Age and sex drive differential behavioral and neuroimmune phenotypes during postoperative pain.

Surgical procedures in the geriatric population are steadily increasing, driven by improved healthcare technologies and longer lifespans. However, effective postoperative pain treatments are lacking, and this diminishes quality of life and recovery. Here we present one of the first preclinical studies to pursue sex- and age-specific differences in postoperative neuroimmune phenotypes and pain. We found that aged males, but not females, had a delayed onset of mechanical hypersensitivity post-surgery and faster resolution than young counterparts. This sex-specific age effect was accompanied by decreased paw innervation and increased local inflammation. Additionally, we find evidence of an age-dependent decrease in hyperalgesic priming and perioperative changes in nociceptor populations and spinal microglia in the aged. These findings suggest that impaired neuronal function and maladaptive inflammatory mechanisms influence postoperative pain development in advanced age. Elucidation of these neuroimmune phenotypes across age and sex enables the development of novel therapies that can be tailored for improved pain relief.

eIF4E phosphorylation modulates pain and neuroinflammation in the aged.

The aged population has a higher probability of developing chronic pain from acute insults because of age-associated low-grade inflammation. Several emerging studies have shown a crucial role of cap-dependent translation in the development of chronic pain in young adult animals; however, its role in the aged has never been reported. Acute and chronic inflammatory responses, including pain, are altered over age, and understanding how cap-dependent translation can represent an important and druggable pathway is imperative for understanding its therapeutic potential. Here we have tested how an inflammatory stimulus, complete Freund's adjuvant (CFA), affects spontaneous and evoked pain, as well as inflammation in young versus aged mice that lack functional cap-dependent translation machinery (eukaryotic translation initiation factor 4E (eIF4E)) compared with age-matched wild-type (WT) mice. Interestingly, we found that CFA-induced acute pain and inflammation are modulated by eIF4E phosphorylation in aged but not young animals. Aged transgenic animals showed attenuated paw temperature and inflammation, as well as a mitigation in the onset and quicker resolution in mechanical and thermal hypersensitivity. We found that levels of interleukin (IL)-1ß and tumor necrosis factor (TNF)-α are elevated in dorsal root ganglia in aged WT and eIF4E transgenic groups, despite faster resolution of acute inflammation and pain in the aged eIF4E transgenic animals. We propose that these cytokines are important in mediating the observed behavioral responses in the young and represent an alternate pathway in the development of age-associated inflammation and behavioral consequences. These findings demonstrate that eIF4E phosphorylation can be a key target for treating inflammatory pain in the aged.

Aging sensitizes male mice to cognitive dysfunction induced by central HIV-1 gp120.

Although highly active antiretroviral therapy has led to improved prognosis and alleviation of some HIV-related disease complications, it has not provided complete protection against HIV-associated dementia. As the population of persons living with HIV grows older and aged persons represent a significant number of new infections, it is important to understand how HIV may affect the aged brain. In the current study, both adult and aged mice were treated with HIV gp120 and trained in a reference memory version of the water maze. Analysis of probe data revealed that aged animals treated with gp120 demonstrated profound decrements in water maze performance compared to gp120 treated young animals and saline treated aged or young animals. Additionally, we examined the neuroinflammatory responses in the aged and adult brain 4 h after treatment with gp120. Pro-inflammatory cytokines associated with neuroinflammation are known to be antagonistic to learning and memory processes and aged and adult animals treated with gp120 demonstrated similar increases in IL-1ß and IL-6 in the hippocampus and cortex. Additionally, gp120 treatment was associated with an increase in MHCII gene expression, a marker of microglial activation, in the hippocampus. Although, the aged brain demonstrated a similar inflammatory profile at the time point measured, aged animals were more sensitive to cognitive dysfunction related to gp120 treatment. This finding supports the theory that aging may be a significant risk factor in the development of HIV-associated dementia.