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

Table 1 Measured Neurotransmitters in response to spinal cord stimulation (SCS)

	Tissue Sampled and Measured Change To:
Neurotransmitter	P-SCS	B-SCS	HF-SCS	DRG-S
Glu	SC: ↓ ^{(Cui et al., 1997)} PAG: ↓ ^{(Stiller et al., 1995)}
5-HT	SC: ↑ ^{(Linderoth et al., 1992; Song et al., 2009)} PAG: ↔ ^{(Stiller et al., 1995)}
GABA	SC: ↑ ^{(Cui et al., 1997; Stiller et al., 1996)} PAG: ↓ ^{(Stiller et al., 1995)} RVM: ↓ ^{(Song et al., 2013c)} Plasma: ↑ ^{(Crosby et al., 2015a)}	Plasma: ↔ ^{(Crosby et al., 2015a)}
NE	SC: ↔ ^{(Song et al., 2013b)} CSF: ↑ ^{(Levin & Hubschmann, 1980; Liu et al., 2008)} Plasma: ↑ ^{(Levin & Hubschmann, 1980)}
ACh	SC: ↑ ^{(Schechtmann et al., 2008)}
SP	SC: ↑ ^{(Linderoth et al., 1992)} PAG: ↔ ^{(Stiller et al., 1995)}

Ascending nociception is modulated by local segmental mechanisms as well as descending antinociceptive pathways that are reflected by changes in neurotransmitters in the spinal cord dorsal horn. The location of tissue sampling in response to SCS is vitally important as neural circuitry may exhibit a pro- or antinociceptive response to a particular neurotransmitter depending on the site. P-SCS modulates nociceptive signal propagation through a change in the balance of excitatory and inhibitory neurotransmitters, most notably 5-HT and GABA. Little is known about neurotransmitter modulation with B-SCS, HF-SCS and DRG-S. Further work will be necessary to clarify the analgesic mechanisms of these newer paradigms. ‘Up’ and ‘down’ arrows represent increases or decreases, respectively in detection. ‘Sideways’ arrows represent no significant change. Glu (Glutamate), 5-HT (5-hydroxytryptamine, serotonin), GABA (Gamma-aminobutyric Acid), NE (Norepinephrine), ACh (Acetylcholine), SP (Substance P), SC (Spinal Cord), PAG (Periaqueductal Gray), RVM (Rostral Ventromedial Medulla), CSF (Cerebrospinal Fluid)