Morphine Accumulates in the Retina Following Chronic Systemic Administration

Abstract

Opioid transport into the central nervous system is crucial for the analgesic efficacy of opioid drugs. Thus, the pharmacokinetics of opioid analgesics such as morphine have been extensively studied in systemic circulation and the brain. While opioid metabolites are routinely detected in the vitreous fluid of the eye during postmortem toxicological analyses, the pharmacokinetics of morphine within the retina of the eye remains largely unexplored. In this study, we measured morphine in mouse retina following systemic exposure. We showed that morphine deposits and persists in the retina long after levels have dropped in the serum. Moreover, we found that morphine concentrations (ng/mg tissue) in the retina exceeded brain morphine concentrations at all time points tested. Perhaps most intriguingly, these data indicate that following chronic systemic exposure, morphine accumulates in the retina, but not in the brain or serum. These results suggest that morphine can accumulate in the retina following chronic use, which could contribute to the deleterious effects of chronic opioid use on both image-forming and non-image-forming visual functions.

A retinal contribution to opioid-induced sleep disorders?

“…Previous studies have also shown that opioids deposit in the mammalian retina/VH following systemic administration (Husain et al, 2012;Gottås et al, 2016;Maskell et al, 2016;Bergum et al, 2022). Recently, our group found that morphine similarly deposits in the mouse retina following systemic injection (Bergum et al, 2022). Surprisingly, our detailed study showed that retinal morphine levels greatly exceeded the concentrations detected in the hypothalamus (Figure 2).…”

“…Surprisingly, our detailed study showed that retinal morphine levels greatly exceeded the concentrations detected in the hypothalamus (Figure 2). In addition to this, we observed sustained increases in morphine levels in the retina compared to Graphical representation of the pharmacokinetic evidence for a retinal contribution to chronic opioid-induced sleep/wake disturbances (as presented in Bergum et al, 2022). Morphine levels in the retina appear to accumulate following chronic systemic exposure, while levels in both the serum and hypothalamus remain the same.…”

“…For opioid drugs to able to suppress ipRGC activity, they must deposit in the retina following systemic exposure. Previous studies have also shown that opioids deposit in the mammalian retina/VH following systemic administration (Husain et al, 2012;Gottås et al, 2016;Maskell et al, 2016;Bergum et al, 2022). Recently, our group found that morphine similarly deposits in the mouse retina following systemic injection (Bergum et al, 2022).…”

“…the hypothalamus following systemic administration (Bergum et al, 2022). Retinal morphine levels remained elevated up to 11 h following systemic exposure, while levels in the hypothalamus dropped to near undetectable levels just 3 h after administration (Bergum et al, 2022). This evidence suggests that morphine can persistently activate retinal targets, while morphine's effect on hypothalamic sleep/circadian centers is restricted to just a few hours following systemic administration.…”

“…the hypothalamus following systemic administration (Bergum et al, 2022). Retinal morphine levels remained elevated up to 11 h following systemic exposure, while levels in the hypothalamus dropped to near undetectable levels just 3 h after administration (Bergum et al, 2022).…”