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Allison Marie Cleymaet, Jozsef Vigh; Opioids trigger waking behavioral activity via melanopsin ganglion cells. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5042.
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Insomnia-type sleep problems occur in approximately 90% of those receiving long-term opioid treatment. Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) projecting to sleep-regulating brain centers are the principal conduits responsible for adjusting biological rhythms expressed in sleep/wake cycle to environmental cycles of light and dark (photoentrainment). We found that ipRGCs express μ-opioid receptors (MORs), and our preliminary data showed that MOR specific agonists strongly attenuate light-evoked firing of ipRGCs. Strong evidence suggests that systemically applied opioids cross the tight blood/retina barrier and reach ipRGCs. We hypothesized that chronic opioid treatments activate MORs expressed by ipRGCs, disrupt ipRGC-mediated behavioral processes, and facilitate the development of irregular sleep patterns. Our purpose was to test if intraocular opioid application alters the circadian rhythm of wheel-running by inhibition of ipRGC signaling via MORs.
Wheel-running activity was analyzed after acute intraocular application of MOR selective agonists in adult wild-type mice, mice lacking MORs (MKO), and mice lacking MORs only in ipRGCs (McKO). Mice were housed in a 12:12 L:D cycle. Bilateral intravitreal injection of the MOR specific agonist DAMGO (1 μL/eye, 2 mg/ml) or saline (1 μL/eye) was performed 7h after lights on. Wheel running for the 2h period following intraocular injections vs. the “no injection” (NI) 3-day average of wheel running for the 2h period corresponding to that analyzed on the day of the injection were compared. Data presented as mean ± SEM.
Intravitreal DAMGO injections resulted in a significant increase in average wheel revolutions/2h vs. the NI average in wild type mice (NI: 5.98±3.34 vs. DAMGO: 171.78±82.38 rev/2hr, n = 17, p<0.0001, one way repeated measures ANOVA) but not in MKO or McKO mice (MKO - NI: 3.19±1.68 vs. DAMGO: 7.71±1.88 rev/2hr, n =7, p>0.99; MckO - NI: 1.50±0.50 vs. DAMGO: 5.50±5.50 rev/2hr, n = 2, p>0.99).
Inhibition of ipRGCs via MORs simulates acute dark exposure and triggers waking behavioral activity. MORs expressed by ipRGCs are critical in mediating the intraocular DAMGO effect on wheel running.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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