BACKGROUND: Pregabalin is a first-line agent for neuropathic pain treatment whose abuse liability remains controversial. Surprisingly, studies exploring the reinforcing properties of pregabalin in operant mouse models are missing. METHODS: We evaluated the acquisition of operant pregabalin self-administration in mice exposed to a partial sciatic nerve ligation (PSNL) or a sham operation. After surgery, mice were trained in operant boxes to intravenously self-administer pregabalin at 1.5 or 3 mg/kg/inf or saline during 10 days. Thermal and mechanical sensitivity were assessed before and after self-medication, and depressive-like behaviour was evaluated after discontinuation of the treatment. RESULTS: Partial sciatic nerve ligation and sham-operated mice exposed to pregabalin at 3 mg/kg/inf showed higher active responding compared to mice exposed to saline. The differences in active responding were more robust in nerve-injured than in sham-operated mice. Self-medication at either dose of pregabalin partially inhibited thermal hypersensitivity, whereas only self-medication at 3 mg/kg/inf reduced mechanical sensitivity. Finally, a depressive-like behaviour was revealed after saline treatment in nerve-injured mice, and this emotional manifestation was abolished after pregabalin treatment at the high dose. CONCLUSIONS: Pregabalin showed reinforcing effects both in PSNL and sham-operated mice and attenuated the nociceptive and emotional manifestations of neuropathic pain in mice self-administering this drug. Therefore, pregabalin self-administration was related to neuropathic pain relief, but also to reinforcing properties related to psychotropic drug effects. This study reveals the improvement in nociceptive and emotional manifestations of neuropathic pain after operant pregabalin self-medication in mice and suggests the reinforcing effects of this drug in an operant paradigm. SIGNIFICANCE: This study shows that mice with a nerve injury self-administer pregabalin at doses effective reducing nociceptive hypersensitivity and depressive-like behaviour associated with the neuropathic pain model. Interestingly, mice without neuropathy also develop operant self-administration behaviour, suggesting potential abuse liability of this first-line drug for neuropathic pain treatment.

This work was supported by the European Commission, FP7 (#HEALTH‐F2‐2013‐602891), Spanish Ministerio de Economía y Competitividad‐MINECO (#SAF2014‐59648‐P) and Instituto de Salud Carlos III, RETICS‐RTA (#RD12/0028/0023) and Generalitat de Catalunya, AGAUR (#2014‐SGR‐1547). We acknowledge the financial support of the AGAUR (ICREA Acadèmia Award 2015) to R.M. FEDER partial funding is also acknowledged.