A Novel Pain Pathway To Elucidate a Connection Between Chronic Pain and Opioid Use

The misuse and heavy reliance on effective opioid painkillers due to the many Americans suffering from chronic pain has added to the current opioid epidemic. Chronic pain is often associated with higher-order processing dysfunction such as anxiety, depression, difficulty with attention to detail, and forgetfulness. Therefore, it is highly likely that the Prelimbic Prefrontal Cortex (PL-PFC), primarily responsible for higher-order processing functionality, is directly neuronally connected with the Rostral Ventromedial Medulla (RVM), an area responsible for modulating pain. This is a major site of action for opioids, and a site of action to the Descending Pain Modulatory Pathway where endogenous opioids are released to act as a natural pain reliever and inhibit ascending pain signals. Preliminary data has shown a link to Kv7 channels in the prelimbic region of the brain and chronic pain. To probe Kv7 type channels in pain states, a specific Kv7 channel blocker, XE-991, was microinjected into PL-PFC to cause a similar state of hyperactivity in the region. Von Frey behavioral testing revealed lower paw withdrawal threshold compared to vehicle injections of artificial cerebrospinal fluid (aCSF), representing more pain with the channel blocker, and a good model to study chronic pain. In a subsequent experiment, lidocaine, a local anesthetic that will temporarily inhibit neuronal activity, was microinjected into the RVM just preceding the PL-PFC injection. If there is a direct connection from the PL-PFC to the RVM, the axon terminals of the projecting neurons and targets will be inhibited and pain will not be detected in behavior testing. Increased paw withdrawal threshold for mechanical allodynia was observed with lidocaine treatment, further adding to the claim that there exists a direct neuronal projection from the PL-PFC to the RVM (PL-RVM). In order to view these direct neuronal projections, fluorescent tract tracing was employed in a subsequent experiment by injecting both anterograde and retrograde neuronal tracers into the PL-PFC and RVM. Microscopic analysis showed areas of significant colocalization to further add evidence to support the hypothesis that there exists a direct projection pain pathway from the PL-PFC and the RVM. If this hypothesis is correct, it would expand our knowledge of the pathways in which pain synapses throughout the brain including parts of the brain that may play a role in an affective component of pain. This allows scientists and medical professionals to develop new, efficacious treatment options for chronic pain patients that may have added pain due to conditions of anxiety as well as depression, including those who suffer from unilateral treatments with opioids and the opioid epidemic.Release after 06/01/202