Abstract
Blockade of Ca2+-permeable AMPA receptors in the rat spinal cord diminishes the development of hyperalgesia and allodynia associated with peripheral injury. Cobalt uptake studies reveal that Ca2+-permeable AMPA receptors are expressed by some substance P receptor-expressing (NK1R+) neurons in lamina I, as well as other neurons throughout the superficial dorsal horn. Selective elimination of NK1R+ neurons in lamina I and lamina III/IV of the dorsal horn also suppresses development of hyperalgesia and allodynia. These observations raise the possibility that Ca2+-permeable AMPA receptors contribute to excitatory synaptic drive onto the NK1R+ neurons associated with allodynia and hyperalgesia. The first synapse in the pain pathway is the glutamatergic excitatory drive from the primary afferent fibres onto dorsal horn neurons. Therefore, we tested whether Ca2+-permeable AMPA receptors are located on lamina I and lamina III/IV NK1R+ neurons postsynaptic to primary afferent fibres, using inward rectification and polyamine toxins for receptor identification. We examined three different populations of dorsal horn neurons; lamina I NK1R+ neurons, including projection neurons, and non-NK1R+ (NK1R-) neurons including interneurons, and lamina III/IV NK1R+ neurons, believed to contribute to the low-threshold mechanosensory pathway. The majority of synapses in all three groups had rectification indices less than 1.0 and greater than 0.4, indicating that the AMPA receptors at these synapses are a mixture of Ca2+-permeable and -impermeable forms. Lamina III/IV NK1R+ neurons and lamina I NK1R- neurons have a significantly higher proportion of postsynaptic Ca2+-permeable AMPA receptors than lamina I NK1R+ neurons. Thus synaptically positioned Ca2+-permeable AMPA receptors directly contribute to low-threshold sensory afferent drive into the dorsal horn, and can mediate afferent input onto interneurons such as GABAergic neurons. These receptors also contribute to high-threshold primary afferent drive onto NK1R+ neurons in the superficial dorsal horn, but do so less consistently.