Abstract
Despite the myriad promising new targets and candidate analgesics recently identified in preclinical pain studies, little translation to novel pain medications has been generated. The pain phenotype in humans involves complex behavioral alterations, including changes in daily living activities and psychological disturbances. These behavioral changes are not reflected by the outcome measures traditionally used in rodents for preclinical pain testing, which are based on reflexes evoked by sensory stimuli of different types (mechanical, thermal or chemical). These measures do not evaluate the impact of the pain experience on the global behavior or disability of the animals, and therefore only consider a limited aspect of the pain phenotype. The development of relevant new outcomes indicative of pain to increase the validity of animal models of pain has been increasingly pursued over the past few years. The aim has been to translate “bedside-to-bench” outcomes from the human pain phenotype to rodents, in order to complement traditional pain outcomes by providing a closer and more realistic measure of clinical pain in rodents. This review summarizes and discusses the most important nonstandard outcomes for pain assessment in preclinical studies. The advantages and drawbacks of these techniques are considered, and their potential impact on the validation of potential analgesics is evaluated.
Highlights
CHALLENGES OF PRECLINICAL PAIN RESEARCHMillions of people world-wide suffer from chronic pain [1]. Pain management is an unmet clinical need and the development of new analgesic drugs with better efficacy/ tolerability than those currently available is a high priority [2]
HISTORICAL PERSPECTIVE OF THE DEVELOPMENT OF CLINICALLY RELEVANT PAIN MODELS AND THE STANDARD CONCEPTUALIZATION OF NOCICEPTION
From the early times of preclinical pain research, when studies were devoted to acute nociception, several advances have been obtained in the search for pain models relevant to human pain conditions
Summary
Millions of people world-wide suffer from chronic pain [1]. Pain management is an unmet clinical need and the development of new analgesic drugs with better efficacy/ tolerability than those currently available is a high priority [2]. Nonreflexive Outcomes in Pain Research sensitivity to drug-induced analgesia played an important role in the shift in the conceptualization of the type of pain being explored in preclinical pain research, and inspired researchers world-wide to develop the current more clinically relevant models of pain in rodents Some of these animal models attempt to mimic inflammatory, osteoarthritis, neuropathic, cancer and postoperative pain in rodents. The Randall-Selitto test, originally developed in 1957 [28], consists of the application of increasing pressure via blunt mechanical stimulation to the hindpaw until a withdrawal reflex, struggling or vocalization appears (reviewed in [13,29]) Recent modifications of this test use fixed pressure to the paw and record the latency to the first pain-like response [30,31]. We will analyze and highlight both the advantages and drawbacks of these approaches, their possible usefulness for testing candidate analgesics, and as possible points for improvement
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