Background & Aims
Chronic postsurgical pain (CPSP) is a potential devastating outcome from a surgical procedure with estimated incidence of ~10% of patients still suffering 12 months after surgery(1). Current rodent CPSP models are based on nerve injury and neuropathic pain, although not all CPSP cases are neuropathic in nature. Finding mechanisms underlying the maintenance of postsurgical pain may provide insights on preventive therapies and identification of high risk patients. We found that male SS-13BN rats(2) meet criteria for clinical CPSP (no pain prior to surgery and post-surgery allodynia persisting for 3 months), while females do not(3). We hypothesized that sex hormones protect against a genetic polymorphism on chromosome 13 responsible for pain persistence, and that facilitatory pathways through the rostroventral medulla (RVM) participate. We aim to use this strain to identify mechanisms involved in the development of post-surgery pain, thus providing targets for intervention in the future.
Methods
Male and female consomic SS-13BN rats were produced by introgressing Brown Norway (BN) chromosome 13 into the Dahl Salt-sensitive (SS) rat genetic background(2,3,4). These rats underwent hind paw-withdrawal threshold evaluation using von Frey filaments before and up to 139 days after a plantar surgical incision (Brennan model)(5) was performed. A separate group of female SS-13BN were ovariectomized 4 weeks post-birth. Paw incision surgery was subsequently performed at 12 weeks of age. Control animals were sham-operated or not-incised groups. In a separate cohort, intracranial cannulas were stereotaxically targeted to the RVM and, 1 week later, plantar incisions were performed. Lidocaine (200nL at 0.2%) was injected into the RVM on days 1, 3, 5, 7, 9, 12, 14 and 28 post-surgery and, the mechanical nociceptive thresholds, evaluated 30 min after each injection.
Results
As typical for the Brennan acute postsurgical pain model, paw-withdrawal thresholds in female SS-13BN rats returned to pre-incision values by the 8th postsurgical day. In contrast, thresholds remained low in males for the whole period of evaluation, 139 days. We then repeated the experiment in ovariectomized female rats and found that the post-incision paw-withdrawal thresholds remained low until the 56th postsurgical day. This suggests sex hormones may protect against the genetic polymorphism on chromosome 13 responsible for the chronification of surgery-induced pain in these rats. In the next experiment, we injected lidocaine into the RVM of SS-13BN rats daily following hind paw incision to test the role of descending pain pathways(6) in the development of chronic pain in this model. We found that lidocaine reduced post-surgery pain after the 7th postsurgical day, suggesting that pain facilitatory pathways became active in male SS-13BN rats around the time pain resolved in females.
Conclusions
This preliminary work indicates the SS-13BN as an effective rodent model of CPSP that can be used in studies to identify pathways responsible for the transition from acute to CPSP. Because of sexual dimorphism in the CPSP phenotype, the SS-13BN can also be used to determine sex-dependent contributors. In addition, lidocaine’s effectiveness on day 9 but not on the earlier post-surgical days suggests a gradual recruitment of RVM-associated circuits in the process of maintenance of the painful state.
References
1. Carley ME, et al. Pharmacotherapy for the prevention of chronic pain after surgery in adults: An updated systematic review and meta-analysis. Anesthesiology 2021;135:304–25.
2. Cowley AW Jr, et al. Application of chromosomal substitution techniques in gene-function discovery. J Physiol. 2004;554:46-55.
3. Ferrari LF, et al. Descending Control of Nociception Poorly Predicts the Development of Persistent Postsurgical Pain-like Behavior in Consomic Dahl S Rat Strains. Anesthesiology. 2023;139(4):476-491.
4. Ferrari LF, et al. Characterization of the Dahl salt-sensitive rat as a rodent model of inherited, widespread, persistent pain. Sci Rep. 2022;12(1):19348.
5. Brennan TJ. A rat model of postoperative pain. Curr Protoc Pharmacol. 2004;Chapter 5:Unit 5.34.
6. Tomim DH, et al. The Pronociceptive Effect of Paradoxical Sleep Deprivation in Rats: Evidence for a Role of Descending Pain Modulation Mechanisms. Mol Neurobiol. 2016;53(3):1706-1717.
Presenting Author
Norman E. Taylor
Poster Authors
Luiz Ferrari
PhD
University of Utah
Lead Author
Topics
- Genetics