Assessment of the sigma‐1 receptor antagonist (SR1A): A model approach for preclinical analgesic drug discovery

Finding the ‘perfect’ analgesic remains an elusive goal in preclinical research and clinical practice. In fact, even defining the ‘perfect’ analgesic is difficult given the complexity of the pain experience. For example, a patient suffering from advanced terminal disease requiring palliation has different needs as compared to a young individual with a chronic pain disorder (e.g., low back pain), where complete pain inhibition could lead to serious untoward consequences (Mannes and Iadarola, 2007). In terms of chronic pain management, the perfect drug would likely be described as one that provides significant pain relief, yet has a low addiction liability, and limited to no side effects. An important aspect in the drug development process is the relevance of the preclinical outcomes to clinical translation – are we using the appropriate measures in animal models that will predict clinical efficacy? Previous works using NK1 antagonists certainly highlight this issue (Boyce and Hill, 2000; Hill, 2000) and I refer the reader to excellent reviews for a more in-depth discussion on the appropriateness of animal models in pain (Rice et al., 2008; Mogil, 2009). In this issue, you will find a paper by Bura et al. (2013), ‘Operant self-administration of a sigma ligand improves nociceptive and emotional manifestations of neuropathic pain’. The authors integrated a number of interesting and important topics related to the preclinical evaluation of a new sigma-1 receptor ( 1R) antagonist (S1RA) in chronic pain. The 1R is implicated in pain modulation, being expressed in relevant pain pathways (e.g., superficial dorsal horn, periaqueductal gray matter), and both genetic 1R knockout and pharmacological antagonist studies demonstrate efficacy in reducing neuropathic pain (de la Puente et al., 2009; Diaz et al., 2009). In fact, these authors have previously demonstrated that S1RA can block both acute (capsaicin, formalin) and chronic neuropathic pain, as demonstrated by significant changes in standard reflex-based outcome measures (e.g., von Frey, thermal plantar) (Romero et al., 2012). Currently, there is a debate in the pain field regarding the appropriate use of operant versus reflex measures (Vierck et al., 2008). To their credit, Maldonado et al. designed their study to include operant outcomes that complement their previous work and their data provide insight regarding the effects of S1RA on both pain sensitivity and motivation, thus assaying both the neurophysiological and the affective aspects of pain. This is particularly important with regard to the relevance to clinical pain management. The authors provided a very well-designed and executed study that demonstrates a significant reduction in neuropathic pain using reflex measures coupled with an operant model of contingent self-administration. They assessed S1RA for spinalmediated outcomes and showed that S1RA is effective in blocking thermal and mechanical hyperalgesia after self-administration of S1RA, but they also gained insight on higher order cortical outcomes, as the neuropathic animals learnt to selectively self-administer the S1RA. With this operant design, the authors were also able to show that self-administration of S1RA did not affect locomotion or sedation, two potential problems with many existing analgesic drugs. Lastly, the authors utilized a clever operant paradigm that assesses other emotional states, such as anhedonia, after induction of chronic pain. In this free choice paradigm, animals were provided a preference for a highly palatable reward solution (2% sucrose). The neuropathic animals showed a significant decrease in the reward solution preference, consistent with previous studies that demonstrate that this preference decreases under conditions of anhedonia (Strekalova and Steinbusch, 2012). In the current study, non-contingent administration of S1RA reversed this state of anhedonia. Given that chronic pain conditions are associated with depressive-like symptoms such as anhedonia, assessment of these traits becomes important for preclinical screening of drugs. One additional area of investigation using SR1A would be to use a purely operant assay that removes the potential investigator bias from the outcome measure. This is important as previous studies have evaluated the influence of the laboratory environment on animal behaviour and found that experimenter