Neuroimmune Mechanisms of Latent Pain Sensitization after Chemotherapy

Abstract

The episodic nature of chronic pain has been described in animal models as latent pain sensitization. For example, after remission from inflammatory or postsurgical pain, assessed by normalization of mechanical pain threshold, injection of opioid receptor inverse agonists reinstates allodynia (1,2,3). To investigate whether latent sensitization is also occurring in neuropathic pain and neuroimmune mechanisms are involved, male and female mice were treated with 3 daily injections of cisplatin (2 mg/kg) to induce a transient neuropathic pain. Mice developed mechanical allodynia that resolved after 3 weeks. Interleukin (IL)-10 mRNA was significantly upregulated in the spinal cord during and after remission from cisplatin-induced neuropathic pain. One week after remission, injection of a neutralizing antibody anti-IL-10 reinstated mechanical allodynia in both male and female mice treated with cisplatin whereas the same treatment had no effect on naive mice. To determine the downstream mechanism of the reinstatement of allodynia by inhibition of IL-10 signaling, we performed RNA-sequencing analysis of dorsal root ganglion (DRG) tissue. Reinstatement of allodynia was associated with a change in gene expression of 168 genes. Among the genes potentially regulated by IL-10 signaling during remission was oprd1 (log2 fold change -0.36 and padjusted