Screening of Drugs for Peripheral Neuropathy

Screening of Drugs for Peripheral Neuropathy

1. Definition, rationale & scope of the screen

• Neuropathic pain is defined in the assay literature as a complex chronic disorder in which the nerve itself is the source of pain: injured, damaged or dysfunctional nerve fibres send incorrect signals to pain centres, and the injury changes the nerve both at the lesion site and in surrounding territory (Vogel 4e V2, Part VIII "Neuropathic Pain", p.1838).
• Neuropathy is the broader syndrome — a disorder/dysfunction of peripheral nerves involving sensory, motor and autonomic fibre derangements; not all neuropathies are painful (numbness/paraesthesia, weakness/paralysis, gastric dysfunction are alternative manifestations) (Vogel 4e V2, Part VIII, p.1838).
• Purpose of the screen: to reproduce, in rodents, the cardinal sensory signs of human peripheral neuropathy — spontaneous burning pain, hyperalgesia, and allodynia — so that candidate analgesic/neuroprotective drugs can be tested against a validated behavioural (and where possible electrophysiological) readout (Vogel 4e V2, Part VIII, "General Considerations", p.1839).
• Causalgia (spontaneous burning pain + hyperalgesia + allodynia following an incomplete peripheral nerve injury) is the human phenotype the surgical rodent models are engineered to mimic; allodynia — pain evoked by a normally innocuous stimulus — is singled out as the most troublesome and most reproducibly modelled symptom (Vogel 4e V2, Part VIII, p.1839).
• Models are classified in the source either by aetiology (painful diabetic neuropathy, post-herpetic neuralgia, post-traumatic neuralgia) or by anatomical lesion (central pain vs peripheral neuralgia) — this dual classification frames how a screen is chosen (Vogel 4e V2, Part VIII, p.1839; ref. Hansson & Dickenson 2005).
• Aetiological spectrum the models are built to represent (Vogel 4e V2, Part VIII, pp.1838–1839):
  • Infectious — post-herpetic neuralgia (varicella–zoster reactivation), leprosy, Lyme, Chagas, HIV, Guillain–Barré.
  • Metabolic — diabetic neuropathy: glycosylation end-products inhibit axonal transport and Na⁺/K⁺-ATPase → axonal degeneration; alcoholic/thiamine (B₁)-deficiency polyneuropathy (distal, longest-axon-first).
  • Toxic — chemotherapy and radiation (commonest), thallium, isoniazid, lead, arsenic.
  • Traumatic — phantom-limb pain, complex regional pain syndrome (CRPS-I = old reflex sympathetic dystrophy; CRPS-II = old causalgia).
  • Autoimmune — CIDP, vasculitic neuropathy.
  • Compressive — carpal-tunnel/entrapment → Wallerian degeneration.
  • Congenital/hereditary — Charcot–Marie–Tooth, Fabry disease, amyloidosis.