Age-related changes in nociception are of significant clinical and scientific interest as in the growing elderly population, pain is often associated with chronic illnesses and is one of the most common reasons prompting the need for medical care. It is unclear whether in addition to increased incidence of chronic illness, age-related physiologic changes on nociception contribute to the increased prevalence of pain in the elderly. Another reason to study age-related changes in nociception is that when pain occurs at younger ages it can lead to long-term changes in pain perception, processing, and development. Therefore, a better understanding of age-related differences on the mechanisms of nociception would enable the development and delivery of age-appropriate therapy. Age-related anatomic and physiologic changes in myelin, sensory neurons, and specific nerve fibers are known to occur. While the impact of age-related physiologic changes on transmission, processing, and perception of pain is incompletely understood, these age-related changes could certainly affect nociception. With regard to sex, it is well know that it impacts on the perception of noxious stimuli. Some studies have shown that in humans, analgesic requirement after surgery are greater in females compared to males. Women have lower response threshold to thermal stimulus compared to males. Therefore in order to properly treat pain, we have to further understand the impact of age and sex on nociception. In humans and animals, few studies have evaluated the effect of aging on A beta (pressure sensation), A delta (well-localized sharp pain), and C (diffuse burning pain) sensory nerve fibers and none has followed animals through the aging process. We are investigating the effects of aging on pain thresholds of A beta, A delta, and C fibers using our nociception assay and measuring current vocalization threshold in male and female mice as they age. We developed this novel assay to evaluate pain thresholds using electrical stimulus of increasing intensity at 5 Hz to stimulate C, 250 Hz to stimulate A beta, and 2000 Hz to stimulate A delta nerve fibers. We define vocalization as the pain-avoiding behavior to electrical stimuli, and measured current vocalization threshold in mice starting at an early age and longitudinally through their life span or 104 weeks. We showed that with the aging process, female mice have a U-shaped response to electrical stimulus. Additional studies have been initiated examining pain perception in older multiparous mice. We have also demonstrated that, as in humans, male mice have higher pain thresholds than female mice at all 3 frequencies. We will conduct studies to evaluate the effect of hormonal perturbations in both male and female mice as animals age.