Electrophysiological evidence about sexual dimorphism in the clonidine-induced inhibition of trigeminal wide dynamic range cell activity

The trigeminal system plays a key role in headaches pathophysiology. In this regard, nociceptive experiments in male rodents have shown that at the trigeminal level, clonidine induces antinociception through α2A- but not α2B/2C-adrenoceptors. Interestingly, although behavioural experiments suggest that males are more sensitive to clonidine-induced antinociception than female rats (an effect linked to hormonal factors), little is known about how neuronal nociceptive processing is affected in females (including the role of the α2A/2B/2C-adrenoceptors subtypes involved). Since trigeminal second-order wide dynamic range (WDR) cells are one of the main gatekeepers involved in decoding and processing nociceptive inputs from peripheral facial structures, this study was designed to test the effect of clonidine on trigeminal WDR cell activity in male and female rats. Extracellular unitary recordings of trigeminal WDR cells were performed in anaesthetised Wistar rats and analysed as Aδ-, and C-fibres associated discharge. Under these conditions, the effect of local clonidine (3.1–31 nmol) on electrical periorbital-evoked firing of WDR cells was recorded in both sexes. Furthermore, considering that at least three α2-adrenoceptor subtypes exist (α2A-, α2B-, and α2C-adrenoceptors), pharmacological blockade of these receptor subtypes was performed using BRL 44408 (α2A), imiloxan (α2B), and JP-1302 (α2C). Clonidine inhibited the activity of Aδ-, and C-fibres in male and female rats. This inhibition was observed in 50–60% of cells recorded. Furthermore, the dose necessary to induce similar electrophysiological antinociception was higher in females (31 nmol vs. 10 nmol). In males, but not in females, clonidine-induced inhibition of Aδ- and C-fibres activity was reversed using BRL 44408. Whereas in females, imiloxan and JP-1302 reversed the clonidine-induced inhibition of Aδ- but not C-fibres. Male rodents are more sensitive than females to clonidine-induced WDR antinociception. In males, but not in females, clonidine-induced inhibition of Aδ- and C-fibres discharge relies on α2A-adrenoceptor activation. However, in females, the activation of α2B/2C-adrenoceptors seems to be relevant to Aδ- but not C-fibre discharge inhibition by clonidine, implying that other mechanism/receptors may be involved in females.