Accepted

Noxious substances, called algogens, cause pain and are used as defensive weapons by plants and stinging insects. We identified four previously unknown instances of algogen-insensitivity by screening eight African rodent species related to the naked mole-rat with the painful substances capsaicin, acid (hydrogen chloride, pH 3.5), and allyl isothiocyanate (AITC). Using RNA sequencing, we traced the emergence of sequence variants in transduction channels, like transient receptor potential channel TRPA1 and voltage-gated sodium channel Na1.7, that accompany algogen insensitivity. In addition, the AITC-insensitive highveld mole-rat exhibited overexpression of the leak channel NALCN (sodium leak channel, nonselective), ablating AITC detection by nociceptors. These molecular changes likely rendered highveld mole-rats immune to the stings of the Natal droptail ant. Our study reveals how evolution can be used as a discovery tool to find molecular mechanisms that shut down pain.

Neuropathic pain is a type of chronic pain induced by either central or peripheral nerve injury. MicroRNAs (miRs) have been recently linked to many diseases, including neuropathic pain. However, the role of miR-7a in neuropathic pain still remains elusive. Thus, we aim to investigate the effects of miR-7a on neuropathic pain based on the spinal nerve ligation (SNL) rat model. After establishment of SNL rat models, rats were infected with adeno associated virus (AAV)-neurofilament light polypeptide (NEFL), AAV-miR-7a or treated with metformin. The paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were assessed afterward, and the expression of miR-7a and NEFL as well as their interaction was determined. Subsequently, miR-7a was overexpressed or silenced in dorsal root ganglion (DRG) cells to investigate the role of miR-7a in neuropathic pain. Furthermore, the regulatory effect of NEFL on neuropathic pain was detected using plasmid overexpressing NEFL. SNL rat model exhibited upregulation of NEFL but downregulation of miR-7a. Additionally, NEFL accumulation or miR-7a inhibition decreased PWT and PWL. Then, NEFL accumulation or miR-7a inhibition was observed to increase the phosphorylation level of STAT3. miR-7a was found to directly target NEFL and downregulate NEFL. In addition, inhibiting the STAT3 signaling pathway was also revealed to increase PWT and PWL. Collectively, our study demonstrated that miR-7a ameliorated neuropathic pain via blocking the STAT3 signaling pathway by repressing NEFL. These findings, if taken further, can be of important clinical significance in treating patients with neuropathic pain.

Occupational exposure to mechanical vibration can produce the Hand-Arm Vibration Syndrome (HAVS), whose most disabling symptom is persistent muscle pain. Unfortunately, the pathophysiology of HAVS pain is still poorly understood, precluding the development of mechanism-based therapies. Since interleukin 33 (IL-33) is essential for inflammation and recovery that follows skeletal muscle injury, we explored its role in muscle pain in a model of HAVS, in adult male rats. Concomitant to mechanical hyperalgesia, an increase in IL-33 in the ipsilateral gastrocnemius muscle was observed 24 h after vibration. A similar hyperalgesia was produced by intramuscular injection of recombinant rat IL-33 (rrIL-33, 10-300 ng). Intrathecal administration of an oligodeoxynucleotide antisense to IL-33R/ST2 mRNA decreased the expression of ST2 in DRG and attenuated both rrIL-33 and vibration-induced mechanical hyperalgesia. Together these data support the suggestion that IL-33 plays a central role in vibration-induced muscle pain by action, at least in part, on skeletal muscle nociceptors. PERSPECTIVE: Our findings provide evidence of the contribution of IL-33, acting on its canonical receptor, in nociceptors, to muscle pain induced by ergonomic vibration. This suggests that targeting IL-33/ST2 signaling may be a useful strategy for the treatment of muscle pain in hand-arm vibration syndrome.