Operant self-administration of a sigma ligand improves nociceptive and emotional manifestations of neuropathic pain

Background The treatment of neuropathic pain is unsatisfactory at the present moment and the sigma 1 receptor has been identified as a new potential target for neuropathic pain. The aim of this study was to use an operant self‐administration model to reveal the potential interest of a new sigma 1 re...

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Published in:	European journal of pain Vol. 17; no. 6; pp. 832 - 843
Main Authors:	Bura, A.S., Guegan, T., Zamanillo, D., Vela, J.M., Maldonado, R.
Format:	Journal Article
Language:	English
Published:	England Blackwell Publishing Ltd 01-07-2013 Wiley-Blackwell
Subjects:	Analgesics - therapeutic use Analgèsics Animals Disease Models, Animal Emotions Hyperalgesia - complications Hyperalgesia - drug therapy Ligands Male Mice Mice, Inbred C57BL Neuralgia - chemically induced Neuralgia - complications Neuralgia - drug therapy Neuràlgia Pain Measurement - methods Pain Threshold - drug effects Receptors, sigma - antagonists & inhibitors Self Administration Sigma-1 Receptor Ús terapèutic
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Summary:	Background The treatment of neuropathic pain is unsatisfactory at the present moment and the sigma 1 receptor has been identified as a new potential target for neuropathic pain. The aim of this study was to use an operant self‐administration model to reveal the potential interest of a new sigma 1 receptor antagonist, S1RA, in chronic pain that was developed in mice by a partial ligation of the sciatic nerve. Methods Once that chronic pain had reached a steady state, mice were trained to maintain an operant behaviour to self‐administer S1RA. The possible abuse liability of the analgesic compound was determined by evaluating operant self‐administration in sham‐operated mice. The influence of S1RA on the anhedonic state related to chronic pain was also evaluated by measuring the preference for palatable drink (2% sucrose solution) using a recently validated and highly sensitive behavioural device. Results Nerve‐injured mice, but not sham‐operated animals, acquired the operant responding to obtain S1RA (6 mg/kg/infusion). After 10 days of S1RA self‐administration, neuropathic pain was significantly reduced in nerve‐injured mice. In addition, an anhedonic state was revealed in nerve‐injured mice by a decreased consumption of palatable drink, which was significantly attenuated by S1RA (25 mg/kg). Conclusions These results reveal the analgesic efficacy of the sigma antagonist, S1RA, in neuropathic pain associated with an improvement of the emotional negative state and that was devoided of reinforcing effects. The operant responses evaluated in this new mouse model can have a high predictive value to estimate the clinical benefit/risk ratio of new analgesic compounds to treat chronic pain, such as S1RA.
Bibliography:	Spanish Ministry of Science and Innovation - No. SAF2007-64062 istex:38F8AEC721ED60E7793AC19F0A2DDE18D4C7E750 ICREA Foundation - No. ICREA Academia-2008 ArticleID:EJP251 Instituto de Salud Carlos III - No. RD06/001/001 Catalan Government - No. SGR2009-00131 DG Research of the European Commission (PHECOMP) - No. LSHM-CT-2007-037669 ark:/67375/WNG-B4RKSSTT-J Conflicts of interest Funding sources S1RA was provided by Esteve as a gift within research projects funded by the CENIT program (CEN‐20061005) from the Centro para el Desarollo Technológico Industrial from the Spanish Ministry of Science and Innovation (#SAF2007‐64062), ‘Redes temáticas de investigación cooperativa en salud (RETICS) del Instituto de Salud Carlos III (RD06/001/001). Red de trastornos adictivos (RTA)’, the Catalan Government (SGR2009‐00131), the ICREA Foundation (ICREA Academia‐2008) and the DG Research of the European Commission (PHECOMP, #LSHM‐CT‐2007‐037669). D.Z. and J.M.V. are employees of the company ‘Esteve’.
ISSN:	1090-3801 1532-2149
DOI:	10.1002/j.1532-2149.2012.00251.x