Advanced age attenuates the antihyperalgesic effect of morphine and decreases μ-opioid receptor expression and binding in the rat midbrain periaqueductal gray in male and female rats

Fullerton, Evan F; Rubaharan, Myurajan; Karom, Mary; Hanberry, Richard I.; Murphy, Anne Z.

doi:10.1016/j.neurobiolaging.2020.10.020

Cited by 10 publications

(16 citation statements)

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“…However, aged males had reduced MOR availability as evidenced by lower Bmax values compared to their adult male counterparts. This result supports our previous finding, that aged males exhibited reduced DAMGO binding, which was assessed using autoradiography on coronal sections through the vlPAG (Fullerton et al, 2021). No impact of persistent inflammatory pain on MOR binding potential was noted, suggesting that persistent inflammatory pain does not alter MOR binding potential in the vlPAG.…”

Section: Impact Of Advanced Age On Mor Binding Potentialsupporting

confidence: 91%

“…(CFA)), we have previously reported a significant impact of age and sex on morphine potency. Specifically, we showed that aged rats (18mos) exhibit an attenuated response to morphine compared to adults (2mos), with aged males requiring greater than 2x the concentration of morphine than their adult counterparts (Fullerton et al, 2021). Similar results have been reported in prior preclinical studies, suggesting that aged rodents require higher doses of opioids to produce antinociception (Kavaliers et al, 1983;Kramer and Bodnar, 1986;Webster et al, 1976).…”

Section: Introductionsupporting

confidence: 84%

“…The present studies are the first to examine the impact of advanced age on MOR signaling in the presence of persistent inflammatory pain in male and female rats. We have previously shown that morphine modulation of persistent inflammatory pain is reduced in aged rats, and that aged animals exhibit reduced DAMGO binding in the vlPAG (Fullerton et al, 2021). In the present study, using saturation radioligand binding assays, we report that adult male rats exhibit greater vlPAG MOR binding potential compared to aged males, and females of either age.…”

Section: Impact Of Advanced Age On Mor Binding Potentialsupporting

confidence: 63%

“…6). As MOR binding and downstream signaling are critical for morphine analgesia, the observed age-induced reductions in vlPAG MOR signaling may drive the reduced morphine potency observed in these assays (Fullerton et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

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

Fullerton

Karom

Murphy

2022

Preprint

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The analgesic effects of opioids are attenuated in aged rats. Opioids such as morphine produce attenuated analgesia in aged rodents compared to adults; however, the neural mechanisms underlying this attenuated response are not yet known. The present study investigated the impact of advanced age and biological sex on opioid signaling in the ventrolateral periaqueductal gray (vlPAG) in the presence of chronic inflammatory pain. Assays measuring mu opioid receptor (MOR) radioligand binding, GTPyS binding, receptor phosphorylation, cAMP inhibition, and regulator of G-protein signaling (RGS) protein expression were performed on vlPAG tissue from adult (2-3mos) and aged (16-18mos), male and female rats. Persistent inflammatory pain was induced by intraplantar injection of Complete Freund's Adjuvant (CFA). Adult males exhibited the highest MOR binding potential and the highest G-protein activation (activation efficiency ratio) in comparison to aged males and females (adult and aged). No impact of advanced age or sex on MOR phosphorylation state was observed. DAMGO-induced cAMP inhibition was highest in the vlPAG of adult males compared to aged males and females (adult and aged). vlPAG levels of RGS4 and RGS9-2, critical for terminating G-protein signaling, were assessed using RNAscope. Adult rats (both males and females) exhibited lower levels of vlPAG RGS4 and RGS9-2 mRNA expression compared to aged males and females. The observed age-related reductions in vlPAG MOR binding potential, G-protein activation efficiency, and cAMP inhibition, along with the observed age-related increases in RGS4 and RGS9-2 vlPAG expression, provide potential mechanisms whereby the response to opioids is attenuated in the aged population. These results have significant implications for pain management in this population.

