Stress-induced antinociception to noxious heat requires α1A-adrenaline receptors of spinal inhibitory neurons in mice

Abstract

It is well known that acute exposure to physical stress produces a transient antinociceptive effect (called stress-induced analgesia [SIA]). One proposed mechanism for SIA involves noradrenaline (NA) in the central nervous system. NA has been reported to activate inhibitory neurons in the spinal dorsal horn (SDH), but its in vivo role in SIA remains unknown. In this study, we found that an antinociceptive effect on noxious heat after acute exposure to restraint stress was impaired in mice with a conditional knockout of α1A-adrenaline receptors (α1A-ARs) in inhibitory neurons (Vgat-Cre;Adra1aflox/flox mice). A similar reduction was also observed in mice treated with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine, a selective neurotoxin for NAergic neurons in the locus coeruleus (LC). Furthermore, whole-cell patch-clamp recordings using spinal cord slices revealed that NA-induced increase in the frequency of spontaneous inhibitory postsynaptic currents in the substantia gelatinosa neurons was suppressed by silodosin, an α1A-AR antagonist, and by conditional knockout of α1A-ARs in inhibitory neurons. Moreover, under unstressed conditions, the antinociceptive effects of intrathecal NA and phenylephrine on noxious heat were lost in Vgat-Cre;Adra1aflox/flox mice. Our findings suggest that activation of α1A-ARs in SDH inhibitory neurons, presumably via LC-NAergic neurons, is necessary for SIA to noxious heat.

Identification of Spinal Inhibitory Interneurons Required for Attenuating Effect of Duloxetine on Neuropathic Allodynia-like Signs in Rats

“…However, the responsible α 1 -AR subtype for the effect of NA on inhibitory neurons in rats may be different from that in mice. Our previous study using mouse spinal cord slices showed that NA increased the frequency of inhibitory postsynaptic currents in substantia gelatinosa neurons via α 1A -ARs [ 26 , 36 ]. The reason for the difference in the α 1 -AR subtypes involved remains unclear, but some possibilities may be considered: the differences in the species (rat vs. mouse), population of inhibitory interneurons (AAV-NpyP + neurons vs. Vgat-Cre + neurons), and the measured responses (depolarization of cell body vs. inhibitory postsynaptic currents in SDH neurons received inputs from NA-responding neurons).…”

“…It has also been shown that idazoxan reduces the suppressive effect of duloxetine repeatedly administered on neuropathic behavioral hypersensitivity [ 19 ] but not that of acutely administered duloxetine [ 22 ]. In addition to α 2 -AR, NA also activates α 1 -AR and has an excitatory effect on inhibitory interneurons in the SDH [ 23 , 24 , 25 , 26 ]. However, the role of duloxetine in attenuating neuropathic pain-like behavior is poorly understood.…”