Unravelling the dorsal periaqueductal grey matter NMDA receptors relevance in the nitric oxide-mediated panicâlike behaviour and defensive antinociception organised by the anterior hypothalamus of male mice

Rationale Previous studies suggested that the dorsal column of the periaqueductal grey matter (dPAG) can be a target of neural pathways from hypothalamic nuclei involved in triggering fear-related defensive responses. In turn, evidence is provided suggesting that microinjection of the nitric oxide (NO) donor SIN-1 into the anterior hypothalamus (AH) of mice evokes panic-like behaviours and fear-induced antinociception. However, it is unknown whether the dPAG of mice mediates these latter defensive responses organised by AH neurons. Objectives This study was designed to examine the role of dPAG in mediating SIN-1-evoked fear-induced defensive behavioural and antinociceptive responses organised in the AH of mice. Methods First, neural tract tracing was performed to characterise the AH-dPAG pathways. Then, using neuropharmacological approaches, we evaluated the effects of dPAG pretreatment with either the non-selective synaptic blocker cobalt chloride (CoCl.sub.2; 1 mM/0.1 [mu]L) or the competitive N-methyl-d-aspartate (NMDA) receptor antagonist LY235959 (0.1 nmol/0.1 [mu]L) on defensive behaviours and antinociception induced by microinjections of SIN-1 in the AH of male C57BL/6 mice. Results AlexaFluor488-conjugated dextran-labelled axonal fibres from AH neurons were identified in both dorsomedial and dorsolateral PAG columns. Furthermore, we showed that pre-treatment of the dPAG with either CoCl.sub.2 or LY235959 inhibited freezing and impaired oriented escape and antinociception induced by infusions of SIN-1 into the AH. Conclusions These findings suggest that the panic-like freezing and oriented escape defensive behaviours, and fear-induced antinociception elicited by intra-AH microinjections of SIN-1 depend on the activation of dPAG NMDA receptors.