The distributed nociceptive system: a novel framework for understanding pain

Despite early apparent successes [1], the identification of brain mechanisms supporting the experience of pain has remained elusive. Recent fMRI studies of very large numbers of participants readily find activation related to nociceptive processing, but either find no or, at best, a minimal amount of activity related to a given individual’s experience of pain [2, 3]. These neuroimaging findings raise serious questions about our current conceptual approach towards understanding pain.

Current approaches, derived from the investigation of single neurons, single molecules, or single brain regions, have provided only limited explanations for the complex symptoms of pain and have been unfortunately ineffective in the development of new treatments. However, decades of pain research, bolstered by these emerging neuroimaging findings, suggest an alternative framework – that pain emerges from highly distributed activity of populations of neurons.

This new framework – The Distributed Nociceptive System [4] – combines two largely neglected elements: (1) the combined action of populations of neurons serves to encode nociceptive information [5] and (2) the processing of nociceptive information occurs in a highly distributed fashion [6]. The central principle of this framework is that the extraction and use of nociceptive information can be accomplished separately by multiple regions within the central nervous system.

Within the spinal cord, nociceptive processing is distributed across multiple laminae. Lamina I, lamina V & VI, lamina VII, and lamina X all contain nociceptive neurons with ascending projections. In these spinal cord regions, there are two different types of nociceptive neurons – nociceptive specific (NS) neurons and wide dynamic range (WDR) neurons. NS neurons largely respond to clearly noxious stimuli, while WDR neurons respond vigorously to both noxious and innocuous stimuli. The contribution of WDR neurons to pain has remained controversial, in part, because the responses of individual neurons have been viewed in isolation from the population of neurons activated by a given stimulus. However, thinking about how populations of these neurons respond to noxious input is critical for understanding their contribution to pain [5]. The receptive fields (RF) of WDR neurons have a complex center-surround organization. The central RF zone is relatively small while the surround RF zone is considerably larger. Both noxious and innocuous stimuli applied to the central RF zone can elicit vigorous activity within the neuron, while progressively more intense noxious stimuli are needed to elicit neural activity as the site of stimulation moves towards the outer boundaries of the peripheral RF zone. Given this considerable overlap of peripheral RF zones across populations of neurons, a mildly noxious stimulus would activate a relatively small number of neurons, while an intensely noxious stimulus would recruit considerably greater numbers of neurons. This progressive recruitment of neurons can provide a potential explanation for both spatial spread and spatial summation of pain. Spatial spread of pain may arise with intense (or pathological) input as neurons that are remote from the somatotopic epicenter of stimulation are progressively recruited. Spatial summation of pain may arise when overlapping populations of neurons are recruited by spatially separated noxious stimuli.

Within the brain, neuroimaging studies have identified numerous regions that are both activated by noxious stimuli and exhibit responses that are graded in response to noxious stimulus intensity [7]. Such regions include the primary somatosensory cortex (SI), secondary somatosensory cortex (SII), anterior cingulate cortex (ACC), posterior insular cortex, and anterior insular cortex. Of these cerebral cortical regions, all receive input in a highly parallel fashion and are just one synapse away from spinal nociceptive input, with synapses in the thalamus or amygdala [8].

Studies of patients with lesions of these areas confirm that the processing of nociceptive input and the generation of an experience of pain is accomplished in a highly distributed fashion. Lesions of SI, SII, ACC, or the insula fail to abolish the experience of pain [4, 9]. Moreover, even the removal of an entire cerebral hemisphere fails to abolish the experience of pain arising from a stimulus contralateral to the absent hemisphere [10].

The highly distributed processing of nociceptive information both within the spinal cord and within the brain poses major challenges for the treatment of pain. The distributed nociceptive system is highly resilient and can clearly instantiate an experience of pain in the presence of substantial injury (or inactivation). Consistent with this resiliency, focal pharmacologic therapies have remarkably limited efficacy. For example, the most widely used drugs for treating neuropathic pain, such as gabapentin and pregabalin, require that more than 5 people are treated in order achieve a meaningful reduction in pain in one [11].

Since pain is a distributed problem, it requires a distributed solution. Multidisciplinary therapies combining pharmacological, physical, and psychological modalities of treatment are needed to simultaneously reduce pain-related activity across the distributed nociceptive system [12, 13].