Inter- and Trans-generational Inheritance of Paternal Chronic Pain to Male and Female Offspring in Mice

Major life events can alter an individual's molecular profile behavior and impact behavior. There is increasing recognition that, in some circumstances, these alterations can be transmitted to offspring through biological (germline) or environmental inheritance. For example, both inter- and trans-generational transmission of stress and trauma have been documented in both humans and rodents. The goal of the present study was to assess inter- and trans-generational inheritance of paternal chronic pain. Nine-month-old CD1 male mice without or with chronic neuropathic pain for 6 months (Sham and Spared Nerve Injury (SNI), respectively) were mated with naïve young CD1 females (F0). Intergenerational inheritance was assessed in their direct progeny (F1) and transgenerational inheritance in further descendants (F2). F2 was generated by mating unrelated females and males from F1 SNI or Sham lineages. Sensitivity to mechanical and cold stimuli were assessed using von Frey filament and acetone tests, respectively. Males and females from F1 and F2 were tested at 2.5 months of age (n=15-70/group). A subset of animals of each sex and generation received intra-plantar CFA (Complete Freud Adjuvant) and were monitored for 3 days (n=11-15/group). No differences between mice from the two lineages were observed in mechanical sensitivity at baseline or in response to CFA. In contrast, F1 females and F2 males from SNI lineages were hypersensitive to cold at baseline compared to sham lineages. Interestingly, F1 females and F2 males from SNI lineages demonstrated weaker behavioral responses to acetone after CFA-injection compared to sham lineages. Paternal experience can influence offspring development. Our results provide evidence that a family history of chronic pain can lead to sex-specific inter- and trans-generational inheritance of cutaneous hypersensitivity. Further studies are required to dissect the mechanisms driving these phenomena. Grant support from Canadian Institutes of Health Research PJT-362909 to LSS.