Chronic pain affects millions of Americans and costs more than $635 billion yearly. The burden of chronic pain is heavily tilted toward older adults. For example, the prevalence of chronic pain is 13.2% in adults 25-44 years old, but 33.6% in population >85 years old. Pain in older adults not only negatively impacts quality of life, increases frailty, but also is related with depression and cognitive decline. As such, studying chronic pain in older individuals, particularly the pathogenesis of pain, the mechanisms behind pain chronification, and the comorbid interactions between pain and other aging related issues is urgently warranted. Age, however, has largely been ignored as a biological variable in preclinical pain research. In preliminary studies, we examined if pain in older animals has unique features than that in younger animals. Specifically, we challenged animals with CFA to induce arthritis, and examined nociceptive behavior in 2 months (young), 12 months (adult), and 25 months old (aged) C57BL/6 mice. Results indicate that the same inflammatory insult in ankle joint led to significant mechanical allodynia in all age groups. However, the duration of mechanical allodynia lasted for about 4 weeks, 4 weeks, and 7 weeks, in young, adult, and aged mice respectively. Thermal hyperalgesia in these animals lasted about 3 weeks, 3.5 weeks, and 6 weeks, respectively. We ruled out unresolved joint inflammatory responses as the cause of prolonged nociceptive responses in aged mice. It is therefore likely that aged animals exhibited pain chronification associated with aging. Our lab has previously found that PGC-1?, a master regulator of mitochondria biogenesis, is implicated in pain chronification. More intriguingly, preliminary data also indicate that aged mice expressed lower levels of PGC-1? in somatosensory cortex than their younger counterparts. PGC-1? is preferentially expressed in, and critical for the function of, interneurons, whose dysfunction has been associated with functional and cognitive decline in aging. As such, we hypothesize that aging is associated with decreased somatosensory cortex PGC-1? levels, which impairs interneuron function and facilitates pain chronification. We plan to carry out two Specific Aims to test this hypothesis.
Aim 1 : To examine the impact of age on neuronal activities in pain.
Aim 2 : To study if pain chronification in aging can be ameliorated by increasing PGC-1? levels in somatosensory cortex S1. Taken together, this R03 GEMMSTAR proposal aims at examining age as a biological variable in pain, particularly in pain chronification associated with aging, in a preclinical model. This is an area that has great clinical significance but has received little research attention to date. This grant is innovative as it combines molecular biology, cutting edge intravital two-photon microscopy, and behavioral assays to examine a key role for PGC-1? and interneuron in aging and pain chronification. Successful execution of this grant will provide novel mechanistic insights into pain chronification associated with aging, to inform future translational and clinical studies.
The purpose of this grant application is to examine the molecular and cellular mechanisms of aging-related pain chronification in a mouse model of inflammatory arthritis. The outcomes of this proposal will provide novel mechanistic insights into the pathogenesis of aging-related pain chronificaiton as well as potential therapeutic targets.
