Differential Impact of miR-21 on Pain and Associated Affective and Cognitive Behavior after Spared Nerve Injury in B7-H1 ko Mouse

Abstract

MicroRNAs (miRNAs) are increasingly recognized as regulators of immune and neuronal gene expression and are potential master switches in neuropathic pain pathophysiology. miR-21 is a promising candidate that may link the immune and the pain system. To investigate the pathophysiological role of miR-21 in neuropathic pain, we assessed mice deficient of B7 homolog 1 (B7-H1), a major inhibitor of inflammatory responses. In previous studies, an upregulation of miR-21 had been shown in mouse lymphocytes. Young (8 weeks), middle-aged (6 months), and old (12 months) B7-H1 ko mice and wildtype littermates (WT) received a spared nerve injury (SNI). We assessed thermal withdrawal latencies and mechanical withdrawal thresholds. Further, we performed tests for anxiety-like and cognitive behavior. Quantitative real time PCR was used to determine miR-21 relative expression in peripheral nerves, and dorsal root ganglia (DRG) at distinct time points after SNI. We found mechanical hyposensitivity with increasing age of naïve B7-H1 ko mice. Young and middle-aged B7-H1 ko mice were more sensitive to mechanical stimuli compared to WT mice (young: p < 0.01, middle-aged: p < 0.05). Both genotypes developed mechanical and heat hypersensitivity (p < 0.05) after SNI, without intergroup differences. No relevant differences were found after SNI in three tests for anxiety like behavior in B7-H1 ko and WT mice. Also, SNI had no effect on cognition. B7-H1 ko and WT mice showed a higher miR-21 expression (p < 0.05) and invasion of macrophages and T cells in the injured nerve 7 days after SNI without intergroup differences. Our study reveals that increased miR-21 expression in peripheral nerves after SNI is associated with reduced mechanical and heat withdrawal thresholds. These results point to a role of miR-21 in the pathophysiology of neuropathic pain, while affective behavior and cognition seem to be spared. Contrary to expectations, B7-H1 ko mice did not show higher miR-21 expression than WT mice, thus, a B7-H1 knockout may be of limited relevance for the study of miR-21 related pain.

Behavioral, Biochemical and Electrophysiological Changes in Spared Nerve Injury Model of Neuropathic Pain

“…Their observations showed high levels of transcriptional activity in dorsal root ganglia (DRG) following nerve injury in adulthood compared to nerve injury in early life, sustained the reduced incidence of neuropathic pain in infants. Macrophages and lymphocytes invasion into the peripheral nerve has been observed 1 week after SNI [77]. The contribution of T cells in SNI-induced pain has been reported by Costigan and coll.…”

“…Impairment in cognitive flexibility was also detected in mice in the attentional rule-shifting task 21 days after SNI surgery [76]. Curiously, no impairment in spatial working memory was found in the Morris water maze 3 to 21 days after SNI in mice by Karl et al [77]. All the evidence described so far highlights close comorbidity existing between neuropathic pain in general and the SNI model in particular and disturbances of affectivity and cognition.…”

An overview of a biopsychosocial model of epigenetics and pain catastrophizing

“…In the case of examining chronic pain with the effects of age in mind, if the specific emotional pain pathway (superficial dorsal horn‐thalamus and surrounding cortices) is strengthened neuronally from a young age, then a child's brain may be “wired” to respond to pain at lower levels of stimulation as discussed above (Karl et al, ). This same phenomenon, may also explain why men and women respond to pain differently, such that women from a young age are conditioned socially to react emotionally to pain (they may cry in their parents arms and be comforted) versus boys who are taught to “be tough” ( they may not be emotionally comforted by a parent).…”

“…While a great deal still remains in fully understanding the modification of miRNA, Sakai and Suzuki (2013) found that an increase in miR-21 was correlated with an upsurge in neuropathic pain behaviors in mice. Other researchers (e.g., Karl, Grießhammer, Üçeyler, & Sommer, 2017) have also highlighted the specific role that increased miR-21 regulation plays with regard to chronic pain.…”

“…In the case of examining chronic pain with the effects of age in mind, if the specific emotional pain pathway (superficial dorsal horn-thalamus and surrounding cortices) is strengthened neuronally from a young age, then a child's brain may be "wired" to respond to pain at lower levels of stimulation as discussed above (Karl et al, 2017).…”