Mechanisms involved in chronic neuropathic pain after avulsion injury

Abstract

Motor vehicle accidents are the most common cause of injuries involving avulsion of spinal roots from the brachial or lumbosacral plexuses. This results in chronic intractable pain that is refractory to pharmacotherapy. This is largely due to lack of information on underlying mechanisms, and lack of an established animal model to test drug treatments. This thesis has: 1) compared the neuroanatomical effects of dorsal root rhizotomy (DRR) and avulsion (DRA) in the spinal cord. DRR is commonly used to model avulsion injury but unlike avulsion it does not damage the spinal cord, as often happens clinically. 2) Developed a behavioural model of spinal root avulsion injury (SRA). 3) Evaluated the behavioural effects of drugs prescribed to treat neuropathic pain or those used clinically to treat other conditions like motoneuron disease or spinal cord injury. DRA produced a greater and prolonged glial, inflammatory, vascular response and cell loss than DRR. SRA produced thermal and mechanical hypersensitivity in the affected hind-paw. Neurodegenerative and neuroinflammatory responses were observed in both the avulsed and adjacent spinal segments, but produced no changes in the neuronal phenotype adjacent dorsal root ganglion neurons, suggesting that the evoked behaviour is mediated by central mechanisms. Administration of amitriptyline or carbamazepine reduced behavioural hypersensitivity in SRA, confirming their limited clinical efficacy in treatment of avulsion injury. Minocycline and riluzole produced therapeutic efficacy. Both compounds prevented the establishment of behavioural hypersensitivity, which correlated histologically with microglial inhibition, although riluzole was transiently effective. Additionally, minocycline reversed the hypersensitivity, an effect that persisted beyond drug washout, whereas riluzole had a limited effect that only lasted whilst the drug was administered. This thesis provides insight into the mechanisms of avulsion-induced neuropathic pain. The establishment of a behaviourally reproducible avulsion model provides a platform to test new pharmacological candidates for treatment, such as minocycline.