Operant self-administration of pregabalin in a mouse model of
, D. Caba
, R. Maldonado
1 Laboratori de Neurofarmacologia, Departament de Ci
encies Experimentals i de la Salut, Universitat Pompeu Fabra, Parc de Recerca Biomedica
de Barcelona (PRBB), Spain
2 IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain
This work was supported by the European
Commission, FP7 (#HEALTH-F2-2013-
602891), the Spanish Ministerio de Econom
y Competitividad-MINECO (#SAF2014-59648-
P/FEDER), Instituto de Salud Carlos III,
RETICS-RTA (#RD12/0028/0023/FEDER) and
the Generalitat de Catalunya, AGAUR (#2014-
SGR-1547) and AGAUR (ICREA Acad
Award 2015) to R.M.
Conﬂicts of interest
Accepted for publication
12 November 2017
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.
© 2017 European Pain Federation - EFIC
Eur J Pain 22 (2018) 763--773