Beyond pain in the brain: A clinician’s guide to interpreting the spinal cord’s role in the pain experience

Abstract

Introduction:

Physical therapy practice has greatly improved in providing a biopsychosocial approach when considering persistent pain. However, the spinal cord is often overlooked as a structure with an important role in modulating nociceptive information.

Purpose:

This article highlights the role of the dorsal horn (DH) in nociceptive processing and its impact on persistent pain conditions as they appear clinically. Key processes occurring in the spinal cord are described, including cellular changes and local spinal network responses to nociceptive stimuli. Additionally, associated clinical symptoms are discussed and some aspects of physical therapy evaluation are challenged based on the mechanisms of nociceptive processing presented in this commentary.

Implications:

The spinal cord is an active participant in nociceptive processing, directly impacting the intensity, spread, and recurrence of pain, including within the context of central sensitization. Changes in the behavior of DH neurons are possible with sufficient stimulation and may occur after injury. Additionally, spinal cord activation patterns may lead to bilateral symptoms given adequate strength and duration despite a single peripheral driver. Viewing the spinal cord as a dynamic structure capable of up or down regulating its response to stimuli gives the clinician a better understanding of the nervous system’s complex response to prolonged nociceptive input.

Integrating psychological and social factors when considering a patient’s pain experience has led to improved outcomes for those with chronic pain conditions. The success of treatments such as Acceptance and Commitment therapy (Gilpin et al., 2017) and Graded Motor Imagery (Moseley et al., 2004) have inspired the phrase “pain is in the brain.” While this statement is technically true - one needs a brain to experience pain - it is a limited perspective overlooking the many contributors to the pain experience within the nervous system.

This commentary will introduce the role of the spinal cord dorsal horn (DH) in nociceptive processing within the broader central nervous system. Appreciating the role of the spinal cord beyond mechanical considerations, such as nerve root compression or disc herniation, is vital to understanding how nociceptive signals from the periphery are processed and how they impact the pain experience. While modulation of nociceptive stimuli occurs at all levels of the nervous system from periphery to brain, this paper emphasizes the contributions of the spinal DH. Evidence of cellular mechanisms from animal studies, spinal cord imaging, and clinical symptom presentation in humans are provided.

1. Why do some patients experience greater than expected pain?

Pain that is disproportionate to a causative stimulus is likely due to central sensitization (Nijs et al., 2021). The International Association for the Study of Pain defines central sensitization as “increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.” (IASP, 2022) This response often leads to diffuse pain symptoms and may be suspected when a patient is experiencing symptoms beyond what may be expected based on tissue injury. Broad symptoms like sensitivity to light, sleep disturbances, and gastrointestinal disturbances may also be experienced (Mayer et al., 2011). While signal amplification and sensitization of the central nervous system is a normal response to an acute injury (Woolf, 1983), these phenomena may persist and become maladaptive.

Central sensitization can occur alongside many neuromuscular and musculoskeletal conditions including both those related to nerve injury (i.e. neuropathic pain) such as thoracic outlet syndrome, whiplash, or carpal tunnel syndrome (Zanette et al., 2010) and those which are primarily considered nociceptive in nature, such as osteoarthritis (Martinez et al., 2007) and lateral epicondylitis (Coombes et al., 2012).

Central sensitization increases the excitability and receptive field size of neurons in the DH, resulting in an amplification of the information these neurons receive from the peripheral nerves (Fig. 1). Excitability changes may be caused by repeated, low-level stimulation as occurs due to post-injury inflammation (Ikeda et al., 2006) or by a brief, intense noxious stimulus like a surgical incision (von Hehn et al., 2012). In a rat model of whiplash, the firing rate and duration of spinal DH neurons increased after injury (Quinn et al., 2010), consistent with increased pain reports and lower pain thresholds in patients with signs of central sensitization.

Fig. 1.

