Differential Activation of Pain Circuitry Neuron Populations in Spinal Cord Injury Induced Neuropathic Pain
Pain serves an important purpose in warning of potential or actual damage to the body. When the nervous system is damaged, pain can become decoupled to injury. This is known as neuropathic or pathologic pain (NP). NP is one of the most common and debilitating comorbidities of spinal cord injury (SCI), and current therapies are often ineffective due in part to an incomplete understanding of the underlying pathogenic mechanisms. Therefore, defining SCI induced changes to central nervous system (CNS) pain processing areas is critical to developing novel therapeutics for SCI induced NP. In particular, it remains unclear how neural and non-neural changes in pain processing areas underly NP. The work in this thesis is focused on SCI induced changes to two pain-relevant populations: (1) Microglia (MMI) of the superficial dorsal (sDH) and (2) Neurons across the pain-processing neuraxis. We used a clinically relevant mouse model of SCI which consistently induces several NP behaviors in both the fore- and hind paws. We found that SCI increased the number of MMI, and increased their expression of pro- and anti-inflammatory markers, in the intact sDH relevant for controlling forepaw behavior. Despite robust hindpaw behavioral phenotypes, these changes were not recapitulated in the corresponding lumbar spinal cord. To explore neuronal activation post-SCI, we took advantage of the immediate early gene c-fos, which is an established marker of neuronal activation. We employed a mouse reporter line with fos-promoter driven Cre-recombinase (TRAP) to define neuronal activity changes in relevant pain circuitry locationsfollowing C5/6 contusion and in response to mechanical and thermal cutaneous stimulation. SCI significantly altered activation of cervical dorsal horn (DH) projection neurons in a subtype dependent manner, as well as increasing activation of both PKCγ and calretinin excitatory DH interneurons. Interestingly, SCI also promoted a significant decrease in activation of nNOS expressing inhibitory interneurons of cervical DH. In addition, SCI altered activation of various supraspinal neuron populations associated with pain processing, including a large increase in thalamus and decrease in periaqueductal gray neuron activation. These findings reveal a complex and diverse set of SCI-induced neuron activity, and non-neuronal phenotypic changes across the pain circuitry neuraxis, which can inform therapeutic targeting of defined cellular populations in NP.
Brown, Eric V, "Differential Activation of Pain Circuitry Neuron Populations in Spinal Cord Injury Induced Neuropathic Pain" (2021). ETD Collection for Thomas Jefferson University. AAI28773653.