Spinal Cord Stimulation Modulates Supraspinal Centers of the Descending Antinociceptive System in Rats with Unilateral Spinal Nerve Injury

Abstract

BackgroundThe descending antinociceptive system (DAS) is thought to play crucial roles in the antinociceptive effect of spinal cord stimulation (SCS), especially through its serotonergic pathway. The nucleus raphe magnus (NRM) in the rostral ventromedial medulla is a major source of serotonin [5-hydroxytryptamine (5-HT)] to the DAS, but the role of the dorsal raphe nucleus (DRN) in the ventral periaqueductal gray matter is still unclear. Moreover, the influence of the noradrenergic pathway is largely unknown. In this study, we evaluated the involvement of these serotonergic and noradrenergic pathways in SCS-induced antinociception by behavioral analysis of spinal nerve-ligated (SNL) rats. We also investigated immunohistochemical changes in the DRN and locus coeruleus (LC), regarded as the adrenergic center of the DAS, and expression changes of synthetic enzymes of 5-HT [tryptophan hydroxylase (TPH)] and norepinephrine [dopamine β-hydroxylase (DβH)] in the spinal dorsal horn.ResultsIntrathecally administered methysergide, a 5-HT1- and 5-HT2-receptor antagonist, and idazoxan, an α2-adrenergic receptor antagonist, equally abolished the antinociceptive effect of SCS. The numbers of TPH-positive serotonergic and phosphorylated cyclic AMP response element binding protein (pCREB)-positive neurons and percentage of pCREB-positive serotonergic neurons in the DRN significantly increased after 3-h SCS. Further, the ipsilateral-to-contralateral immunoreactivity ratio of DβH increased in the LC of SNL rats and reached the level seen in naïve rats, even though the number of pCREB-positive neurons in the LC was unchanged by SNL and SCS. Moreover, 3-h SCS did not increase the expression levels of TPH and DβH in the spinal dorsal horn.ConclusionsThe serotonergic and noradrenergic pathways of the DAS are involved in the antinociceptive effect of SCS, but activation of the DRN might primarily be responsible for this effect, and the LC may have a smaller contribution. SCS does not potentiate the synthetic enzymes of 5HT and norepinephrine in the neuropathic spinal cord.

Monoamines as Drug Targets in Chronic Pain: Focusing on Neuropathic Pain

“…Although spinal adrenergic alterations have received special attention in the development of chronic pain, supraspinal noradrenergic areas have also been seen to change in a manner that is relevant to chronic pain. Thus, an increase in dopamine beta-hydroxylase (DBH), tyrosine hydroxylase (TH), NAT and α2-ARs has been observed in the LC of rats with long-term neuropathic pain (Alba-Delgado et al, 2013;Tazawa et al, 2015). All these changes might try to balance the reduced spinal noradrenergic tone observed in neuropathic pain, although in recent decades these alterations have been seen to be relevant for the development of secondary co-morbidities in chronic pain, such as anxiety and depression (Alba-Delgado et al, 2013.…”

Lack of Analgesic Synergy of the Cholecystokinin Receptor Antagonist Proglumide and Spinal Cord Stimulation for the Treatment of Neuropathic Pain in Rats

“…SCS activates large diameter Aβ fibers in the dorsal columns, and triggers the release of a variety of neurotransmitters in the spinal cord such as GABA , acetylcholine , noradrenaline , serotonin , and opioids . SCS also activates descending inhibitory pathways including neurons in the RVM , and supraspinal serotonin pathways . GABAergic mechanisms play a significant role in the analgesia produced by SCS in animal models of neuropathic pain.…”

Supraspinal Mechanisms of Spinal Cord Stimulation for Modulation of Pain

“…73 Using immunohistochemical methods, a separate group also examined the role of serotonin in descending inhibition; however, they looked at the dorsal raphe nucleus, another source of serotonin, in the ventral periaqueductal grey matter rather than the nucleus raphe magnus or rostral ventromedial medulla (Figures 2, 3, and 4). 74 While additionally examining the role of the noradrenergic system via the locus coeruleus, they determined that spinal cord stimulation-induced antinociception is mediated by both serotonin and norepinephrine, with increased synthesis of these monoamines observed in the dorsal raphe nucleus and locus coeruleus, respectively (Figures 2, 3, and 4). 74 In another study, the Saade team concurrently lesioned the dorsal columns and administered antagonists known to inhibit the effects of descending pain pathway activation.…”

“…74 While additionally examining the role of the noradrenergic system via the locus coeruleus, they determined that spinal cord stimulation-induced antinociception is mediated by both serotonin and norepinephrine, with increased synthesis of these monoamines observed in the dorsal raphe nucleus and locus coeruleus, respectively (Figures 2, 3, and 4). 74 In another study, the Saade team concurrently lesioned the dorsal columns and administered antagonists known to inhibit the effects of descending pain pathway activation. 75 Pain inhibition by conventional spinal cord stimulation applied rostral to the lesion was partially attenuated by an adrenergic antagonist, and enhanced by an adrenergic agonist, suggesting that the supraspinal neurochemical mechanisms for spinal cord stimulation-induced pain inhibition at least partially involve the adrenergic system (Figure 1j).…”