Pain is a prevalent symptom in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, and its management remains a challenge. Based on the current understanding of their pathophysiological mechanisms, these diseases involve the dysregulated activation of the innate and adaptive immune system, leading to high levels of inflammation that damage tissue in the periphery and central nervous system along with the sensitization of primary sensory neurons, culminating in pain and disability (1–5).
Inflammation is not always detrimental, however. For instance, after injury, immune-mediated inflammation can trigger regenerative mechanisms, assisting in debris clearance or promoting regeneration (6–8). Inflammation is a dynamic process that can be initiated in response to various stimuli and then resolve when no longer required (9–11). In individuals with multiple sclerosis (MS), an inflammatory autoimmune disease characterized by periods of attack and remission, these inflammatory processes can coincide with periods of disability. Although inflammation can resolve in MS, it is not always the case, and persistent low-grade inflammation may lead to neurodegeneration, emphasizing the importance of the resolution process (12, 13). Chronic inflammation can lead to disability and may also play a role in the induction of chronic pain. As inflammation is adaptive and designed to resolve, its persistence may indicate an impairment in the resolution process.
Dorsal root ganglion (DRG) neurons have an innate capacity for growth after injury to their distal axons(14, 15). This plasticity can be demonstrated in cell culture. Dissociated DRG neurons can readily establish and send out axons in short periods of time, a process that can be encouraged by the priming of these cells with ‘conditioning lesions’(16–18) or discouraged by inhibition of retrograde transport along the injured axon(19, 20). Furthermore, the structural plasticity of neurons can be modulated by pharmacological manipulation of ion channels. For example, inhibition of Ca2+ channel trafficking to the membrane(21) with gabapentin can modulate synaptogenesis and neural circuitry rewiring(22, 23). This effect is also observed in vivo as gabapentinoids can be used to increase regeneration of axons after spinal cord injury (24–26). Similarly, Baclofen reduces the amplitude of voltage-gated Ca2+-currents in DRG neurons (27, 28) and promotes their regeneration after spinal cord injury. The growth state of sensory neurons can also be modulated by inflammation (29–32). Not only can the inflammatory response to injury, even potentially sterile injury, have effects on outgrowth, but inflammation triggered by adaptive or innate immunity can also affect outgrowth. Therefore, inflammation can be seen as a critical driver of structural plasticity and the growth status of sensory neurons (33).
It is also widely recognized that inflammation can alter the excitability of neurons, and traditional mechanisms of inflammation can result in increased action potential frequencies and lowered thresholds for action potential generation (i.e., sensitization). Inflammatory mediators like TNFα and IL-1β can regulate neuronal expression of voltage-gated sodium and potassium channels, increasing neuronal excitability (34–38). This phenomenon has been observed in both electrophysiological recordings of single cells (39) and nerve conduction studies (40, 41). Heightened excitability and sensitization of peripheral sensory neurons results in an increased perception of pain, although this phenomenon may resolve as inflammation subsides.
While inflammation can independently affect both the excitability and growth status of neurons, increasing excitability through electrical stimulation can promote axonal growth, indicating that there may be a connection between the two processes (42–44). Additionally, some researchers have proposed that the inflammation-induced changes in excitability may be directly involved in changes to neuronal growth status (45–47). Increasing neuronal excitability using optogenetics enhances axonal growth in the presence of an inflammatory stimulus (48, 49). This suggests that the increase in neuronal excitability may be one of the mechanisms by which inflammation promotes structural plasticity.
Overall, the relationship between inflammation, excitability, and the capacity for structural plasticity of DRG neurons is complex and likely involves multiple signaling cascades. To investigate this relationship, we conducted a series of experiments examining the effect of inflammation on neuronal excitability and neurite outgrowth. Our findings indicate that an early phase of increased neuronal excitability results in an increased growth status of primary sensory neurons, and that the neuron’s excitability is intricately linked to its structural phenotype.