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

Abstract

The present study investigated the impact of advanced age on morphine modulation of persistent inflammatory pain in male and female rats. The impact of age, sex, and pain on μ-opioid receptor (MOR) expression and binding in the ventrolateral PAG (vlPAG) was also examined using immunohistochemistry and receptor autoradiography. Intraplantar administration of Complete Freund’s adjuvant induced comparable levels of edema and hyperalgesia in adult (2-3mos) and aged (16-18mos) male and female rats. Morphine potency was highest in adult males, with a two-fold decrease in morphine EC50 observed in aged versus adult males (10.22mg/kg versus 5.19mg/kg). Adult and aged female rats also exhibited significantly higher EC50 values (10.69 mg/kg and 9.00 mg/kg, respectively) compared to adult males. The upward shift in EC50 from adult to aged males was paralleled by a reduction in vlPAG MOR expression and binding. The observed age-related reductions in morphine potency and vlPAG MOR expression and binding have significant implications in pain management in the aged population.

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

“…However, aged males had reduced MOR availability as evidenced by lower B max 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.…”

“…These studies are the first to show that advanced age leads to an attenuation in vlPAG opioid signaling in both male and female rats. Taken together with our previous findings, our results suggest that age-induced reductions in vlPAG MOR expression and binding, combined with attenuated downstream MOR signaling, contribute to the diminished opioid potency seen in aged rats (Fullerton et al, 2021). The results of our analyses demonstrate that aged rats exhibit reduced MOR agonist binding, G-protein activation, and cAMP inhibition, along with increased G-protein regulation by RGS proteins.…”

“…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).…”

“…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.…”

“…Using a preclinical model of persistent inflammatory pain (intraplantar Complete Freund’s Adjuvant; (CFA)), we have previously reported a significant impact of age and sex on morphine potency. Specifically, we showed that aged rats (18mos) exhibit a decreased morphine potency compared to adults (2mos), with aged males requiring greater than 2x the concentration of morphine than their adult counterparts to produce equivalent analgesia (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).…”