Age-Induced Changes in µ-Opioid Receptor Signaling in the Midbrain Periaqueductal Gray of Male and Female Rats

Abstract

Declarations of interest: JMS has an equity stake in Botanical Results, LLC and is co-founder and equity holder in Teleport Pharmaceuticals, LLC. No company products or interests were tested in this study.

Cell type-specific effects of age and sex on human cortical neurons

“…Another example of an age-increased gene in L2-4 IT neurons was the mu opioid receptor, OPRM1 (FDR<0.05, >2-fold increase). Altered opioid receptor signaling has been reported in aged rodents 39 .…”

Morphine-context associative memory and locomotor sensitization in mice are modulated by sex and context in a dose-dependent manner

“…1-3). This is unsurprising given the evidence in both humans and rodents that morphine and other opioids can have diverging physiological effects depending on sex (Fullerton et al, 2018(Fullerton et al, , 2022Averitt et al, 2019). For example, women require more morphine than men to produce a similar degree of analgesiaClick or tap here to enter text., are more susceptible to overdose death from opioid prescriptionClick or tap here to enter text., and are more likely to escalate use of prescription opioids to the more potent and harmful illicit opioids, such as heroin (Cepeda & Carr, 2003;Ait-Daoud et al, 2019).…”

Molecular and Cellular Mechanisms of Neuropathic Pain in Aging

“…142 Alzheimer's disease (AD) is the most prevalent form of dementia among elderly individuals and has a significant impact on the pain processing system in brain. 143 AD patients demonstrate decline in opioid receptor abundance and opioidmediated analgesia 161,163 pro-inflammatory and activating features appear in microglia 174,175 inducing long-lasting neuroinflammation 180,181 brain decline in brain volume 141 presence of senile neuroinflammatory plaques 142 Alzheimer's disease exerts notable effects on the pain, cognition, and endocrine system 145 long-term chronic pain may lead to changes in brain morphology 147−149 reduced number of serotonin receptors in the prefrontal cortex and noradrenergic terminals in the spinal dorsal horn 154 dysregulation of the hypothalamic−pituitary−adrenal axis 104 decline in the concentration and turnover rates of catecholamines, GABA, and opioid receptors in the limbic system 155 more pronounced facial expressions during invasive clinical examinations, compared to their healthy counterparts. 144 The disease exerts notable effects on the pain, cognition, and endocrine system of the cingulate cortex, insular cortex, and frontal lobe regions.…”

“…162 Notably, the diminished expression of MOR protein, decreased binding affinity of MORs, lower efficiency of G protein activation, and downstream cAMP inhibition in the vlPAG of elderly rats may contribute to the waning efficacy of opioid drugs in this population. 163…”

“…Upon MOR activation, AC inhibition ensues, resulting in reduced cAMP expression, neuronal hyperpolarization, and analgesia . Notably, the diminished expression of MOR protein, decreased binding affinity of MORs, lower efficiency of G protein activation, and downstream cAMP inhibition in the vlPAG of elderly rats may contribute to the waning efficacy of opioid drugs in this population …”