μ-Opioid Receptor Activation Directly Modulates Intrinsically Photosensitive Retinal Ganglion Cells

Abstract

Intrinsically photosensitive retinal ganglion cells (ipRGCs) encode light intensity and trigger reflexive responses to changes in environmental illumination. In addition to functioning as photoreceptors, ipRGCs are post-synaptic neurons in the inner retina, and there is increasing evidence that their output can be influenced by retinal neuromodulators. Here we show that opioids can modulate light-evoked ipRGC signaling, and we demonstrate that the M1, M2 and M3 types of ipRGCs are immunoreactive for μ-opioid receptors (MORs) in both mouse and rat. In the rat retina, application of the MOR-selective agonist DAMGO attenuated light-evoked firing ipRGCs in a dose-dependent manner (IC 50 < 40 nM), and this effect was reversed or prevented by co-application of the MOR-selective antagonists CTOP or CTAP. Recordings from solitary ipRGCs, enzymatically dissociated from retinas obtained from melanopsin-driven fluorescent reporter mice, confirmed that DAMGO exerts its effect directly through MORs expressed by ipRGCs. Reduced ipRGC excitability occurred via modulation of voltage-gated potassium and calcium currents. These findings suggest a potential new role for endogenous opioids in the

Endogenous Opioid Signaling in the Mouse Retina Modulates Pupillary Light Reflex

“…The dark-adapted PLRs of MKO, McKO, and WT control mice were not significantly different; this may be due to compensatory mechanisms developed in the knockout mice from birth. CTAP’s enhancement of the rod/cone-driven PLR in the dark-adapted retina and melanopsin-driven PLR under photopic conditions in WT mice is consistent with our prior finding that the MOR-selective antagonist CTOP both recovered and increased the intrinsic light responses compared to control of rat ipRGCs recorded on multielectrode array (MEA) [ 33 ]. Thus, the intraocular application of CTAP appears to mimic the loss of in-circuit opioid effects achieved via knockout of MORs.…”

“…As previously mentioned, synaptic inputs onto ipRGCs downstream of rods and cones, including ON/OFF bipolar cells and amacrine cells, have been shown to extend the dynamic range of ipRGCs in both the intensity and temporal frequency domains [ 40 ]. Given that our prior work showed that MOR action in ipRGCs reduces excitability without affecting phototransduction [ 33 ], DAMGO is expected to reduce ipRGC signaling both when driven by rod/cone inputs and by the intrinsic melanopsin phototransduction pathway under bright light conditions. The greater pupillary constriction in the MKO group vs. the McKO group suggests that in the McKO group, in which MORs are absent from ipRGCs alone, opioids may be exerting inhibitory effects on elements of the retinal circuit downstream of the rod-cone photoreceptors [ 41 ], which are relevant for the integrated rod–cone and melanopsin-mediated PLR in response to bright blue irradiance [ 28 ], or alternatively, there may be centrally mediated endogenous opioid effects that are absent in MKO animals.…”

“…For these endogenous opioids to regulate the PLR, there must also be receptors for opioids on cells within the retinal circuit relevant to the PLR. Retinal opiate binding sites have been demonstrated in several species, including chick, rabbit, goldfish, rat, mouse, cow, toad, and skate [ 33 , 41 , 46 , 47 ]. It has been shown that opioid receptor subtypes facilitate different, stereospecific opioid effects on pupil control [ 48 ].…”

“…Our prior work demonstrated that in the adult mouse retina, the opioid peptide β-endorphin is expressed by cholinergic amacrine cells [ 32 ] and that opioids, via β-endorphin-preferring opioid receptors (MORs), strongly attenuate the light-evoked firing of ipRGCs in mice and rats [ 33 ]. Modulatory processes that are capable of inhibiting ipRGC activity have been proposed to inhibit ipRGC-mediated, light-driven behavior [ 26 ].…”

Transcriptomic Signatures of Postnatal and Adult Intrinsically Photosensitive Ganglion Cells

“…The mu opioid receptor gene Oprm1 is differentially expressed in ipRGCs; it could regulate their light responses interacting with L-type calcium channels, which carry the majority of light-evoked inward calcium current in ipRGCs (Moises et al, 1994; Diaz et al, 1995; Doğrul et al, 2001; Hartwick et al, 2007). Recently, μ-opioid receptors (MORs) immunoreactivity was identified on rodent M1–M3 ipRGCs and MOR activation reduced ipRGC excitability via modulation of voltage-gated potassium and calcium currents (Cleymaet et al, 2019). Our data appear at odds with earlier reports that M1 and M4 ipRGCs express the melatonin receptor genes Mtnr1a and Mtnr1b (Sengupta et al, 2011; Pack et al, 2015; Sheng et al, 2015).…”