Negative reinforcement reveals non-evoked ongoing pain in mice with tissue or nerve injury

Patients with chronic pain experience spontaneous or ongoing pain as well as enhanced sensitivity to evoked stimuli. Spontaneous or ongoing pain is rarely evaluated in preclinical studies. In fact, it remains controversial whether ongoing or spontaneous pain even develops in mice after tissue or nerve injury. This study tested a hypothesis that negative reinforcement can be used to unmask the presence of pain in mice with tissue or nerve injury. We found that spinal administration of clonidine or lidocaine did not elicit conditioned place preference (CPP) in uninjured or sham-operated mice. However, these agents produced CPP in mice with chronic inflammation induced by complete Freund's adjuvant (CFA) or following L5/L6 spinal nerve ligation (SNL). These data indicate the presence of non-evoked (ie, stimulus-independent) ongoing pain in mice with chronic inflammation (CFA) or following nerve injury (SNL). In addition, this study validates the use of negative reinforcement to unmask non-evoked ongoing pain in mice. Given the existence of a large collection of transgenic and knockout mice, our data show the application of this approach to elucidate molecular mechanisms underlying non-evoked pain and to contribute to drug discovery for pain. Perspective: We demonstrated the presence of non-evoked ongoing pain in mice with chronic inflammation or following nerve injury. The study also validates the use of negative reinforcement to unmask non-evoked pain in mice. We propose to apply this approach to identify molecular mechanisms and effective drugs for chronic pain.