Paternal exposure to morphine during adolescence potentiates morphine withdrawal in male offspring: Involvement of the lateral paragigantocellularis nucleus

J Psychopharmacol. 2020 Nov;34(11):1289-1299. doi: 10.1177/0269881120953993. Epub 2020 Oct 8.

Abstract

Background: Opiate exposure during adolescence perturbs the brain's maturation process and potentially confers long-term adverse consequences, not only in exposed individuals but also in their posterity. Here, we investigate the outcomes of adolescent paternal morphine exposure on morphine withdrawal profile in male offspring.

Methods: Male Wistar rats were chronically subjected to 10 days of an escalating regimen of morphine during adolescence. After a 20-day washout period, adult males were allowed to copulate with naïve females. The adult male offspring were tested for somatic and affective components of naloxone-precipitated morphine withdrawal using conditioned place aversion. Moreover, electrical activity of the lateral paragigantocellularis (LPGi) nucleus, which is involved in development of opiate dependence, was recorded in response to a challenge dose of morphine via extracellular single-unit recordings.

Results: Morphine-sired offspring exhibited augmented expression of naloxone-induced somatic and affective signs of opiate withdrawal compared to the control saline-sired counterparts. In vivo recording revealed that LPGi neurons displayed heterogeneous responses (inhibitory, excitatory, and no change) to acute morphine administration in both morphine- and saline-sired animals. The morphine-induced discharge inhibition was potentiated in morphine-sired offspring. However, the extent of discharge excitation in response to morphine did not reach significance in these subjects. Moreover, the lack of alteration in maternal behavior toward morphine-sired offspring indicates that this is due to germline-dependent transmission of epigenetic traits across generations.

Conclusions: Preconception paternal exposure to morphine during adolescence potentiates opiate withdrawal signs in male offspring which is mediated, at least in part, by epigenetic alteration of LPGi-related brain circuitry.

Keywords: Morphine withdrawal; adolescence; extracellular single-unit recording; intergenerational; lateral paragigantocellularis nucleus; paternal.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Animals
  • Disease Models, Animal
  • Electrophysiological Phenomena / drug effects*
  • Epigenesis, Genetic / drug effects*
  • Male
  • Medulla Oblongata / drug effects*
  • Medulla Oblongata / physiopathology*
  • Morphine / adverse effects*
  • Naloxone / pharmacology
  • Narcotic Antagonists / pharmacology
  • Narcotics / adverse effects*
  • Patch-Clamp Techniques
  • Paternal Exposure / adverse effects*
  • Rats
  • Rats, Wistar
  • Substance Withdrawal Syndrome / etiology
  • Substance Withdrawal Syndrome / physiopathology*

Substances

  • Narcotic Antagonists
  • Narcotics
  • Naloxone
  • Morphine