Neuropathic pain Flashcards
(18 cards)
Neuropathic pain
- pain generated by nerves
- positive symptoms = paraesthesia, allodynia, hyperalgesia and spontaneous pain
- negative symptoms = hyperaesthesia and numbness
- peripheral neuropathic pain is driven by peripheral nerve damage
- central neuropathic pain results from spinal damage (e.g. stroke)
Animal models of neuropathic pain
animal models target the sciatic nerve
1. SNL = spinal nerve lesion
2. CCI = chronic constriction injury
3. PSNI = partial sciatic nerve injury
4. SNI = spared nerve injury
more clinically relevant models
- streptozotocin - model for diabetic neuropathy
- oxaliplatin - model for chemotherapy-induced neuropathy
Mechanisms underlying neuropathic pain
- when a nerve trunk is injured, some of the axons undergo anterograde degeneration
- axons are exposed to the degeneration products
- degeneration evokes an inflammatory response, immune cells infiltrate and proinflammatory mediators are released
- trafficking of ion channels/receptors in injured axon
- disrupted = leads to accumulation at atypical sites
- non-injured axons have increased availability of neurotrophins - impacts expression profile
Spontaneous firing underlying neuropathic pain
- Navs in nociceptors alone do not appear to drive spontaneous firing
- both Nav1.7 and 1.8 KO mice in DRG develop neuropathic pain
- no role of Nav1.7 in oxaliplatin-induced neuropathy
- Nav1.6 appears to be important in neuropathy
- TTX/Nav1.6 inhibition = relief from allodynia
- HCN is pivotal for spontaneous firing
- activating cAMP signalling generates repetitive firing, like in neuropathic pain
- in neuropathic pain model, HCN2 deletion in Nav1.8 neurones = symptomatic relief
Ivabradine
- trial in neuropathic pain patients
- showed relationship between dose and pain score
- highest in diabetic neuropathy
- larger trials and HCN2 selective agonists needed
Neuropathic pain and TrkB
- TrkB is expressed by mechanoreceptors
- ablating TrkB positive neurones specifically decreases light touch response
- reduces neuropathic pain but not inflammatory
- suggests TrkB positive neurones have a role in neuropathic pain
- optical stimulation of TrkB positive neurones triggers neuropathic pain
- photoablation of TrkB positive neurones decreases variety of pain phenotypes
Sensitisation
- peripheral sensitisation of nociceptor channels
- central sensitisation = processes in spinal cord produce enhancement of function of nociceptive neurones and circuits
- in neuropathic pain, reversal potential of GABA-evoked currents shifts in the depolarising direction
- normally, GABA evokes hyperpolarisation, via a chloride influx due to low intracellular calcium levels
- low calcium is maintained by NKCC2 and KCC2
Sensitisation - KCC2
- KCC2 levels are reduced in neuropathic pain
- KCC2 knockdown induces pain
so, in pain:
- KCC2 levels change
- disrupts calcium homeostasis
- GABA becomes excitatory
- pain circuitry switched on
Sensitisation - BDNF and microglia
- injury activates spinal cord microglia and proliferation
- evokes pain
- BDNF causes allodynia, GABA-mediated excitation and downregulation of KCC2
so:
- activated microglia release BDNF
- BDNF downregulates KCC2
- disinhibition of GABAergic pathways
KCC2 as an analgesic target
- CLP25 rescues KCC2 expression
- KCC2 remains in membrane
- GABA continues to be inhibitory
Sex-dependent role of microglia
- inhibition of microglia-P2X4-BDNF pathway only alleviates pain in males
- BDNF decreases KC22 expression in human males but not females
- KCC2 decreased in both males and females during neuropathic pain
- so is a possible therapeutic target in both sexes
- but microglia-P2X4-BDNF pathway is only present in males
Pharmacological therapies
- gabapentin
- carbamazepine
- oxcarbazepine
- SNRIs and TCAs
- opioids
- topical agents e.g. lidocaine, capsaicin
Pharmacological therapies - carbamazepine
- Nav blocker
- use-dependent
- blocks spontaneous firing
- side effects: ataxia, hepatic enzyme induction
Pharmacological therapies - oxcarbazepine
- maintained efficacy but reduced side effects compared to carbamazepine
- raised Nav1.1 in trigeminal neuralgia so used for this over other forms of neuropathic pain
Pharmacological therapies - SNRIs and TCAs
- block NA and 5-HT reuptake
- boost descending modulatory pain pathway
- amitriptyline had efficacy
- side effects include blurred vision and arrhythmias
Pharmacological therapies - opioids
- for some forms of neuropathic pain
- 4 receptors - mu, kappa, delta or ORI (Gi/o)
- beta-gamma interact with GIRKs to increase hyperpolarisation
- and Cavs to decrease neurotransmitter release
- inhibition of adenylyl cyclase
Pharmacological therapies - topical agents
- e.g. lidocaine (Nav blocker) and capsaicin (nociceptor dysfunctionalisation)
- patches or creams
- massive calcium entry
- depolarisation block of Navs
- depolymerisation of cytoskeleton
- dysfunctional mitochondria
- nociceptor degeneration
Future therapies
- TRPV1 has a large pore
- opening allows QX314 entry into TRPV1 positive fibres
- i.e. nociceptor-specific anaesthesia
- but still get burn!
- or selective Nav inhibitors - approved Jan 2025
