Operant self-medication for assessment of spontaneous pain relief and drug abuse liability in mouse models of chronic pain
The search for safe and efficient chronic pain treatments is dampened by the lack of reliable models that faithfully reproduce current pharmacological treatments for chronic spontaneous pain in humans. Preclinical models often assess the antinociceptive efficacy of non-contingent pharmacological treatments evaluated in the short-term. Here, we provide a protocol of contingent operant self-medication in mice, which allows the estimation of spontaneous pain relief and drug abuse liability in models of persistent pain. This paradigm requires preliminary habituation and animal handling, followed by training of mice in operant conditioning boxes, to allow subsequent analgesic drug self-administration. After the initial acquisition of food-maintained operant behavior, a chronic pain sensitization is induced. Posterior intravenous jugular catheterization and coupling of operant conditioning boxes to perfusion pumps allow quantification of operant responding for intravenous drug self-administration. All mice show an initial operant drug self-administration behavior associated with the previous food-maintained operant training. This initial operant responding is extinguished after administration of ineffective treatments, but continues when the compounds have analgesic efficacy or intrinsic reinforcing properties. The identification of a significant drug self-administration selectively expressed in mice exposed to the chronic pain condition is indicative of analgesic drug effects, whereas persistent self-administration in control mice is indicative of abuse liability. The present protocol provides the behavioral and surgical procedures needed to assess spontaneous pain relief and potential for abuse of pharmacological treatments, through contingent analgesic self-medication in mice. ; This work was supported by the European Comission [NeuroPain, FP7-602891-2], the European Union's Horizon 2020 research and innovation programme under grant agreement No 848068 [QSPainRelief, H2020-SC1-2019-2-RTD-848068], the Spanish Ministerio de Economía y Competitividad-MINECO (#SAF2017-84060-R- AEI/FEDER-UE), the Spanish Instituto de Salud Carlos III, RETICS-RTA (#RD12/0028/0023), the Generalitat de Catalunya, AGAUR (#2017 SGR-669), ICREA-Acadèmia (#2015) and the Spanish Ministerio de Sanidad, Servicios Sociales e Igualdad, Plan Nacional Sobre Drogas (#PNSD- 2017I068) to R.M., Fundació La Marató-TV3 (#2016/20-30) and Plan Nacional Sobre Drogas of the Spanish Ministry of Health (#PNSD-2019I006) to E.M-G. The methodology described was previously used in Bura et al. (2013, 2018) and Cabañero et al. (2020, doi:10.7554/eLife.55582). Authors also want to thank E. Senabre and R. Martín for their critics and technical support.
