ABSTRACT:
Delayed Onset of Neuropathic Pain in Aged Males After Peripheral Nerve Injury
Objective and Aims
The objective of these studies is to understand the impact of advanced age and neuroinflammation on chronic pain development. Projections predict the U.S. population of individuals aged 65 or older will double to over 20% by 2050. Unfortunately, one of the consequences of increased longevity is neuropathic pain associated with falls/injury, diabetes, and chemotherapy, with 40-80% of the aged population experiencing pain on a daily basis adversely impacting quality of life. The mechanisms that underlay the development of chronic pain are highly sought after, because current therapeutics fail to offer relief in over half of patients. We believe, a hyperactive immune system during aging leads to maladaptive hyper-excitability in the nervous system that plays a role in the development of neuropathic pain. However, very little is known about how aging alters the onset and development of neuropathic pain after surgery. Therefore, we sought to determine the behavioral and inflammatory response following spared-nerve injury (SNI) in aged versus adult animals.
Methods and Results
Adult (3-6 month) and aged (24-26 month) male FBN rats underwent SNI and the development of neuropathic pain was assessed at various time points post-surgery. Surprisingly, aged animals took significantly longer to reach neuropathic pain levels similar to adult animals (21 days vs. 5 days). Spinal cords and DRGs were collected at 5 and 60 days post-surgery to assess gene expression, protein levels, and IHC. When we assessed DRG and spinal cord tissue ipsilateral to the injury for inflammatory and ER stress genes we observed an age-and surgery-related upregulation of ATF4, ATF6, and IL-6 5 days post- surgery. However, there was no difference in behavior or gene expression 60-days post-surgery.
Conclusions
These experiments demonstrate a connection between age, inflammation, ER stress, and pain plasticity. The altered kinetics in the onset of neuropathic pain after injury in the aged hints at potential therapeutic targets in resolution pathways and unveils a separation of inflammation and pain that has become the dogma.