Table 1.
Summary of studies investigating the effect of altered K+ channel expression and function on acute, neuropathic, and inflammatory pain phenotypes
| Superfamily | Subunit | Manipulation | Expression/excitability changes | Pain phenotype | Comments | Refs |
|---|---|---|---|---|---|---|
| Voltage-gated | Kv1.1 | KO transgenic | Loss of IKmech currents ↓Mechanical threshold (HTM-C fibers) ↓Firing adaptation (Aβ-fibers) |
↑Mechanical ↑Heat ↑Formalin |
Reduced morphine antinociception | 28, 31 |
| Morvan's syndrome Neuromyotonia | ↑Peripheral excitability | ↑Mechanical allodynia ↑Heat hyperalgesia |
Autoantibodies to Kv1 complexes; cause disease when transferred to cells; immunomodulatory therapy useful | 111, 112, 113 | ||
| Kv1.2 | Nerve injury (SNL) Kv1.2 knockdown |
↓K+ current, ↓firing threshold ↑RMP, ↑firing rate |
↑Mechanical ↑Cold |
SNL induces Kv1.2 antisense RNA; pre-emptive sense RNA alleviates pain | [30] | |
| Kv1.4 | Nerve injury (SNT, SNL) Diabetic neuropathy Inflammation |
↓Kv1.4 expression | ND | – | 25, 101, 124 | |
| Kv2.1 | Nerve injury (SNL, SNT) | ↓Kv2.1 expression | ND | – | 26, 38 | |
| Kv2.2 | Nerve injury (SNL, CCI) | ↓Kv2.2 expression | ND | – | 27, 38 | |
| Oxaliplatin Kv2.2 knockdown (cortex) |
↓Kv2.2 expression (cortex) | ↑Mechanical ↑Cold |
– | [40] | ||
| Kv3.4 | Nerve injury (SNL) Kv3.4 knockdown Diabetic neuropathy |
↓Kv3.4 expression ↑AP duration |
↑Mechanical | PKC phosphorylation slows Kv3.4 inactivation and decreases AP duration | 43, 44, 101 | |
| Kv4.2 | KO transgenic | DH neurons: ↑RMP, ↓firing threshold ↑Repetitive firing ↓IA current,↑excitability |
↑Mechanical, ↑heat ↓Formalin, ↓Carrageenan |
Quicker resolution of mechanical allodynia after CCI; defects in central sensitization | [52] | |
| Kv4.3 | Nerve injury (SNL) Diabetic neuropathy Kv4.3 knockdown |
↓Kv4.3 expression | ↑Mechanical | REST antisense blocks Kv4.3 downregulation | 44, 99, 101 | |
| Kv7.2 Kv7.3 |
Nerve injury (PSNL) | ↓Kv7.2 expression ↓IM current |
↑Mechanical ↑Heat |
Perisciatic flupirtine reverses pain; antagonized by XE-991 blocker | [54] | |
| Bone cancer | ↓IM current, ↑excitability | ↑Mechanical ↑Heat |
– | [55] | ||
| Retigabine (opener) after nerve injury or inflammation | ↓Excitability (DRG, neuroma, DH neurons) |
↓Mechanical (CCI, SNI, bone cancer) ↓Heat (bone cancer) ↓Cold (CCI) ↓Formalin, ↓Carrageenan ↓CFA ↓Visceral pain |
Antinociception reversed by XE-991; no effect on intact fibers or acute pain | 12, 55, 58, 60, 61, 62 | ||
| Kv9.1 | Kv9.1 knockdown Nerve injury (SNL) |
↓Kv9.1 expression ↑SA, ↑firing, ↑after-discharge |
↑Mechanical | Mediated through Kv2 | [122] | |
| Human SNPs | ND | ↑Risk of phantom limb pain ↑Risk of chronic back pain ↑HIV neuropathy pain intensity |
– | 125, 126 | ||
| Two-pore | TRESK | Human DN mutation | ↓TRESK currents | ↑Migraine pain | – | [67] |
| Nerve injury (SNT) TRESK knockdown |
↓TRESK expression | ↑Mechanical | Trend for thermal pain | [68] | ||
| TRESK overexpression after nerve injury (SNI) |
↑TRESK expression | ↓Mechanical allodynia | – | [69] | ||
| TREK1 | KO transgenic | ↓TREK1 expression ↑AP firing |
↑Mechanical, ↑heat ↓Inflammatory |
Reduced cold hypersensitivity after SNL; TREK1 inhibited by PGE2 and cAMP | [71] | |
| TRAAK | KO transgenic | ↓TRAAK expression | ↑Mechanical, ↑heat | TREK1/TRAAK KO: ↑noxious cold pain but reduced cold sensitivity after oxaliplatin | 74, 75 | |
