Inflammatory Pain Upregulates Spinal Inhibition via Endogenous Neurosteroid Production

Abstract

Inhibitory synaptic transmission in the dorsal horn (DH) of the spinal cord plays an important role in the modulation of nociceptive messages because pharmacological blockade of spinal GABA A receptors leads to thermal and mechanical pain symptoms. Here, we show that during the development of thermal hyperalgesia and mechanical allodynia associated with inflammatory pain, synaptic inhibition mediated by GABA A receptors in lamina II of the DH was in fact markedly increased. This phenomenon was accompanied by an upregulation of the endogenous production of 5␣-reduced neurosteroids, which, at the spinal level, led to a prolongation of GABA A receptor-mediated synaptic currents and to the appearance of a mixed GABA/glycine cotransmission. This increased inhibition was correlated with a selective limitation of the inflammation-induced thermal hyperalgesia, whereas mechanical allodynia remained unaffected. Our results show that peripheral inflammation activates an endogenous neurosteroid-based antinociceptive control, which discriminates between thermal and mechanical hyperalgesia.

Elevated Neurosteroids in the Lateral Thalamus Relieve Neuropathic Pain in Rats with Spared Nerve Injury

“…At earlier time points (days 7 and 14), their levels remained unchanged. This pattern was consistent with previous studies in the spinal cord and the brain [15,17,39].…”

“…However, most research has focused on the spinal level [15][16][17]39]. Only two studies have reported elevated neurosteroids in nociceptive supraspinal nuclei [39] and the brain [17].…”

“…A growing number of studies have reported the analgesic effects of neurosteroids and their analogs by enhancing spinal inhibition [15,48]. Though a few studies have reported increased neurosteroids in the nociceptive Fig.…”

“…Systemic or intrathecal injection of neurosteroids has strong analgesic effects in animals [15][16][17]. The lateral thalamus, including the ventral posterior thalamus (VP) and the reticular thalamic nucleus, is a key relay station for the transmission of peripheral somatosensory and nociceptive information to the neocortex [18,19].…”

Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways

“…In fact, we propose that inhibition of sEH reveals the activity of a physiological system that is already in place to cope with inflammatory pain. Second, Poisbeau et al (49) reported that during peripheral inflammatory pain GABA A receptormediated synaptic inhibition was enhanced in lamina II dorsal horn neurons in a manner that can be reversed with finasteride, a neurosteroid synthesis inhibitor. The inhibitory influence of GABAergic tone on ascending pain transmission and the excitability of dorsal horn neurons are well established (50).…”