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Section: Impact Of Advanced Age On Mor Binding Potentialsupporting

confidence: 91%

Section: Introductionsupporting

confidence: 84%

Section: Impact Of Advanced Age On Mor Binding Potentialsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

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

Fullerton

Karom

Murphy

2022

Preprint

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“…The KOR level (which mediates aversive feelings), instead appears to remain unchanged with age [65]. On the contrary, a study on adult and older rats identified a marked age-related reduction in MOR expression in the periaqueductal grey matter, which corresponded to higher morphine requirements to obtain analgesia in older rats compared to adults [66].…”

Section: Brain and Supraspinal Changesmentioning

confidence: 97%

Chronic Pain in the Elderly: Mechanisms and Distinctive Features

Tinnirello¹,

Mazzoleni

Santi

2021

Biomolecules

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Background: Chronic pain is a major issue affecting more than 50% of the older population and up to 80% of nursing homes residents. Research on pain in the elderly focuses mainly on the development of clinical tools to assess pain in patients with dementia and cognitive impairment or on the efficacy and tolerability of medications. In this review, we searched for evidence of specific pain mechanisms or modifications in pain signals processing either at the cellular level or in the central nervous system. Methods: Narrative review. Results: Investigation on pain sensitivity led to conflicting results, with some studies indicating a modest decrease in age-related pain sensitivity, while other researchers found a reduced pain threshold for pressure stimuli. Areas of the brain involved in pain perception and analgesia are susceptible to pathological changes such as gliosis and neuronal death and the effectiveness of descending pain inhibitory mechanisms, particularly their endogenous opioid component, also appears to deteriorate with advancing age. Hyperalgesia is more common at older age and recovery from peripheral nerve injury appears to be delayed. In addition, peripheral nociceptors may contribute minimally to pain sensation at either acute or chronic time points in aged populations. Conclusions: Elderly subjects appear to be more susceptible to prolonged pain development, and medications acting on peripheral sensitization are less efficient. Pathologic changes in the central nervous system are responsible for different pain processing and response to treatment. Specific guidelines focusing on specific pathophysiological changes in the elderly are needed to ensure adequate treatment of chronic pain conditions.

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Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu‐opioid receptor

Zhang

Song

Dai

et al. 2022

MedComm

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Opioid abuse and addiction have become a global pandemic, posing tremendous health and social burdens. The rewarding effects and the occurrence of withdrawal symptoms are the two mainstays of opioid addiction. Mu‐opioid receptors (MORs), a member of opioid receptors, play important roles in opioid addiction, mediating both the rewarding effects of opioids and opioid withdrawal syndrome (OWS). The underlying mechanism of MOR‐mediated opioid rewarding effects and withdrawal syndrome is of vital importance to understand the nature of opioid addiction and also provides theoretical basis for targeting MORs to treat drug addiction. In this review, we first briefly introduce the basic concepts of MORs, including their structure, distribution in the nervous system, endogenous ligands, and functional characteristics. We focused on the brain circuitry and molecular mechanism of MORs‐mediated opioid reward and withdrawal. The neuroanatomical and functional elements of the neural circuitry of the reward system underlying opioid addiction were thoroughly discussed, and the roles of MOR within the reward circuitry were also elaborated. Furthermore, we interrogated the roles of MORs in OWS, along with the structural basis and molecular adaptions of MORs‐mediated withdrawal syndrome. Finally, current treatment strategies for opioid addiction targeting MORs were also presented.

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Advanced age attenuates the antihyperalgesic effect of morphine and decreases μ-opioid receptor expression and binding in the rat midbrain periaqueductal gray in male and female rats

Cited by 10 publications

References 93 publications

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

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

Chronic Pain in the Elderly: Mechanisms and Distinctive Features

Mechanism of opioid addiction and its intervention therapy: Focusing on the reward circuitry and mu‐opioid receptor

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