Endogenous Opioid Signaling in the Mouse Retina Modulates Pupillary Light Reflex

Abstract

Opioid peptides and their receptors are expressed in the mammalian retina; however, little is known about how they might affect visual processing. The melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs), which mediate important non-image-forming visual processes such as the pupillary light reflex (PLR), express β-endorphin-preferring, µ-opioid receptors (MORs). The objective of the present study was to elucidate if opioids, endogenous or exogenous, modulate pupillary light reflex (PLR) via MORs expressed by ipRGCs. MOR-selective agonist [D-Ala2, MePhe4, Gly-ol5]-enkephalin (DAMGO) or antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) was administered via intravitreal injection. PLR was recorded in response to light stimuli of various intensities. DAMGO eliminated PLR evoked by light with intensities below melanopsin activation threshold but not that evoked by bright blue irradiance that activated melanopsin signaling, although in the latter case, DAMGO markedly slowed pupil constriction. CTAP or genetic ablation of MORs in ipRGCs slightly enhanced dim-light-evoked PLR but not that evoked by a bright blue stimulus. Our results suggest that endogenous opioid signaling in the retina contributes to the regulation of PLR. The slowing of bright light-evoked PLR by DAMGO is consistent with the observation that systemically applied opioids accumulate in the vitreous and that patients receiving chronic opioid treatment have slow PLR.

Morphine Accumulates in the Retina Following Chronic Systemic Administration

“…Interestingly, our group has identified a subset of intrinsically photosensitive retinal ganglion cells (ipRGCs) that express the µ-opioid receptors (MOR), which are the main molecular targets for opioid drugs such as morphine [ 40 ]. Moreover, these studies have shown that the MOR-selective agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) not only directly affects ipRGC firing activity via the modulation of specific ionic currents, but also that MOR activation attenuates the ipRGC-dependent PLR in mice [ 40 , 42 ].…”

“…However, pupillary light reflex (PLR) is altered in opioid-tolerant patients [ 41 ]. Similarly, mice intraocularly injected with the MOR-selective agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) exhibit deficits in PLR [ 42 ]. These observations support the idea that morphine accumulation in the retina could have functional consequences within the eye.…”

Endogenous opioid signaling in the retina modulates sleep/wake activity in mice

“…Our recent work has shown that ipRGCs express μ-opioid receptors (MORs) and that the MOR-selective agonist [D-Ala 2 , MePhe 4 , Gly-ol 5 ]-enkephalin (DAMGO) inhibits light-evoked firing by ipRGCs ( Cleymaet et al, 2019 ). Intraocular injection of DAMGO eliminated PLR triggered by light intensities activating rods and cones, and slowed PLR evoked by bright light sufficient to activate the melanopsin in ipRGCs ( Cleymaet et al, 2021 ). Interestingly, PLR was not inhibited by DAMGO in mice which lacked MORs globally (MKO) or specifically from ipRGCs (McKO), suggesting MORs expressed by ipRGCs are important for mediating the effect of opioids on PLR ( Cleymaet et al, 2021 ).…”

“…Intraocular injection of DAMGO eliminated PLR triggered by light intensities activating rods and cones, and slowed PLR evoked by bright light sufficient to activate the melanopsin in ipRGCs ( Cleymaet et al, 2021 ). Interestingly, PLR was not inhibited by DAMGO in mice which lacked MORs globally (MKO) or specifically from ipRGCs (McKO), suggesting MORs expressed by ipRGCs are important for mediating the effect of opioids on PLR ( Cleymaet et al, 2021 ). Furthermore, the MOR-selective antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP) enhanced rod/cone-driven PLR in dark-adapted retinas, suggesting that endogenous activation of MORs expressed by ipRGCs in the dark inhibits PLR ( Cleymaet et al, 2021 ).…”

Special Issue of International Journal of Molecular Sciences “Opioid Receptors and Endorphinergic Systems 2.0”

“…Concerning the third issue (iii), the presence of β-endorphin-preferring, µ-opioid receptors (MORs) within the melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) has stimulated the interest of Cleymaet et al [14] in investigating the potential role of an MOR system in ipRGCs. The authors found that the MOR-selective agonist [D-Ala 2 , MePhe 4 , Gly-ol 5 ]-enkephalin (DAMGO) abrogated the pupillary light reflex (PLR) evoked by light with intensities below the melanopsin activation threshold, but did not affect the PLR evoked through the activation of melanopsin signaling by bright blue irradiance.…”