Pain consists of a sensory component (the detection and transmission of painful stimuli) and an affective component (the processing of emotional and behavioural responses). Writing in Neuron, Braz and colleagues show that different populations of nociceptors — neurons that sense painful stimuli — might engage parallel ascending pathways that target limbic (affective) and motor regions of the brain.

Nociceptors, which are located in the dorsal root ganglia and trigeminal ganglia, have a peripheral axonal branch that receives sensory information from the peripheral tissues, and a central branch that transmits signals to the spinal cord, from where they are relayed to the brain. There are two main types of nociceptor: peptidergic nociceptors, which express neuropeptides and terminate in the most superficial laminae of the dorsal horn, targeting lamina I projection neurons and interneurons of outer lamina II; and nonpeptidergic nociceptors, which target interneurons of inner lamina II.

In this study, Braz et al. looked at nonpeptidergic circuits by genetically targeting a transneuronal tract tracer, wheat germ agglutinin, to a subpopulation of nonpeptidergic nociceptors that express the tetrodotoxin-resistant sodium channel Nav1.8. They found that the major ascending circuits begin with the interneurons of inner lamina II, which are targeted by nonpeptidergic nociceptors. These interneurons are connected to lamina V projection neurons, which, in turn, target neurons in the amygdala, hypothalamus and bed nucleus of the stria terminalis — limbic regions of the brain that are also targeted by peptidergic nociceptors through a polysynaptic pathway involving the parabrachial nuclei of the dorsolateral pons.

In addition, there is a remarkably concentrated projection to the globus pallidus, an area of the brain rarely considered when discussing ascending nociceptive circuits. As the globus pallidus is involved in regulating motor functions, this newly discovered pain target might explain why noxious stimuli almost always induce changes in motor behaviours as well as evoking perception and the emotional responses of pain, which are mediated by limbic regions of the brain.

Therefore, nonpeptidergic nociceptors might give rise to a parallel, independent pain pathway that targets predominantly motor and limbic centres. It will be interesting to determine how peptidergic and nonpeptidergic circuits interact in the brain and whether they converge on the same limbic subregions.