Aging, peripheral pain and analgesia

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DESCRIPTION (provided by applicant): Management of pain is a significant problem in the geriatric population. The incidence of pain for those over the age of 65 can reach as high as 80%, with many reporting persistent pain that limits daily activity and interferes with quality of life. Moreover, the elderly are more sensitive to adverse effects of drugs and are often taking multiple medications that increase the likelihood of adverse drug interactions, especially those within the CNS. Thus, there is a substantial need for more effective analgesic treatments in older adults, which will only become more critical as the geriatric population (aged over 65) is expected to double by 2050. Not only do the elderly have more pain-causing diseases and conditions, their nociceptive (pain-sensing) sensory system may also be more sensitive to noxious stimuli. Peripheral sensory neurons (i.e., pain-sensing neurons also called "nociceptors") respond to noxious stimuli and transmit signals to the CNS that are interpreted as pain. These neurons participate in a variety of pain conditions, including acute injury, acute inflammatory disorders and the most prevalent form of neuropathic pain (peripheral). However, there are very few studies on the effect of aging on peripheral pain-sensing neurons. Our preliminary data show that compared to young rats (4 month), aged rats (26 month) are considerably more sensitive to induction of pain in response to certain nociceptor stimulators (e.g. inflammatory mediators). This finding, that nociceptors are more sensitive in aged rats, suggests that drugs that inhibit nociceptors would be effective analgesics. Opioid receptors are expressed by nociceptors and when activated inhibit nociceptor pain signaling. Peripherally-restricted opioid drugs that do not enter the CNS would be powerful analgesics for the elderly that are devoid of severe CNS- mediated adverse effects (e.g. respiratory depression, addiction, dysphoria). However, nothing is known of the effects of age on the function and regulation of peripheral opioid receptors. A major goal of this work is to delineate the effects of age on nociceptor function and regulation using an integrated series of in vivo rat behavioral assays and ex vivo experiments with rat nociceptors in culture. Further, we propose to investigate the effects of age on opioid receptor systems in nociceptors. Our specific aims are: 1) To determine the effect of age on the responsiveness of peripheral nociceptors, and 2) To delineate the effect of age on function of peripheral opioid receptors expressed by nociceptors. We hypothesize that 1) the responsiveness of nociceptors increases with age, and 2) peripherally-restricted opioid agonists have increased analgesic potency and/or efficacy with age. Results from this work will provide fundamental information about the effects of aging on function and regulation of peripheral pain-sensing neurons (nociceptors). These data are necessary to develop hypotheses of mechanisms (e.g. changes in protein expression, receptor affinity, etc.) that underlie age-related changes in nociceptor function and peripheral opioid receptor system responsiveness and that may lead to new peripherally-restricted, safer analgesics for the geriatric population.