Virally-associated pain states exhibit a wide variety of presentations across and within viral families, whereby the patient demonstrates varying degrees of allodynia hyperalgesia, paresthesias, and dysesthesias. These pain phenotypes can manifest immediately following infection and persist in the presence of a viral titer, result in changes which persist after a loss of viral titer, or they may present after a pain-free interval. The latter may occur because the virus goes dormant and reactivates after a latent period, or because the initiating event (e.g., central sensitization) takes time to reach the threshold of perception. i)

Influenza virus characteristically produces an acute infection within the respiratory tract. By 2–3 days post-infection, pain presents in the form of sore throat and headache (frontal or retro-orbital), as well as a whole-body pain referred to the musculature (e.g., myalgias) and the joints (arthralgia) (1). Symptoms typically persist until 7–10 days post-infection, corresponding with the clearance of virus. However, Influenza has also been associated with post-viral chronic pain conditions, including post-viral myositis (2, 3), arthralgias (4), and fibromyalgia (5).

The introduction of a virus into an organism has three consequences impacting system function. i)

Viral particles in the extracellular space or on the cell surface lead to the activation of innate and adaptive host immunity involving populations of natural killer (NK) cells, macrophages, and T and B lymphocytes. Immune activation leads to the secretion of humoral products like cytokines, chemokines, and antibodies to viral epitopes that impact local cell populations through afferent axons and distal cell populations via vascular uptake. From a psychoneuroimmunological perspective, these cytokines—such as TNFα, IL1β, and IL6—play a critical role in modulating pain by directly sensitizing nociceptive neurons and indirectly influencing pain through neuroimmune interactions (19, 20). As the DRG lies outside the blood brain barrier, circulating factors can gain access to the DRG cell systems, from sacral to trigeminal, through the DRG-vascular barrier (21), which can generate ectopic activity and enhanced afferent traffic through the complement of neuronal and nonneuronal cells (22). The concept of neuroimmune crosstalk is central here, as this interaction between immune cells and neurons contributes to the development and persistence of pain, highlighting the importance of immune-driven changes in neuronal excitability in virally-induced pain states.

Influenza infection can also lead to a robust immune response in the CNS mediated by proinflammatory cytokines and chemokines and subsequent reactivity in microglia (30–35). The reactive state in microglia induced by these inflammatory mediators plays a key role in shaping the pain response and can lead to long-lasting alterations in neuronal function (36, 37). Studies on the effects of influenza viruses on microglia suggest that infection likely induces a priming state in microglia, which could have profound consequences on the regulatory role that microglia play in local neuronal excitability in the brain and spinal systems (33–35). Primed microglia are more sensitive to milder stimuli, wherein a second stimulus/hit leads to an exacerbated response compared to the first stimulus/hit, akin to temporal summation, a phenomenon observed with central sensitization. Priming results in increased immune reactivity to a secondary insult and makes microglia more resistant to negative/regulatory feedback, leading to impaired synaptic plasticity, and neurodegeneration (36–39). These changes contribute to the persistence and amplification of pain following viral infections. Notably, most of this work focuses on the brain with few references regarding the effect upon spinal or DRG function, though several studies emphasize the potential relevance of these targets. Future research should expand on these areas to provide a more comprehensive understanding of how microglial reactivity contributes to virally-induced pain across different levels of the nervous system. ii)

Once in the cell, the virus alters the cellular transcriptome to initiate synthesis of proteins necessary for viral replication, which can have ancillary effects on cellular function. There are increasing examples whereby viruses can lead to persistent changes in cellular signaling, even in reduction or absence of viral titers or where viral advantage is unclear. Viral infection can induce these changes via prominent epigenetic changes in the host cell, a phenomenon commonly observed with the herpesviruses in latently infected cells (40) and Influenza A targets, including immune cells relevant to sensitization like macrophages (41). Innate immune signaling, as occurs through activation of TLR4, can lead to the enlargement of lipid rafts that lead to a persistent aggregation of proinflammatory channels and receptors on the lipid rafts of spinal and DRG glial and afferent soma (22, 42–44). This activation leads to long term changes in cellular excitability, mediated by epigenomic effects. In the case of SARS-CoV-2, viral entry can be mediated by lipid rafts and impaired by depleting membrane cholesterol (45). These data confirm lipid rafts play an important role in viral infection and the ensuing pathophysiology, although their contribution to virally-initiated pain states remains incompletely investigated.

