The contribution of AMPA receptors to neuropathic pain

Neuropathic pain is defined as pain arising as a result of damage to or dysfunction of the nervous system and is often resistant to opiate analgesics, making it difficult to treat using conventional therapies. Underlying the development of this chronic pathological pain state is a process of neuronal plasticity termed central sensitisation, involving changes from the spinal to the cortical levels of the central nervous system. Central sensitisation may result in thermal hyperalgesia and mechanical and cold allodynia which are commonly found in this condition. Neurons in the dorsal horn undergo plastic changes during central sensitisation, markedly altering their response profile to sensory stimulation. Glutamate is the major excitatory neurotransmitter at synapses between primary afferents and spinal dorsal horn neurons and plays a vital role in the generation of neuronal plasticity. Several key receptors are involved in altering the sensitivity of these neurons, including ionotropic and metabotropic glutamate receptors and peptidergic receptors.

This study was designed to investigate the role of AMPA, NMDA, mGlu group I and VPAC₂ receptors (Rs) in the generation of neuropathic pain. Firstly, the behavioural reflex responses of naive rats to intrathecal administration of low doses of these receptor agonists, singly or in combinations were investigated. Combinations of two or more agonists caused increased behavioural responses to thermal and mechanical stimuli. The combination of AMPA with mGluR group I and VPAC₂ R agonists, showed a synergistic effect whereas other combinations were less than additive

Expression of AMPA R GluRl and GluR2 subunits in the superficial dorsal horn was studied using confocal immunofluorescence. In the chronic constriction injury (CCI) model of neuropathic pain both the number of GluRl-immunopositive cell bodies and the level of GluRl expression within cells decreased significantly in lamina II of the dorsal horn, ipsilateral to the injury. In contrast, there was no change in GluR2 expression or the degree of colocalisation of GluRl and GluR2 subtypes within individual cells following CCI.

The subcellular distribution of GluRl subunits was also noted to change significantly as a result of CCI. GluRl subunits were found to redistribute distally into neuronal processes in lamina II cells ipsilateral to CCI and also in response to acute intrathecal AMPA treatment. This redistribution may reflect an increase in the number of GluRl-containing receptors associated with synaptic sites.

The relationship between the presynaptic marker protein, Bassoon and GluRl - immunopositive cells was investigated, showing a significant increase in the number of Bassoon immunopositive puncta associated with each GluRl-immunopositive cell ipsilateral to nerve injury. The subcellular redistribution of GluRl subunits caused by CCI was reversed upon behavioural recovery and also by intrathecal administration of a combination of antagonists to NMDA R, mGluRl/5 and VPAC₂ R, whereas an AMPA R antagonist alone had no effect.

These results suggest that AMPA Rs are important in the central sensitisation underlying neuropathic pain. However, it is clear that several receptors are involved in triggering maximal behavioural responses, and potential therapeutic interventions may be more effective if designed to target more than one receptor type. There is also evidence to suggest that AMPA Rs may have differing roles dependant upon their subtype composition, so subtype-specific antagonists may potentially be useful in treatment of neuropathic pain.