Background & Aims
The experience of pain is highly modifiable by an individual’s expectations of its intensity. Placebo analgesia is an expectation-driven reduction in pain perception that can be attributed to a treatment context or operant-induced internal states. Previous work shows reduction of BOLD activity and increased endogenous opioid release in medial thalamic neurons during placebo analgesia. A subset of medial thalamic neurons, the rostral intralaminar thalamus (rILN), contains neurons that receive ascending inputs from the spinal cord, parabrachial nucleus, and the ventrolateral periaqueductal gray (vlPAG), and their activity increases in response to nociceptive stimuli. rILN nuclei transmit nociceptive information to the cortex and densely express mu-opioid receptors (MORs), indicating the potential modulation of pain signals by endogenous opioid release at this site. We aim to investigate MOR+ vlPAG and rILN activity in response to nociceptive stimuli and endogenous antinociception.
Methods
Here, we utilize instrumental conditioning to drive expectation-mediated analgesia. In our optimized endogenous analgesia conditioning (EAC) paradigm, mice are placed in a two-chamber maze with distinct visual and tactile contexts, with continuous free access to explore either chamber at will. Each chamber has a temperature-programmable floor plate. During conditioning, the experimental plate is set at a noxious temperature for EAC-conditioned mice, or an innocuous temperature, for non-conditioned controls, while with the other plate remains stably innocuous to serve as the expected safe environment. Following multiple within and across-day conditioning sessions where mice can instrumentally escape to the innocuous context, both plates are set to noxious temperatures and cameras record exploratory and nocifensive behaviors. We utilize this paradigm to investigate the calcium activity of MOR+ vlPAG and rILN (vlPAGMOR and rILNMOR) neurons during nociception and endogenous analgesia.
Results
Our EAC paradigm induced conditioned place aversion against the noxious-associated context and reduced nocifensive responses to the inescapable noxious heat stimulus/environment during the ~90 second “putative placebo” period in EAC-conditioned mice. When recording the calcium activity of vlPAGMOR during EAC, we observed increased activity in neurons in response to nociceptive stimuli and reduced activity in this population during the endogenous analgesia response in the “putative placebo” period. vlPAG neurons project to rILN, which also exhibit increased activity in response to nociceptive stimuli. Chemogenetic inhibition of rILNMOR reduces nocifensive behavioral responses to noxious heat stimuli and we are investigating rILNMOR activity dynamics during the endogenous analgesia response.
Conclusions
Endogenous analgesia conditioning induces a ~90 second period of endogenous antinociception that is behaviorally and neurally distinct from the subsequent
“putative extinction” period in which nocifensive behavioral and nociceptive neural responses are restored. Aversion to the noxious-associated context also diminishes during the “putative extinction” period. vlPAGMOR is a nociceptive-active population whose activity is modulated during the endogenous analgesia response. Further studies will investigate the activity of rILNMOR neurons and their projections to the rostral anterior cingulate cortex during nociception and endogenous analgesia.
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(Last name, First Initial et al., Journal. Publication Year. PMID)
Presenting Author
Lindsay Ejoh
Poster Authors
Topics
- Placebo