The role of mu-opioid receptor signaling in the dorsolateral periaqueductal gray on conditional and unconditional responding to threatening and aversive stimuli

Here we examined how mu-opioid receptor signaling in the periaqueductal gray (PAG) mediates conditional and unconditional responses to aversive stimuli. The mu-opioid agonist morphine (MOR) and/or the partially mu-selective antagonist naltrexone (NAL) were infused into dorsolateral PAG (dlPAG) during a fear conditioning task, in which rats were trained to fear an auditory conditional stimulus (CS) by pairing it with a unilateral eyelid shock unconditional stimulus (US). During drug-free test sessions, the CS elicited movement suppression responses (indicative of freezing) from trained rats that had not recently encountered the US. In trained rats that had recently encountered the US, the CS elicited flight behavior characterized by turning in the direction away from the eyelid where US delivery was anticipated. Infusions of MOR (30 nmol/side) into dlPAG prior to the test session did not impair CS-evoked movement suppression, but did impair CS-evoked turning behaviors. MOR infusions also reduced baseline motor movement, but US-evoked reflex movements remained largely intact. NAL was infused at two dosages, denoted 1x (26 nmol/side) and 10x (260 nmol/side). Infusions of NAL into dlPAG did not affect CS- or US-evoked behavioral responses at the 1x dosage, but impaired CS-evoked movement suppression at the 10x dosage, both in the presence and absence of MOR. When rats were co-infused with MOR and NAL, MOR-induced effects were not reversed by either dosage of NAL, and some measures of MOR-induced movement suppression were enhanced by NAL at the 1x dosage. Based on these findings, we conclude that mu-opioid receptors in dlPAG may selectively regulate descending supraspinal motor pathways that drive active movement behaviors, and that interactions between MOR and NAL in dlPAG may be more complex than simple competition for binding at the mu receptor.

► Intra-dlPAG morphine impaired some learned (but not innate) fear responses.
► Intra-dlPAG naltrexone only affected fear responding at very high doses.
► Co-infusion of morphine and naltrexone had additive, not competitive effects.
► Mu-opioid drugs interact in a more complex way than simple binding competition.