Effects of Neuroprotective Minocycline (MIN) with Ketorolac or Buprenorphine for Pain Management as a Strategy to Improve Reflex Bladder Function in Rats with Contusion SCI

Spinal cord injury (SCI) includes both primary and secondary injury mechanisms that result in damage of axonal connections between the spinal cord and brain, cell death, and tissue loss that can lead to motor, sensory, and autonomic functional deficits below the level of the injury. While the primary injury is related to the initial (mechanical) trauma to the spinal cord, this initial trauma initiates a persistent and widespread secondary cascade of pathological processes that leads to further cellular/tissue damage and loss, and it has been suggested that inflammation is one of the key mediators in the progression of the secondary injury cascade. As such, strategies aimed at reducing the extent of secondary SCI-induced inflammation and cellular/tissue damage ( i.e., neuroprotection) are being pursued in order to preserve neural substrate following SCI in an attempt to enhance spontaneous functional recovery. To this end, administration of the FDA-approved antibiotic minocycline (MIN), which also exerts anti-inflammatory and anti-apoptotic effects, has been shown to exert neuroprotective actions in central nervous system injury/disease. Since SCI at any level between the lumbosacral spinal cord and the pontine micturition center exerts a profound negative impact on bladder function, resulting in detrusor over-activity, high bladder pressures, inefficient voiding, and urine retention that are associated with a high degree of morbidity and a poor quality of life, examination of the therapeutic potential of MIN on recovery of bladder function following SCI is warranted. Here, we investigated the effects of daily 7-day MIN administration initiated at 24-hr after SCI on reflex micturition behaviors in adult female Sprague-Dawley rats with moderate contusion SCI. For these experiments in addition to MIN treatment, post-operative animal care included administration of either the NSAID ketorolac (KET; ca. 2-4 mg/kg, sc; n=10) or the opioid buprenorphine (BUP; ca. 0.02 mg/kg, sc; n=7), which was administered immediately after SCI and at ~12 hr intervals, as needed, for post-operative pain management. At 3 weeks after completion of MIN treatment ( i.e., 4 weeks post-SCI), reflex micturition event (rME) behaviors were assessed under urethane anesthesia by continuous flow cystometry; these data were compared to previously acquired data from SCI rats that received the antibiotic Baytril (BAY; 5 mg/kg, sc; antibiotic control) as part of their routine post-operative care. As is typical following SCI, the pattern of rME behaviors seen on the BP record consisted of both non-voiding (NVC) and voiding (VC) bladder contractions; however, MIN-treated rats exhibited fewer NVCs compared to BAY-treated rats. In addition, detrusor-sphincter dyssynergia (DSD) characterized by either absent or weak EUS bursting with incomplete EUS relaxation during voiding that is commonly observed in untreated and BAY-treated rats was replaced by fairly strong EUS bursting with complete EUS relaxation (characteristic of naïve rats) in ~67% of the MIN-treated rats studied. To determine if post-operative pain management could have influenced the observations noted in MIN-treated rats, we further classified bladder dysfunction severity into mild, moderate, and severe phenotypes based on the NVC/VC ratio, with the distributions being ~37.5%, ~37.5%, and ~25% (respectively) for KET rats and ~66.7% ~16.7%, and ~16.7%, (respectively) for BUP rats, with both groups exhibiting a similar proportion of improvement in DSD. These preliminary findings indicate that while MIN may exert some beneficial effects on bladder function in SCI, the effects of these pain medications on MIN-induced improvements requires additional experiments. NYS DOH SCIRB C35598GG This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.