Nociceptor Sensitisation Flashcards
(11 cards)
Allodynia
pain at a stimulus intensity that you normally wouldn’t have
Hyperalgesia
stimuli that previously caused pain and now cause more pain
Nociceptor sensitisation
- allodynia and hyperalgesia
- occur following injury
- as a protective measure
- neuronal and non-neuronal cells release a plethora of substances in injured or damaged tissue
Prostaglandins
- inflammation = increased arachidonic acid and increased COX2 = increased PGs
- PGE2 acts on several receptors, including EP4 (GPCR)
- these receptors are upregulated in DRG neurones following inflammation
- PGE2 activates EP4 so increased cAMP, activates PKA
- PKA activated exchange protein directly activated by cAMP (epac)
- cAMP, PKA and epac can produce nociceptor sensitisation via different pathways
Pathways of nociceptor sensitisation
- PGE2 and Nav1.8
- PGE2 causes hyperpolarising shift in activation
- and increase in peak amplitude
- PKA-dependent - PGE2 and HCNs
- activated by hyperpolarisation
- current injection evokes APs in DRG neurones
- PGE2 increases firing frequency
- inhibiting PKA has no effect
- HCN2 drives effect in nociceptors
- PGE2 -> EP4 -> cAMP -> HCN2 -> AP firing - TRPV1
- activating PKA pathway sensitises TRPV1 via S116
- PGE2-mediated sensitisation requires AKAP79/150
- targeting TRPV1/AKAP150 interaction in vivo reduces inflammatory hyperalgesia
Bradykinin
- formed because of kallikrein enzyme activity in inflammation
- BK activates and sensitises nociceptors via predominantly Gq-mediated pathways
- results in activation of PKC, via an increase in intracellular calcium
- but can couple to other G proteins
- sensitises heat-gated current in DRG neurones, mimicked by activating PKC with PMA and PKC-epsilon
- sensitises TRPV1 via phosphorylation at S502 and S800 sites
- BK increases piezo2 amplitude
- and decreases the time constant of inactivation (inactivation is slower)
Nerve growth factor
- mutations in NGF, or its receptor TrkA, result in CIP
- NGF is increased in inflammatory states
- long-lasting hyperalgesia due to changes in gene expression
- NGF increases protein levels of many nociceptive ion channels and receptors - TRPV1, ASIC3, NAvs etc
- NGF-induced thermal hyperalgesia is present in TRPV1 KO mice
NGF pathway
- Julius group = NGF acts via PLC signalling to relieve TRPV1 of PIP2 inhibition
- McNaughton group = NGF acts via PI3K signalling to increase membrane expression
both are right!
- NGF = increased current amplitude and reduced activation threshold
- increased expression = increased amplitude
- removal of PIP2 inhibition = reduced threshold
- PI3K activates src which phosphorylates TRPV1 at Y200 and initiates membrane trafficking = increased amplitude
- PLC cleave PIP2 = TRPV1 sensitisation
- mAb against PIP2 causes TRPV1 activation at <43 C
- addition of PIP2 = increased activation threshold
Nociceptor unsilencing and mechanical hyperalgesia
nociceptor unsilencing drives mechanical hyperalgesia
- NGF induces CHRNA3 positive neuronal mechanosensitivity
- ERK1/2 drives gene transcription
- piezo2 required for NGF sensitisation
- NGF increases TMEM100 expression
- transfecting TMEM100 induces mechanosensitivity
- knee joint CFA injection causes local pain and secondary hyperalgesia
Anti-NGF Abs
- novel pain therapy?
- tanezumab = phase III against arthritis
- removed in 2021 by the FDA due to cases of rapidly progressing osteoarthritis
Gene therapy
AAVs:
- low pathogenicity
- negligible immune response
- high tropism to different cell types depending on capsid proteins
challenges with transducing DRG neurones from the knee
- long distance from the periphery
- large structure
GiDREADD activation reverses CFR-induced decreased aging
- DREADDs = designer receptors exclusively activated by designer drugs
- knee AAV = injection transduces functional GiDREADD into DRG
- C21 reverses CFA-induced reduction in AP threshold