| TASK | Inflammation (CFA) | ↓TASK1, TASK2, TASK3 expression | ND | – | [65] | |
| TWIK1 | Nerve injury (SNI) | ↓TWIK1 expression | ND | – | [66] | |
| Inward rectifiers | Kir2.1 | Nerve injury (CCD) plus Kir2.1 overexpression | ↑Kir2.1 expression ↓RMP, ↑firing threshold, ↓SA |
↓Mechanical hyperalgesia | Late treatment had no affect | [91] |
| Kir3.1 | Nerve injury (PSNL) Inflammation (formalin) |
↑Phospho-Kir3.1 (SC) | ND | Predicted to increase excitability by decreasing Kir3.1 activity | [86] | |
| Kir3.2 | Eight human SNPs | ND | ↓Acute pain tolerance ↑Chronic back pain intensity |
– | [87] | |
| Kir4.1 | Nerve injury (CCI) Kir4.1 knockdown |
↓Kir4.1 expression (SGC of TG) | ↑Facial pain | – | [117] | |
| Inflammation (CFA) | ↓Kir4.1 expression (SGC of TG) ↓Kir4.1 currents, ↑RMP (SGC of TG) |
↑Facial pain | – | [118] | ||
| KATP | Nerve injury (CCI) | ↓Kir6.1 expression (SGC of spinal cord) | ↑Mechanical, ↑heat | Cromakalim (opener) reversed pain; antagonized by carbenoxolone | [119] | |
| Nerve injury (SNL) | ↓Kir6.2 expression (DRG, Schwann cells) ↓KATP activity |
↑Mechanical | Diazoxide (opener) or CAMKII activate residual KATP channels | 94, 95 | ||
| Pinacidil and diazoxide (openers) | ↓DRG excitability | ↓Inflammatory ↓Mechanical, ↓thermal |
Antagonized by KATP blocker glyburide | [93] | ||
| Calcium-activated | SKCA/IKCA | Apamin (blocker) | ↑AP frequency, ↑excitatory transmission | ↑Mechanical, ↑heat | NR1 KO in DRG has same effects | [82] |
| Nerve injury (CCI) Inflammation (CFA) |
No change in SK1–3 expression | ND | Targeting residual SK may be viable for pain treatment |
[76] | ||
| Nerve injury (avulsion) | ↓IK1 expression | ND | IK1 was upregulated in vitro by NT-3 | [81] | ||
| 1-EBIO (opener) | ↓Excitability after mechanical stimulation | ND | Effects reversed by UCL-1848 (blocker) | [83] | ||
| BKCA | Iberiotoxin (blocker) | ↓BKCA current ↑AP duration, ↑firing frequency |
ND | NS-1619 (opener) decreases excitability | [77] | |
| Nerve injury (SNL) | DRG: ↓BKCA expression SC: ↑BKCA expression (DREZ) |
↑Mechanical, ↑heat | Iberiotoxin reduces mechanical thresholds; BKCA opener (NS-1619) reverses SNL pain | [79] | ||
| Nerve injury (SNL) | ↓BKCA current (DRG) ↓ BKα1 mRNA (DRG) |
ND | BDNF reduced BKCA currents. Anti-BDNF reversed BKCA reduction |
[102] | ||
| Inflammation (CFA) | ↓BKCA current (DRG) | ND | No change in BKCA expression | [80] | ||
| Charybdotoxin (blocker) | ↓P2X4 and BDNF in microglia | ↓Tactile allodynia | Mediated via inhibition of microglial activation |
[121] | ||
| KO transgenic | ↓BKCA expression (nociceptors) | ↑Inflammatory | Acute and neuropathic pain unaffected | [133] |
Unless stated otherwise, entries in expression and excitability refer to sensory neurons. Abbreviations: AGJ, astroglial gap junction; AP, action potential; CCD, chronic compression of the dorsal root ganglion; CFA, complete Freund's adjuvant; CCI, chronic constriction injury; DH, dorsal horn; DN, dominant-negative; DREZ, dorsal root entry zone; DRG, dorsal root ganglion; HTM, high-threshold mechanoreceptor; KO, knockout; ND, not determined; PSNL, partial sciatic nerve ligation; RMP, resting membrane potential; SA, spontaneous activity; SC, spinal cord; SGC, satellite glial cells; SNI, spared nerve injury; SNL, spinal nerve ligation; SNP, single-nucleotide polymorphism; SNT, sciatic nerve transection; TG, trigeminal ganglion.