Excitatory and inhibitory neuronal signaling in inflammatory and diabetic neuropathic pain

Table 1 Membrane receptors in pain signaling

(A) Ionotropic receptors
Receptor	Type	Agonist	Ion	Description
Excitatory receptors
TRPV1	Ionotropic capsaicin receptor	e.g., capsaicin, piperin	Cation	PKC activated nociceptor, activated by temperature/ chemical stimuli,	PNS, CNS
TRPA1	Ionotropic cannabinoid receptor	e.g., isothiocyanates formalin	Ca²⁺	PKA activated nociceptor, detection for pain, cold and itch	PNS, CNS
ASIC	Proton-gated cations	Protons	Cation	Nociceptor, acid sensing receptor	PNS, CNS
HCN	GPCR pairs voltage-gated	cAMP	\(\underline{\text{Na}^{+}}{\text{K}^{+}}\) cation	Constitutively open at V near the resting potential	PNS, CNS
P2X3R	Ionotropic non-selective cations	ATP	\(\underline{\text{Ca}^{2+}}\), Na⁺, K⁺	activates intracellular signalling pathway	PNS, CNS
Nav1.7/1.8	Voltage-gated		Na⁺	Triggers action potential firing	PNS
Cav2.3	Voltage-gated		Ca²⁺	Conducts Ca²⁺ currents	PNS, CNS
NMDA-R	Ionotropic ligand-gated	Glutamate, glycine	\(\underline{\text{Ca}^{2+}}\), Na⁺	Ligand is subunit-dependent	PNS, CNS
AMPA-R	Ionotropic ligand-gated	Glutamate, AMPA	\(\underline{\text{Na}^{+}}\), Ca²⁺	Four subunit types encoded by genes GluA1-4	PNS, CNS
Inhibitory receptors
Kv4.2	Voltage gated		K⁺	Conducts K⁺ currents	PNS, CNS
GABA_A-R	Ionotropic ligand-gated	GABA	Cl⁻	Controls majority of inhibitory signalling in CNS	PNS, CNS
Glycine-R	ionotropic ligand-gated	glycine	Cl⁻	controls inhibitory signalling in CNS	PNS, CNS

(B) Metabotropic receptors/Transporters
Receptor	Type	Agonist	Description
GABA_B-R	GPCR	GABA, baclofen	Activates K⁺ channels, inactivates VGCCs	PNS, CNS
CB1-R	Metabotropic, GPCR	Cannabinoid	Suppression of inhibition + excitation	PNS, CNS
MOR	GPCR	Morphine	Inhibits adenylate cyclase, lowering cAMP	PNS, CNS
TrkA	Catalytic receptor	Neurotrophin, NGF	Phosphorylates itself + MAPK members	PNS, CNS
P2YR	GPCR	ATP, ADP etc	Mediate cellular responses	PNS, CNS
BK-R	GPCR	Bradykinin	Induces release of substance P, neurokinin	PNS. CNS
NK-R	GPCR	Substance P	Sensitises the dorsal horn neurons	PNS, CNS
CCR2	GPCR, chemokines	CCL2	Activates intracellular signalling cascades	PNS, CNS
CXCR1	GPCR, chemokines	IL-8, CXCL1	Activates adenylyl cyclase and protein kinase C	PNS, CNS
PGE2	GPCR	PG2
TNF-R	Cytokine	TNF-α	Mediates apoptosis and inflammation	PNS, CNS
IL-1R	Cytokine	interleukin 1	Mediates inflammation, signal transduction	PNS, CNS
TLR	Toll-like receptors	e.g., LPS	Pattern recognition receptor	PNS, CNS
Transporters
GlyT1	2Na⁺, 1 Cl⁻, 1 glycine		Mainly expressed in PM of glial cells	CNS
GlyT2	3Na⁺, 1Cl⁻, 1 glycine		Mainly expressed at pre-synaptic terminals	CNS
GAT-1	2Na⁺, 1Cl⁻, 1 GABA		Expressed in axon terminals, astrocytes	CNS
GAT-2/3	2Na⁺, 1Cl⁻, 1 GABA		Expressed in axon terminals distant form the synaptic cleft, astrocytes	CNS
KCC2	K⁺-Cl⁻ co-transporter		Expressed in neurons; mediates crosstalk between excitatory/ inhibitory transmission	CNS

TRPV1 transient receptor potential cation channel subfamily V member 1 (capsaicin receptor, vanilloid receptor1); TRPA1 Transient receptor potential cation channel, subfamily A, member 1, ASIC Acid sensing ion channels; HCN Hyperpolarization-activated cyclic nucleotide-gated Channel; P2X3R purinergic receptor 3; Nav/Cav/Kv voltage-gated sodium/ calcium/potassium channel; R receptor; NMDA N-methyl-D-aspartate; AMPA α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GABA Gamma-aminobutyric acid; CB1 cannabinoid 1; MOR µ opioid receptors; TrkA Tropomyosin receptor kinase A; BK bradykinin; NK neurokinin receptor; CCR2 C–C chemokine receptor type 2; CXCR1 C-X-C motif chemokine receptor 1; PGE2 prostaglandin 2; TNF tumor necrosis factor; IL-1R interleukin 1 receptor; TLR Toll-like receptor; CCL2 chemokine (C–C motif) ligand 2; GlyT Glycine transporter; GAT GABA transporter; KCC2 K⁺-Cl⁻ co-transporter; underlined entries indicate predominant location of receptor/transporter

ISSN: 1528-3658