Modulation of mu-opioid receptor function alters electroshock seizure responses in mice

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We studied the effects of mu-opioid receptor (MOR) modulation on seizure responses to electroshock stimulation in C57BL/6J (B6) and DBA/2J (D2) mice of both sexes. Using a genetic approach, we show that B6 and D2 mice with a constitutive deletion of the MOR gene Oprm1 have a significantly reduced maximal electroconvulsive shock (ECS) seizure threshold. Using a pharmacological approach, we show that morphine treatment (25 mg pellet, s.c.) significantly reduces expression of maximal ECS seizures in both wild type strains, and conversely, that naltrexone treatment (1–10 mg/kg, s.c.) increases maximal ECS seizure susceptibility, more so in B6 mice than in D2. Unexpectedly, we observe that higher doses of naltrexone (100–500 mg/kg, i.p.) elicit generalized seizures, with D2 mice displaying significantly greater susceptibility than B6. Together, results suggest that decreasing MOR function increases ECS seizure susceptibility in mice, whereas increasing MOR function decreases ECS seizure susceptibility. The greater sensitivity of D2 mice to the direct proconvulsant effect of high dose naltrexone is consistent with the relative response of this strain to other chemoconvulsants and suggests that endogenous opioids play a role in mediating the previously reported robust difference in seizure susceptibility between D2 and B6 mice. On the other hand, our finding that naltrexone intensifies ECS seizures more in B6 mice than D2 underscores the complex nature of seizure susceptibility and the interaction between opioids and seizures. We conclude that further refinement of approaches to modulate neuronal signaling linked to the effect of the MOR on electroshock seizure responses may provide clues for development of new anti-epilepsy treatments. • Mu-opioid receptor knockout mice have a lower threshold for maximal electroshock seizures compared to wild type mice. • Morphine treatment protects mice against maximal electroshock seizures. • Naltrexone treatment exacerbates electroshock seizure responses in mice. • C57Bl/6 (B6) and DBA/2 (D2) mice are differentially sensitive to certain opioid-related seizure responses. • Ferraro et al., Modulation of mu-opioid function alters electroshock seizure responses in mice.

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