Loss of lumbar disc height with age and its impact on pain and sensitivity associated behaviors in mice.

PURPOSE: Aging is a risk factor for several debilitating conditions including those related to chronic back pain and intervertebral disc degeneration, both of which have no cure. Mouse models are useful tools for studying disc degeneration and chronic back pain in a tightly controlled and clinically relevant aging environment. Moreover, mice offer the advantage of carrying out longitudinal studies to understand the etiology and progression of disc pathology induced by genetic or surgical strategies. Previously, age-related behavioral trends of discomfort and enhanced nociception in mice were reported; however, whether these measures are mediated by structural and pathological changes in the disc is unknown. METHODS: The goal of the present observational study was to identify behavioral correlates of age-related degenerative changes in the disc. Towards this, we collected radiographs from 150 mice (77 females) between three and 23 months of age and measured the disc height index for each level of lumbar disc. Behavioral measures were collected on several of these mice which included rearing and distance travelled in an open field test; time spent in rearing, reaching, immobile, and self-suspended in the tail suspension test; bilateral hind paw licking in response to cold allodynia using acetone; and unilateral hind paw licking in response to heat hyperalgesia using capsaicin. RESULTS: Results show that the lower lumbar discs lose height with age and these changes are independent of body composition measures including body weight, bone mineral density, fat mass, lean weight mass, percent fat mass, and percent lean mass. Disc height positively correlates with rearing and mobility in the open field test, immobility in the tail suspension test, and thermal hyperalgesia. Disc height negatively correlates with cold allodynia and rearing in the tail suspension test. Furthermore, mediation analysis shows that the lumbosacral disc significantly mediates the effect of age on rearing in the open field test, but not cold allodynia, suggesting this behavior is a useful measure of age-related axial discomfort due to disc degeneration. CONCLUSION: In summary, the findings from the current study show that disc height are associated with measures of axial discomfort and nociception in mice.

Age-related molecular changes in the lumbar dorsal root ganglia of mice: Signs of sensitization, and inflammatory response.

Aging is a major risk factor for numerous painful, inflammatory, and degenerative diseases including disc degeneration. A better understanding of how the somatosensory nervous system adapts to the changing physiology of the aging body will be of great significance for our expanding aging population. Previously, we reported that chronological aging of mouse lumbar discs is pathological and associated with behavioral changes related to pain. It is established that with age and degeneration the lumbar discs become inflammatory and innervated. Here we analyze the aging lumbar dorsal root ganglia (DRGs) and spinal cord dorsal horn (SCDH) in mice between 3 and 24 months of age for age-related somatosensory adaptations. We observe that as mice age there are signs of peripheral sensitization, and response to inflammation at the molecular and cellular level in the DRGs. From 12 months onwards the mRNA expression of vasodilator and neurotransmitter, Calca (CGRP); stress (and survival) marker, Atf3; and neurotrophic factor, Bdnf, increases linearly with age in the DRGs. Further, while the mRNA expression of neuropeptide, Tac1, precursor of Substance P, did not change at the transcriptional level, TAC1 protein expression increased in 24-month-old DRGs. Additionally, elevated expression of NFκB subunits, Nfkb1 and Rela, but not inflammatory mediators, Tnf, Il6, Il1b, or Cox2, in the DRGs suggest peripheral nerves are responding to inflammation, but do not increase the expression of inflammatory mediators at the transcriptional level. These results identify a progressive, age-related shift in the molecular profile of the mouse somatosensory nervous system and implicates nociceptive sensitization and inflammatory response.