Table 2.
Predominant NaV isoforms contributing functionally to visceral sensation
| A. Healthy states | |||
|---|---|---|---|
| Species | Test | Response | Reference |
| Human | Appendix distension (ex vivo extracellular recordings of mesenteric afferents) before and after exposure to PF‐5198007 (Nav1.7 antagonist) | No difference in mesenteric afferent peak firing | (Hockley et al. 2017) |
| Mouse | Colonic mechanical stimulation (ex vivo extracellular recordings of colonic afferents in the splanchnic nerve) after Hm1a (highly selective Nav1.1 agonist, mucosal application) | Increase in colonic nociceptor response to mechanical stimuli in a sub‐population of afferents. | (Osteen et al. 2016) |
| Colonic stretch (ex vivo extracellular recordings of colorectal afferents in the pelvic nerve) μ‐conotoxin GIIIa, and μ‐conotoxin PIIIa, serosal/mucosal application) | Reduced action potential firing of stretch‐sensitive afferent response | (Feng et al. 2015) | |
| Colonic stretch (ex vivo extracellular recordings of colorectal afferents in the pelvic nerve) ‐ ProTxII (Nav1.7 antagonist, serosal/mucosal application) | No difference in stretch‐sensitive afferent response | (Feng et al. 2015) | |
| Ciguatoxin (pan‐Nav agonist) (intracolonic) | Increased pain behavioural response | (Inserra et al. 2017) | |
| Colonic incubation with A‐803467 (Nav1.8 antagonist) (ex vivo extracellular recordings of colorectal nociceptors), followed by ciguatoxin | Inhibited afferent firing induced by ciguatoxin | ||
| Incubation with supernatant from colitis patients | Increased excitability of colonic DRG neurons associated with enhanced NaV1.8 currents | (Ibeakanma & Vanner, 2010) | |
| Tumour necrosis factor‐α incubation | |||
| B. Knock‐out and knock‐down models | ||||
|---|---|---|---|---|
| Model | Species | Test | Response | Reference |
| NaV1.7Nav1.8 | Mouse | Formalin (intraplantar) | Reduction in pain behavioural response in phase I and phase II of formalin response | (Nassar et al. 2004) |
| Complete Freund's adjuvant (intraplantar) | Reduction in thermal hyperalgesia and mechanical allodynia from day 1 to day 10 | |||
| Carrageenan (intraplantar) | Reduction in thermal hyperalgesia from 1 to 4 h | |||
| Nerve growth factor (intraplantar) | Absence of phase I thermal hyperalgesia and reduction in phase II | |||
| Colonic distension (ex vivo extracellular recordings of lumbar splanchnic nerve activity) | No difference in afferent firing in physiological range (0–80 mmHg) | (Hockley et al. 2017) | ||
| Reduction in firing in supramaximal range (80–145 mmHg) | ||||
| Capsaicin (intracolonic) | Normal pain behavioural response | |||
| Mustard oil (intracolonic) | ||||
| Cyclophosphamide‐induced cystitis | Normal level of referred mechanical hyperalgesia responses | |||
| NaV1.8−/− | Mouse | Whole‐cell patch clamp | Reduced action potential amplitude in retrogradely labelled neurons projecting to the peritoneal cavity (DRG, T9–T13) | (Hillsley et al. 2006) |
| Nippostrongylus brasiliensis post‐infectious stage, whole‐cell patch clamp | Absence of neuronal hyperexcitability 19–25 days post‐infection in retrogradely labelled neurons projecting to the peritoneal cavity (DRG, T9–T13) | |||
| Acetylcholine (intraperitoneal injection) | Normal pain behavioural response | (Laird et al. 2002) | ||
| Capsaicin (intracolonic) | Reduced pain behavioural response | |||
| Mustard oil (intracolonic) | ||||
| Cyclophosphamide‐induced cystitis | Normal pain and inflammatory responses | |||
| NaV1.8 knock‐down (L6–S1) | Rat | Cystometry (saline) | No change in intercontraction intervals | (Yoshimura et al. 2001) |
| Acetic acid (intravesical) | Hyper‐reflexia attenuated | |||
| NaV1.9−/− | Mouse | Whole‐cell patch clamp | Normal excitability and action potential characteristics in colonic neurons (DRG T9–T13) | (Hillsley et al. 2006) |
| Nippostrongylus brasiliensis post‐infectious stage, whole‐cell patch clamp | No change in neuronal hyperexcitability 19–25 days post‐infection in retrogradely labelled neurons projecting to the peritoneal cavity (DRG, T9–T13) | |||
| Colorectal distension | Normal pain behavioural response | (Martinez & Melgar, 2008) | ||
| R‐848 (toll‐like receptor 7 activator)‐induced colonic inflammation, colorectal distension | Reduced pain behavioural response | |||
| Colonic distension (ex vivo extracellular recordings of splanchnic nerve activity) | Reduced afferent discharge | (Hockley et al. 2014) | ||
