Peripheral nerve injuries and diseases often lead to pain persisting beyond the resolution of damage, indicating an active disease-promoting process, which may result in chronic pain. This is regarded as a maladaptive mechanism resulting from neuroinflammation that originally serves to promote regeneration and healing. Knowledge on these physiological and pathophysiological processes has accumulated over the last few decades and has started to yield potential therapeutic targets. Key players are macrophages, T-lymphocytes, cytokines, and chemokines. In the spinal cord and brain, microglia and astrocytes are involved. Recently, data have been emerging on the regulation of these players. MicroRNAs and other noncoding RNAs have been discussed as potential master switches that may link nerve injury, pain, and inflammation. Clinical disorders most intensely studied in the context of neuroinflammation and pain are the complex regional pain syndrome, polyneuropathies, postherpetic neuralgia, and the fibromyalgia syndrome, in which recently a neuropathic component has been described. Research from several groups has shown an important role of both proinflammatory and anti-inflammatory cytokines in neuropathic and other chronic pain states in humans. There is ample evidence of an analgesic action of anti-inflammatory cytokines in animal models. The interplay of anti-inflammatory cytokines and the nociceptive system provides possibilities and challenges concerning treatment strategies based on this concept.

Alterations in the neuro-immune balance play a major role in the pathophysiology of chronic neuropathic pain. MicroRNAs (miRNA) can regulate both immune and neuronal processes and may function as master switches in chronic pain development and maintenance. We set out to analyze the role of miR-132-3p, first in patients with peripheral neuropathies and second in an animal model of neuropathic pain. We initially determined miR-132-3p expression by measuring its levels in white blood cells (WBC) of 30 patients and 30 healthy controls and next in sural nerve biopsies of 81 patients with painful or painless inflammatory or non-inflammatory neuropathies based on clinical diagnosis. We found a 2.6 fold increase in miR-132-3p expression in WBC of neuropathy patients compared to healthy controls (p<0.001). MiR-132-3p expression was also slightly up-regulated in sural nerve biopsies from neuropathy patients suffering from neuropathic pain compared to those without pain (1.2 fold; p<0.001). These promising findings were investigated further in an animal model of neuropathic pain, the spared nerve injury model (SNI). For this purpose miR-132-3p expression levels were measured in dorsal root ganglia and spinal cord of rats. Subsequently, miR-132-3p expression was pharmacologically modulated with miRNA antagonists or mimetics, and evoked pain and pain aversion were assessed. Spinal miR-132-3p levels were highest 10 days after SNI, a time when persistent allodynia was established (p<0.05). Spinal administration of miR-132-3p antagonists via intrathecal (i.t.) catheters dose dependently reversed mechanical allodyina (p<0.001) and eliminated pain behavior in the place escape avoidance paradigm (p<0.001). Intrathecal administration of miR-132-3p mimetic dose-dependently induced pain behavior in naïve rats (p<0.001). Taken together these results indicate a pro-nociceptive effect of miR-132-3p in chronic neuropathic pain.

Fibromyalgia syndrome (FMS) is a chronic widespread pain condition probably comprising subgroups with different underlying pathomechanisms. There is increasing evidence for small nerve fiber impairment in subgroups of patients with FMS. MicroRNAs (miRNAs) regulate molecular factors determining nerve de- and re-generation. We investigated whether systemic and cutaneous miRNA expression in patients with FMS is related to small nerve fiber pathology. We confirmed previous findings of disturbed small fiber function and reduced intraepidermal nerve fiber density in subgroups of patients with FMS. We found 51 aberrantly expressed miRNAs in white blood cells of patients with FMS, of which miR-let-7d correlated with reduced small nerve fiber density in patients with FMS. Furthermore, we demonstrated miR-let-7d and its downstream target insulin-like growth factor-1 receptor as being aberrantly expressed in skin of patients with FMS with small nerve fiber impairment. Our study gives further evidence of small nerve fiber pathology in FMS subgroups and provides a missing link in the pathomechanism that may lead to small fiber loss in subgroups of patients with FMS.