The Role of Mediodorsal Thalamic Projections to Prelimbic Medial Prefrontal Cortex in Affective Pain Processing and Pain Tolerance

Abstract

Both human and rodent studies demonstrate that the mediodorsal (MD) thalamus, a target of spinothalamic tract neurons, is involved in processing the affective component of pain. The specific role of MD nuclei and their projections in pain remains incompletely understood. MD projects to several cortical regions, one of which is the prelimbic region of the prefrontal cortex (PL), an area thought to play a role in pain processing and modulation. The purpose of this study was to elucidate the role of MD neurons that project to the PL in affective pain processing and pain tolerance. We utilized viral vectors and the Cre-lox system to specifically express designer receptors exclusively activated by designer drugs (DREADDs) in MD pyramidal neurons that project to the PL to activate or deactivate the circuit with CNO. Mice received chronic constriction injuries (CCI) contralateral to viral injections. This was followed by conditioned place aversion (CPA) or preference tests and the operant plantar thermal assay (OPTA). Activating the unilateral MD-PL circuit using excitatory DREADDs in naïve mice did not produce a conditioned place aversion. It did, however, produce place aversion in mice with CCI. Unilaterally inhibiting the MD-PL circuit in mice with CCI did not produce a place preference. There was no difference in the time spent tolerating a noxious temperature to receive a sucrose reward when this circuit was either activated or inhibited in mice with CCI. The MD-PL circuit is involved in the enhancement of aversion in mice with chronic pain. This circuit, however, is not sufficient to produce aversion in pain-free mice. This circuit may not be necessary for the affective component of pain, as unilaterally inhibiting it did not result in preference in mice with CCI. Finally, this circuit may not be involved with the modulation of pain tolerance in mice with CCI. Grant support from R01 NS107356.