| Ex vivo extracellular recordings of lumbar splanchnic nerve activity following inflammatory soup (bradykinin, ATP, histamine, PGE2 and 5‐HT), or inflammatory bowel disease patient colonic supernatant application | Reduced afferent fibre responses | |||
| Ex vivo extracellular recordings of lumbar splanchnic nerve activity following UTP (P2Y2 and P2Y4 agonist) or ADP (P2Y1, P2Y12 and P2Y13 agonist), application | Reduced afferent fibre responses | (Hockley et al. 2016a) | ||
| Cystometry (saline) | No change in basal urodynamics | (Ritter et al. 2009) | ||
| Cyclophosphamide‐induced cystitis | ||||
| Bladder distension (ex vivo extracellular recordings of bladder nerve activity) following PGE2 bladder infusion application | Reduced afferent excitability | |||
| C. Inflammatory hypersensitivity models | ||||
|---|---|---|---|---|
| Model/disease | Species | Test | Response | Reference |
| Neonatal induced colitis | Rat | Protein expression | Increase in NaV1.7 and Nav1.8 protein in colonic (DRG, T13–L2) neurons post‐inflammation | (Qu et al. 2013) |
| Whole‐cell patch clamp | Increase in Na+ current in colonic neurons (DRG, T13–L2) 6 weeks post‐inflammation | |||
| No change in Na+ current in colonic neurons (DRG, T13–L2) 10 weeks post‐inflammation | ||||
| No change in Na+ current in non‐colonic neurons (DRG, L4–L5) 6 or 10 weeks post inflammation | ||||
| Acute TNBS‐induced colitis | Mouse | Whole‐cell patch clamp | Increased slow TTX‐R Na+ current in colonic neurons (DRG, T9–L1) 7–10 days post‐ induction | (Beyak et al. 2004) |
| No change in persistent TTX‐R Na+ currents in colonic neurons (DRG, T9–L1) 7–10 days post‐induction | ||||
| Gene and protein expression | No change in NaV1.7 mRNA or protein in retrogradely labelled colonic neurons (DRG, T9–T13) 1 week post‐induction | (King et al. 2009) | ||
| Gene expression | Tenfold reduction in NaV1.8 mRNA 2–4 days post‐induction, no change at day 7, in retrogradely labelled colonic neurons (DRG, T9–T13) | |||
| Protein expression | No change in NaV1.8 protein 2–4 days post‐induction, up‐regulation at day 7, in retrogradely labelled colonic neurons (DRG, T9–T13) 1 week post‐induction | |||
| No change in Nav1.9 protein in colonic neurons (DRG, T9–T13) day 7 post‐induction | ||||
| Post‐TNBS‐induced colitis | Mouse | Whole‐cell patch clamp in the presence of Hm1a (Nav1.7 agonist) | Pronounced increase in excitability of colonic DRG neurons: significant lowering of rheobase and a dramatic increase in the number of action potentials fired at 2× rheobase | (Osteen et al. 2016) |
| Gene expression | Up‐regulation of NaV1.7 mRNA in retrogradely labelled colonic neurons (DRG, L6–S1) 4 weeks post‐induction | (Campaniello et al. 2016) | ||
| Nippostrongylus brasiliensis post‐infectious stage | Mouse | Gene expression | No change in NaV1.8 or Nav1.9 mRNA 19–25 days post ‐infection in retrogradely labelled neurons projecting to the peritoneal cavity (DRG, T9–T13) | (Hillsley et al. 2006) |
| Interstitial cystitis/bladder pain syndrome | Human | Neosaxitoxin (blocker of TTX‐S Nav channels) (bladder infiltration) | Analgesia and reduced frequency lasting up to 90 days | (Manriquez et al. 2015) |
| Cyclophosphamide‐induced cystitis | Rat | A‐803467 administration (intraperitoneal) | No change in pain behavioural response | (Jarvis et al. 2007) |
| D. Non‐inflammatory hypersensitivity models | ||||
|---|---|---|---|---|
| Model/disease | Species | Test | Response | Reference |
| Clinical rectal hypersensitivity | Human | Protein expression (full thickness rectal biopsies) | Increased NaV1.7‐immunoreactive nerve fibres in mucosal, submucosal and muscle layers | (Yiangou et al. 2007) |
| Maternal separation model (visceral hypersensitivity) | Rat | Gene expression | No change in NaV1.8 mRNA in colonic neurons (DRG, T13–L2) | (Hu et al. 2013a) |
| Protein expression | Increase in NaV1.8 protein in colonic neurons (DRG, T13–L2) | |||
| Whole‐cell patch clamp | Increased TTX‐R Na+ current in colonic neurons (DRG, T13–L2) | |||
| Streptozotocin‐induced diabetes (visceral hypersensitivity) | Protein expression | Increase in NaV1.7 and NaV1.8 protein in colonic neurons (DRG, T13–L2) | (Hu et al. 2016) | |
| Whole‐cell patch clamp | Increased TTX‐R Na+ current in colonic neurons (DRG, T13–L2) | |||
| Partial colonic obstruction (visceral hypersensitivity) | Gene expression | Increase in NaV1.8 mRNA in colonic neurons (DRG, T13–L2) | (Lin et al. 2017) | |
| Whole‐cell patch clamp | Increased TTX‐R Na+ current in colonic neurons (DRG, T13–L2) | |||
| T8 spinal transection | Whole‐cell patch clamp | Reduced TTX‐R Na+ current in bladder neurons | (Yoshimura & deGroat, 1997) | |