Consequences for pain differ based on a virus' ability to gain access and entry into cells that modulate pain phenotypes, such as neurons and companion immune cells within the PNS and CNS.

The cellular tropism of the virus at one level depends upon the nature of the mechanisms it employs to gain entry to the cell, such as binding to specific cell surface receptors and/or fusion to epitopes often dependent upon a fusion protein embedded in the protein capsid coating. Binding at specific membrane sites leads to viral particle internalization though the formation of pores and engulfment by endosomes or, on other occasions, direct injections of genetic material. For example, hemagglutinin molecules coating the envelope of Influenza viruses bind to receptors containing sialic acid on the cell surface, resulting in the endocytosis and endosomal entry of viral particles (60). VZV uses a combination of envelope glycoproteins (glycoprotein B, H, and L, referred to as gB, gH, and gL) to facilitate virion binding to several host cell receptors (myelin associated glycoprotein/Siglec4, Mannose-6-phosphate/MPR, insulin degrading enzyme/IDE) and facilitate fusion of the host membrane and virion envelope (61). The spike protein of SARS-CoV-2 binds to the angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cells, and this event is followed by the cleavage of the spike protein by the host protease and viral fusion to enter the host cell (62). These viral proteins and processes enhance the ability of viruses to directly infect neurons, leading to damage or alteration of signaling pathways which alter excitability, as well as amplifying immune responses that also contribute to changes in neuronal excitability. Many of these receptors localize to lipid rafts in the host plasma membrane, and virus entry often depends on the size and integrity of lipid rafts (63, 64).

The ability of a virus to infect certain cell types also depends on the viral capability to traffic to the appropriate location to contact the target cell. VZV directly infects neurons and likely accesses the innervating peripheral nervous system including the DRG through retrograde transport (65), and possibly through a hematogenous route based on data employing a similar virus, the Seneca Valley Virus (SVV) (66). In addition to its effect on peripheral terminals, there is evidence that Influenza viruses can be trafficked by retrograde transport in the afferent component of cranial and somatic nerves (67, 68). This suggests that the virus has access to the DRG neuronal soma and is trafficked to second order synapses in the dorsal horn. Viruses infecting neurons may migrate along the axon to the soma and often beyond to the first order synapse. Influenza may access the CNS through direct infection via the olfactory bulb (69) or by hematogenous spread due to enhanced permeability of brain microvascular endothelial cells following infection (34, 70). How SARS-CoV-2 infiltrates the CNS is not completely clear, but it has been postulated that it travels through the bloodstream, penetrating the brain through the vascular wall and transcytosing through the infected vascular endothelial cells (71) or potentially through infection of the olfactory bulb (72).Therefore, there are several routes by which a virus can access the PNS and CNS, including retrograde transport following direct peripheral terminal access, hematogenous routes, or direct infection into the CNS via the olfactory bulb.

Whereas many animal models of pain exist, there are few model systems created to specifically address pain induced by viral infections. A model of influenza-initiated pain was developed in which rodents acquire a similar pain profile in terms of presentation and duration (73). However, this model has not been employed since its introduction and pain analysis is limited to mechanical withdrawal thresholds measured after stimulation using Von Frey filaments (73). The pain phenotype of VZV has been more extensively studied despite major limitations in modeling herpetic pain due to the human-specificity of the virus (74). Although rodent models of VZV-induced acute and persistent pain exist, there is still no model that simulates pain during VZV reactivation from latency (12). Moreover, many VZV models do not accurately replicate the robust inflammatory response observed in humans after infection (12), making this component's contribution to pain difficult to quantify. There is a hamster model of pain following SARS-CoV-2 infection (57), but studies are rare due to the robust safety measures infection with SARS-CoV-2 necessitates. Among the models of virally associated pain that do exist, few if any account for important epidemiological factors that play a role in pain such as sex or age or consider how antivirals or general analgesics may impact pain sensation for a given viral infection.

As exemplified through SARS-CoV2, VZV, and influenza, the study of how a virus causes pain is complicated by the heterogeneity of viral pain states and presentations, and has begun dissection through the navigation of the (in)direct effects on (neuronal) cell function, and the mechanisms of entry into the DRG or intracranial systems. This area requires more detailed characterizations of animal models to be used in complement with in vitro studies to dissect the molecular, cellular, and neuroimmune-mediated mechanisms of pain initiation and chronification. The viral pain niche is a complicated, emerging field (75, 76) that calls for the interdisciplinary efforts of virologists, neuroscientists, immunologists, and pain researchers, which we hope to attract and inspire with this special topic.