Not Just Neurons: Pain Is Orchestrated in Partnership with Many Non-neuronal Cells

Pain is a symptom common to a wide variety of conditions and one that severely impacts an individual's everyday life, as well as having broader socioeconomic repercussions. In recent years, there has been spectacularly rapid progress in the understanding of the molecular basis of sensory neuron function and pain in preclinical models. However, the number of analgesics interacting with novel targets that have received regulatory approval in recent years has been limited. Examples include monoclonal antibody and small molecule therapies disrupting calcitonin gene-related peptide signaling for treating migraine and, most recently, suzetrigine, a small molecular inhibitor of the voltage-gated sodium channel Na_V1.8 subunit. In this review, we step away from focusing on the sensory neuron as the transmitter of nociceptive information and examine the role of non-neuronal cells in modulating sensory neuron activity. One potential appeal of disrupting the activity of peripherally located non-neuronal cells is the likely bypassing of side effects associated with modulating a target receptor that is expressed by neurons within both the peripheral and central nervous systems, although targeting of peripheral, non-neuronal cells will not of course necessarily be side effect-free. Here, we examine the key roles of non-neuronal cells in orchestrating pain across a diverse set of conditions, from joint pain to bone pain, chemotherapy-induced neuropathic pain, Fabry disease, and chronic pain in general.