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

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.

Development of anxiety‐like behaviors during adolescence: Persistent effects of adolescent morphine exposure in male rats

“…Also, a previous study presented that the effects of morphine exposure on weight gain pattern were different in male and female Long Evans rats, so that chronic morphine injection inhibited normal weight gain in male rats, whereas in female rats, it improved weight gain (Bobzean, Kokane, Butler, & Perrotti, 2019). On the other hand, it has been reported that weight gain in male offspring whose paternal were chronically exposed to morphine during adolescence was significantly reduced compared to the control group (Azadi, Gompf, & Azizi, 2020). Therefore, morphine intake during adolescence can have long-term effects on the feeding behaviors of the animals (Bodnar, 2011).…”

Prolonged morphine exposure during adolescence alters the responses of lateral paragigantocellularis neurons to naloxone in adult morphine dependent rats

“…Detailed surgical protocols are fully described in our previous studies [ 13 , 16 , 27 ]. In brief, adult rats (70 days old) were anesthetized by urethane injection (1.2 g/kg, i.p.).…”

“…In the next step, LPGi coordinates were obtained from the rat brain atlas [ 28 ] and right above the nucleus, a tiny hole (2 mm in diameter) was drilled on the skull surface (12 mm caudal to bregma, and 1.5 mm lateral to midline). Spike activities of LPGi neurons were recorded by glass micropipettes (OD: 1.2 mm, ID: 0.94 mm, Sutter Instruments, USA) which were pulled using a horizontal programmable microelectrode puller (P-97, Sutter Instrument, USA) and filled with a solution containing 2% pontamine sky blue dye dissolved in 0.5 M sodium acetate (3–12 MΩ resistance) [ 13 , 16 ]. Micropipettes were gently lowered down into the brain to reach the LPGi region (located nearly 10.2–10.8 mm ventral to the skull level).…”

“…Also, we observed that the neuronal responses of lateral paragigantocellularis (LPGi) nucleus to acute morphine injection are altered in adult rats with the experience of adolescent morphine exposure [ 13 ]. Our research works targeted the LPGi, because it is well recognized in literature as a key brain center mediating opiate effects [ 14 – 16 ]. For example, electrical stimulation of LPGi causes withdrawal-like signs in rats [ 17 ].…”

Adolescent Substance Abuse, Transgenerational Consequences and Epigenetics

“…Azadi and colleagues reported an enhancement in the development of the somatic and affective aspects of naloxone-precipitated morphine withdrawal mediated, at least in part, by alteration of lateral paragigantocellularis nucleus-related circuitry in the male offspring of sires exposed to morphine during adolescence. This study revealed that exposure to morphine in male rats during adolescence increases morphine-induced discharge inhibition in the lateral paragigantocellular nucleus (LPGi) neurons in male offspring [ 81 ]. Additionally, the decay slope of action potentials and the amplitude of after-hyperpolarizations increased in locus coeruleus neurons only in the rat offspring of males exposed to morphine during their adolescence [ 82 ].…”