Parallel "pain" pathways arise from subpopulations of primary afferent nociceptor

A major unanswered question concerning "pain" circuitry is the extent to which different populations of primary afferent nociceptor engage the same or different ascending pathways. In the present study, we followed the transneuronal transport of a genetically expressed lectin tracer, wheat germ agglutinin, in Na(V)1.8-expressing nociceptors of the nonpeptide class. We found that interneurons of lamina II are at the origin of the major ascending circuits targeted by the nonpeptide nociceptors. These interneurons contact lamina V projection neurons, which in turn predominantly target fourth-order neurons in the amygdala, hypothalamus, bed nucleus of the stria terminalis, and to a remarkable extent, the globus pallidus. These circuits differ greatly from the lamina I-based projection that is targeted by the peptide class of nociceptors. Our results indicate that parallel, perhaps independent pain pathways arise from different nociceptor classes and that motor as well as limbic targets predominate in the circuits that originate from the nonpeptide population.