Endogenous Opioid Signaling in the Mouse Retina Modulates Pupillary Light Reflex

Int J Mol Sci. 2021 Jan 8;22(2):554. doi: 10.3390/ijms22020554.


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.

Keywords: intrinsically photosensitive ganglion cell; melanopsin; opioids; pupillary light reflex; retina.

MeSH terms

  • Animals
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Enkephalins / antagonists & inhibitors
  • Enkephalins / genetics
  • Humans
  • Light
  • Mice
  • Opioid Peptides / genetics*
  • Peptides / pharmacology
  • Receptors, Opioid / genetics
  • Receptors, Opioid, mu / antagonists & inhibitors
  • Receptors, Opioid, mu / genetics*
  • Reflex / genetics
  • Retina / metabolism*
  • Retina / pathology
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / physiology
  • Signal Transduction / drug effects
  • Visual Perception / drug effects
  • Visual Perception / genetics*
  • beta-Endorphin / genetics


  • Enkephalins
  • Opioid Peptides
  • Peptides
  • Receptors, Opioid
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • beta-Endorphin
  • connective tissue-activating peptide