPI) in adult male rats treated with a single subcutaneous bolus of Bup-SR-Lab or saline 15 min post-injury. Microscopic assessments were performed at 1 day post-injury. Cell impermeable dextran was infused intraventricularly prior to sacrifice to assess neuronal membrane disruption. Axonal injury was assessed by investigating labeling of the anterogradely transported amyloid precursor protein. Neuroinflammation was assessed by analyzing Iba-1 + microglial and GFAP + astrocyte histological/morphological features as well as cytokine levels in both regions of interest (ROIs). Myelin pathology was assessed by evaluating the expression of myelin basic protein (MBP) and the propensity of MBP + myelin debris. Acute physiologic data showed no difference between groups except for reduction in weight loss following cFPI in Bup treated animals compared to saline. There were no discernable differences in axonal injury or membrane disruption between treatment groups. Cytokine levels were consistent between Bup and saline treated animals, however, microglia and astrocytes revealed region specific histological changes at 1d following Bup treatment. Myelin integrity and overall MBP expression showed no differences between Bup and saline treated animals, but there were significant regional differences in MBP expression between the cortex and thalamus. These data suggest effects of Bup treatment on weight following CFPI and potential regional specificity of Bup-associated microglial and astrocyte alterations, but very little change in other acute pathology at 1-day post-injury. Overall, this preliminary study indicates that use of Bup-SR-Lab in preclinical work does have effects on acute glial pathology, however, longer term studies will be needed to assess potential effects of Bup treatment on more chronic pathological progressions.

Sex specific effects of buprenorphine on behavior, astrocytic opioid receptor expression and neuroinflammation after pediatric traumatic brain injury in mice

“…These results are consistent with a previous study in which the BPN treatment decreased synovial joint iNOS level in a murine model of collagen-induced arthritis ( Hemshekhar et al, 2017 ). BPN did not significantly change the expression of pro- and anti-inflammatory cytokines in males, which is consistent with a previous study in a rat model of diffuse traumatic brain injury ( Ryu et al, 2021 ). Meanwhile, BPN treatment increased TGF-β1 mRNA expression, compared to controls.…”

“…In this study, all animals lost weight following TBI, however, female animals treated with BPN demonstrated a better maintenance of body weight at 3-day post-injury, compared to the saline group. Studies have shown that buprenorphine treatment decreased initial post-operative weight loss ( Ryu et al, 2021 ), but caused prolonged weight loss in rats, suggesting buprenorphine may have long-term adverse effects on intestinal function due to its enterohepatic circulation ( Brennan et al, 2009 ; Cooper et al, 2005 ; Jablonski et al, 2001 ). In addition, studies indicate that the effects of BPN on body weight depend on the dose and treatment regimen ( Chum et al, 2014 ).…”

The Neurobehavioral Effects of Buprenorphine and Meloxicam on a Blast-Induced Traumatic Brain Injury Model in the Rat

“…Preclinical studies of TBI in animals are often performed without using pain relieving medications, such as opioids, prompted by concerns that these medications can alter the injury-induced neurobiological perturbations and the resultant behavioral, physiologic, pathologic, and cognitive outcomes after TBI ( 27 – 29 ) and have been shown to be neuroprotective in some cases ( 30 , 31 ). The mechanism(s) underlying opioids' neuroprotective effect remains to be elucidated, but it is hypothesized to be due to their action as inhibitory modulators of neurons ( 30 ) mediated through interactions with specific opioid receptors ( 31 ).…”

“…For example, one study found no significant differences in gene expression, nerve conduction, functional recovery (grid walking and beam crossing), or histopathological changes between rats receiving and those not receiving buprenorphine after spinal cord injury ( 36 ). Meanwhile, another study found significant acute gene expression changes and activation of cortical microglia and thalamic astrocytes in animals given sustained-release buprenorphine after central fluid percussion brain injury ( 29 ).…”

Post-injury Buprenorphine Administration Is Associated With Long-Term Region-Specific Glial Alterations in Rats

“…For this, animals were anesthetized 4w post-injury, as described above, and a 2mm diameter burr hole was drilled into the left parietal bone overlaying the left lateral ventricle (0.8 mm posterior, 1.3 mm lateral, and 2.5 to 3 mm ventral relative to bregma) through which a 25-gauge needle, connected to a pressure transducer and a micro infusion pump 11 Elite syringe pump (Harvard Apparatus) via PE50 tubing, was placed into the left ventricle. Appropriate placement of the infusion pump into the lateral ventricle was verified via a 2.3μl/min infusion of sterile saline within the closed fluid pressure system during needle placement 22,24,27 . The needle was held in the lateral ventricle for at least 5 minutes to record ICP.…”