Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action

Jacob Caylor; Rajiv Reddy; Sopyda Yin; Christina Cui; Mingxiong Huang; Charles Huang; Ramesh Rao; Dewleen G. Baker; Alan Simmons; Dmitri Souza; Samer Narouze; Ricardo Vallejo; Imanuel Lerman

doi:10.1186/s42234-019-0023-1

Bioelectronic Medicine

Table 2 Spinal cord stimulation exerts analgesia by activating specific receptor subtypes

From: Spinal cord stimulation in chronic pain: evidence and theory for mechanisms of action

Analgesia-Response To:
Neurotransmitter	Receptor Subtype	P-SCS	B-SCS	HF-SCS	DRG-S
5-HT	5-HT₁: 5-HT₂: 5-HT₃: 5-HT₄: 5-HT₆: 5-HT₇:	↔ ^{(Song et al., 2011)} ↑ ^{(Barchini et al., 2012)} ↑ ^{(Song et al., 2011; Barchini et al., 2012)} ↑↑ ^{(Song et al., 2011)} ↑ ^{(Song et al., 2011)} ↔ ^{(Song et al., 2011)} ↔ ^{(Song et al., 2011)}
GABA	GABA_A: GABA_B:	↑ ^{(Duggan & Foong, 1985; Song et al., 2011; Barchini et al., 2012)} ↔ ^{(Cui et al., 1996)} ↑↑ ^{(Song et al., 2009; Song et al., 2011; Cui et al., 1996; Barchini et al., 2012)}
NE	α1 adrenergic: α2 adrenergic: β1 adrenergic: β2 adrenergic:	↑ ^{(Barchini et al., 2012)} ↑↑ ^{(Barchini et al., 2012; Schechtmann et al., 2004)} ↑ ^{(Barchini et al., 2012)} ↑ ^{(Barchini et al., 2012)}
Dopamine	D2 D3	↑ ^{(Barchini et al., 2012)} ↑ ^{(Barchini et al., 2012)}
ACh	M1 mAChR: M2 mAChR: M3 mAChR: M4 mAChR: nAChR:	↑ ^{(Schechtmann et al., 2008)} ↑ ^{(Schechtmann et al., 2008; Song et al., 2008)} ↔ ^{(Schechtmann et al., 2008)} ↑↑ ^{(Schechtmann et al., 2008; Song et al., 2008)} ↔ ^{(Song et al., 2009)} ↔ ^{(Schechtmann et al., 2008)}

Activation of specific receptor subtypes contributes to P-SCS mediated analgesia. Experiments used receptor antagonists and agonists to clarify the role of particular receptors to SCS-mediated analgesia. 5-HT₃ receptor, GABA_B receptor, α2 adrenergic receptor and M4 mAChR pathways were found to contribute to this analgesia to a greater extent than other receptor subtypes. An “up” arrow indicates that activation of that particular receptor subtype contributed to analgesia. ‘Double up’ arrows represent a greater increase and the predominant pathway. ‘Sideways’ arrows represent no contribution to analgesia. Acronyms: Glu (Glutamate), 5-HT (5-hydroxytryptamine, serotonin), GABA (Gamma-aminobutyric Acid), NE (Norepinephrine), ACh (Acetylcholine), 5-HT₁ (5-hydroxytryptamine receptor 1), 5-HT₂ (5-hydroxytryptamine receptor 2), 5-HT₃ (5-hydroxytryptamine receptor 3), 5-HT₄ (5-hydroxytryptamine receptor 4), 5-HT₆ (5-hydroxytryptamine receptor 6), 5-HT₇ (5-hydroxytryptamine receptor 7), GABA_A (Gamma-aminobutyric Acid A Receptor), GABA_B (Gamma-aminobutyric Acid B Receptor), α1 (Alpha 1 Adrenergic Receptor), α2 (Alpha 2 Adrenergic Receptor), β1 (Beta 1 Adrenergic Receptor), β2 (Beta 2 Adrenergic Receptor), D1 (Dopamine 1 Receptor), D2 (Dopamine 2 Receptor), M1 mAChR (Muscarinic 1 Acetylcholine Receptor), M2 mAChR (Muscarinic 2 Acetylcholine Receptor), M3 mAChR (Muscarinic 3 Acetylcholine Receptor), M4 mAChR (Muscarinic 4 Acetylcholine Receptor), nAChR (Nicotinic Acetylcholine Receptor)

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