Friday, September 28, 2018 4:05 PM–5:05 PM abstracts: basic science of spinal fusion: 237. Effect of a systemic postoperative cannabinoid receptor agonist on spine fusion in rat model

Abstract

BACKGROUND CONTEXT Following spine surgery, most patients receive opioid medication for analgesia. Opioids have caused controversy in popular culture because of frequent overuse and negative side effects. Given the current opioid epidemic, alternative postoperative analgesic strategies are being explored. The endocannabinoid system, a known regulator of pain reception, has been shown to have anti-nociceptive activity in animal models of acute tissue and nerve injury. Likewise, endocannabinoids are important to bone homeostasis via activity at CB1 and CB2 receptors; increasing numbers of osteoblasts and limiting the development of osteoporosis. Like the FDA approved synthetic cannabinoid agonists currently used to treat cancer pain, WIN55.212-2 (WIN55) acts as a dual agonist at both CB1 and CB2 receptors. Our in vitro work has demonstrated that WIN55 has no negative effect on the osteogenic differentiation capacity of rat bone marrow stem cells (BMSC). Hence, WIN55 was examined as a postoperative pain analgesic in rats following posterolateral spinal fusion. PURPOSE To determine whether the dual cannabinoid receptor agonist, WIN55.212-2, has a quantifiable effect on spinal fusion when used for postoperative analgesia. METHODS Sprague Dawley rat BMSC was cultured under osteogenic conditions and treated with WIN55. Alkaline phosphatase (ALP) activity assay, matrix mineralization assay, and qPCR were performed. Forty-five female Sprague Dawley rats underwent L4-L5 PLF with placement of acellular-collagen sponge loaded with 1ug of recombinant bone morphogenetic protein-2. Experimental groups received either low dose (0.5mg/kg, n=15) or high dose (2.5mg/kg, n=15) WIN55, delivered postoperatively for 5 days via intraperitoneal injection. A control group (n=15) received intraperitoneal DMSO for 5 days postoperatively. All animals received routine intra-and postoperative pain control per protocol. Spine fusion was assessed using radiography, manual palpation-based fusion scoring, and microCT. For fusion scoring, an established scoring system was used whereby spines with an average score ≥1 were considered fused. RESULTS Early and late markers of osteogenic differentiation, ALP activity, and mineralization, were not inhibited by treatment of WIN55. mRNA expression of Alp and Run×2 was similar between DMSO and WIN55 treated cells. Rats treated with low dose WIN55 demonstrated the most robust fusion rate (93%) and mean fusion score (1.69). The high dose group had a fusion rate of 73% and a mean fusion score of 1.43. DMSO controls had the lowest fusion rate (60%) and score (1.17). The low dose group had a significantly greater fusion rate and mean score than the control group (pl0.05, pl0.05). No significant differences in fusion existed between the low dose and high dose groups. CONCLUSIONS The opioid crisis has prompted strong interest in the development of alternative strategies for pain management after spine procedures. However, clear evidence that alternative treatments have no negative impact on bone healing is necessary before consideration of their use. We have presented preclinical evidence that WIN55, a dual cannabinoid receptor agonist, does not adversely affect spinal fusion in a rat model. These results support the notion that cannabinoid receptor agonists may be used for postoperative analgesia following spine surgeries without risk of inhibiting bone healing. Continued analysis of microCT imaging will allow us to further quantify the effects of WIN55 on new bone growth.