Sex-specific lateralization of the effects of exogenously-induced neuroimmune activation in the amygdala on pain-like behaviors.

Introduction: Chronic pain is a global healthcare issue. Mechanistic insight into pain mechanisms in the brain is needed. Increasing evidence has demonstrated a critical role for neuroimmune signaling factors in the pathogenesis of chronic pain. The amygdala, a bilateral limbic structure, is involved in the emotional-affective dimensions of pain and pain-modulation. There is good evidence for pain-related hemispheric lateralization in the central nucleus of the amygdala (CeA) in different pain models, but pain-related lateralization of neuroimmune signaling in the CeA remains to be determined. This study addressed the question if the well-documented right-hemispheric lateralization in pain conditions also occurs with the exogenous activation of neuroimmune signaling, which would suggest intrinsic differences between right and left CeA as the basis for pain-related hemispheric lateralization. Methods: To do so, either lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) agonist, or polyinosinic:polycytidylic acid (PolyI:C), a TLR3 agonist, was injected stereotaxically into the CeA. Mechanosensitivity, emotional-affective responses, and anxiety-like behaviors were evaluated in male and female rats 3 and 7 days post drug administration. Left and right CeA were collected at the end of the experiments for Quantitative Reverse Transcription Polymerase Chain Reaction (qRT-PCR) analysis from female rats. Results: Our results suggest that both right and left CeA are capable of generating sensory and emotional pain-like behaviors when activated exogenously by immunostimulants at the early stage (day 3) of neuroimmune activation in both sexes. At the later stage (day 7), sex-, treatment- and hemisphere-specific differences emerged with a TLR3-mediated right hemispheric CeA lateralization in females but not in males. qRT-PCR analysis confirmed local neuroimmune activation in both right and left CeA, with treatment-dependent gene expression changes occurring mainly ipsilateral to the injection site. Discussion: Therefore, exogenous neuroimmune activation is possible in both the left and right CeA and generates pain-like behaviors initially, whereas females, but not males, develop lateralization subsequently, perhaps suggesting resilience developing in the left but not right CeA in terms of output and coupling to pain modulatory systems. Mechanistic insights into the hemispheric lateralization of neuroimmune signaling-related pain modulation in the amygdala may aid the development of therapeutic strategies for chronic pain relief.