Translational challenges and analgesic screening assays.

Progress in the development of novel treatments for chronic pain syndromes relies, in part, on both clinically-relevant animal model simulations and analgesic screening procedures [5]. Simulations purport to mimic the features of a clinical syndrome and screenings are geared towards drug discovery. The validity of any animal model simulation is based on how well that model fits the human clinical syndrome in terms of etiology, symptomatology, pathophysiology and response to treatments [9]. The validity of any screening assay requires that it correctly identify compounds that have clinical benefits, screens out compounds that do not and avoids false positives and false negatives [10]. In this issue of Pain, Gutierrez et al. [2] performed a series of well-designed studies to examine cannabinoid (CB) 2 receptormediated modulation of neuropathic pain. One interesting aspect of this research, beyond that of showing that the CB2 receptor may be a viable target for analgesic drug development, is their use of a more clinically relevant analgesic screening procedure. Such advances in screening protocols may facilitate drug discovery efforts. Research has shown that both CB1 and CB2 receptors are potential targets for novel analgesics. However, CB1 receptor activity is also associated with an abuse liability, making this receptor less than an ideal target for analgesic drug development. Using a variety of assessment procedures including a self-administration (SA) paradigm, Gutierrez et al. offers evidence that rats will self-medicate a CB2 receptor agonist to reduce allodynia in a nerve injury model of neuropathic pain and that this effect is mediated by CB2 receptor activation alone. Moreover, they demonstrate that CB2 receptor agonism does not support self-administration in sham-operated controls. This latter finding suggests that CB2 receptor agonists are unlikely to possess an abuse liability. The incorporation of self-administration procedures in pain protocols is an important step in developing novel therapeutics in pain models. Concerns have long been raised over the clinical relevance of traditional analgesic screening assays that use high intensity phasic stimuli to elicit reflex responses. Among these assays include the hot-plate test with thermal stimuli, paw-pressure test with mechanical stimuli and abdominal constriction test with chemical stimuli. The introduction of animal model simulations of chronic pain syndromes represents a significant advance. Among these simulations include arthritic models using complete Freund’s adjuvant, urate crystals or carrageenan, neuropathic models using various procedures of sciatic nerve ligation, and cancer models using tumor implantation. While evidence exists that increased nociceptive activity and central sensitization is long lasting, current analgesic screening assays continue to rely on evoked responses to noxious (i.e., hyperalgesia) and non-noxious (i.e., allodynia) stim-