Negative Reinforcement Reveals Non-Evoked Ongoing Pain in Mice With Tissue or Nerve Injury

Abstract

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 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 (i.e., 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.

Role of Prelimbic GABAergic Circuits in Sensory and Emotional Aspects of Neuropathic Pain

“…Blue-light-mediated activation of PVIN enhances pain behavior and the aversive state, whereas, yellow-light-mediated inhibition of PVIN alleviates pain and the aversive state. It is believed that relief of pain causes reward via a negative reinforcement mechanism driven by a strong motivation to seek pain relief (Craig, 2002;He et al, 2012;King et al, 2009). Therefore, it is important to consider the possibility that our optogenetic manipulations did not modulate pain perception per se but affected the rewardseeking process directly.…”

“…To address this issue, we used a conditioned place preference (CPP) paradigm-a well-established, stimulus-independent, voluntary behavioral test to assess how local circuit neurons modulate pain behavior in free-moving animals (He et al, 2012;King et al, 2009;Park et al, 2013). The test is based on the fact that pain in animals, similar to human pain experience, is aversive and produces a strong motivational drive to seek relief (Craig, 2002), and relief of pain caused by a specific treatment is rewarding and can produce CPP selectively with nerve injury (but not SHAM) in both rats and mice (He et al, 2012;King et al, 2009;Park et al, 2013). Animals implanted with an optic fiber cannula (separate from threshold measurement groups) were attached to a DPSS laser via a patch cable and rotary joint and were subjected to the 5-day CPP testing.…”

Inhibition of CaMKII in the Central Nucleus of Amygdala Attenuates Fentanyl-Induced Hyperalgesia in Rats

“…Indeed, lidocaine or clonidine could not induce conditioned place preference in uninjured animals (He et al, 2012) including animals with OIH (He, Hu, and Wang, unpublished data). The present study demonstrates directly that increased amygdala activity in the absence of tissue or nerve injury can exacerbate physiologic pain responses, such as thermal hyperalgesia evoked by noxious heat stimuli and allodynia induced by otherwise in noxious stimulation.…”

Identification of Early RET+ Deep Dorsal Spinal Cord Interneurons in Gating Pain

“…In addition to the evoked responses, we tested stimulus-independent spontaneous pain by adopting a conditional place preference paradigm (He et al, 2012). This paradigm relies on the fact that analgesic agents (e.g., lidocaine), which are not rewarding in the absence of pain, should become rewarding in the presence of spontaneous/ongoing pain.…”