Sensory signals are relayed from the periphery to the spinal dorsal horn. The above image represents a transverse view of a rat spinal cord. The area has been treated in a way that labels neurons. The most superficial layers (top) are densely packed with neurons and thought to be the site where nociceptive signal from the periphery enter the dorsal horn. Reproduced with permission from Todd. Nat Rev Neurosci, 2010.

Receptive field changes in spinal DH neurons during central sensitization are possible because of redundancy in their circuits, allowing the number of peripheral neurons from which a single spinal DH neuron collects information to increase with sensitization (Coghill, 2020; Mendell, 1966). When individuals with complete spinal cord injury were exposed to a neural irritant, the area of the foot eliciting a reflexive withdrawal response increased, illustrating how DH neurons may adjust their receptive fields to become more sensitive to nociceptive stimuli even without input from the brain (Biurrun Manresa et al., 2014). This modulation of the receptive field may explain why patients with central sensitization sometimes experience sensitivity extending beyond the area of affected tissue. However, it is important to note that while changes within the DH play an important role in central sensitization, amplification of nociceptive signal also occurs due to changes at multiple levels of the nervous system, including the brain(van Ettinger-Veenstra et al., 2019), brainstem (Zambreanu et al., 2005), dorsal root ganglion (Yu et al., 2020), and the injury site (Woolf, 1983).

2. Why do some patients with chronic pain struggle to describe the location of their symptoms?

Redundancy of circuits within the DH allow spinal responses to change based on intensity or duration of the stimulus or sensitivity of the nervous system (Bosma et al., 2015, 2016; Rempe et al., 2014, 2015; Weber et al., 2016), potentially resulting in diffuse symptoms. This is an example of convergence, which is present throughout the central nervous system, and allows for complex sensory processing and integration, as well as the ability for the nervous system to up or down regulate its response to nociceptive stimuli (Schaible et al., 1987).

One consequence of redundancy within the spinal cord is the ability to recruit multiple spinal segments in response to strong or repeated stimulation. Local spinal cord tracts connect DHs of adjacent spinal segments and contralateral DHs within the same segment (Petkó and Antal, 2000). These tracts are composed of inhibitory or excitatory interneurons (Todd, 2010) and receive information directly from neurons in the periphery, allowing activity of a single peripheral neuron to amplify or reduce responses of many DH neurons, even when outside the DH neuron’s receptive field (Coghill, 2020). These connections allow the spinal cord to engage more neurons over multiple spinal segments in response to more intense or repeated stimuli, known as synaptic scaling.^.28

Functional MRI studies of the spinal cord illustrate scaling by correlating increases in spinal cord activity with increased thermal stimulation temperature (Bosma et al., 2015, 2016; Rempe et al., 2014, 2015; Weber et al., 2016). Results of these studies show the amount of activation within the segment of the stimulated dermatome increasing as thermal stimuli become more extreme. The number of segments showing activation in response to the thermal stimulus also increased with the stimulus intensity (Fig. 2). This pattern was seen after both innocuous and noxious stimuli, with noxious stimuli showing greater total activation (Bosma et al., 2015, 2016; Rempe et al., 2014, 2015; Weber et al., 2016). In addition, noxious stimuli caused bilateral activations in the segment corresponding to the stimulated dermatome (Rempe et al., 2015; Weber et al., 2016).

Fig. 2.

Functional MRI of the human cervical spinal cord in response to (A) warm and (B) painful thermal stimuli given on the lateral ventral region of the right proximal forearm. Note the increase in number of segments showing increased activation in response to painful as opposed to innocuous stimuli. (C) Shows the coordinates of the coronal, sagittal and axial slices and labeled vertebrae. Reproduced with permission from Weber et al., NeuroImage, 2016.

Temporal summation occurs when an identical stimulus evokes greater pain when repeated (Price, 1972). At the cellular level, this phenomenon can be explained by sensitization of DH neurons through NMDA-mediated activation of voltage-gated channels, which increase the likelihood of the cell to fire again (Gu et al., 2009). At a neural population level, functional MRI studies of the spinal cord have revealed a scaling response resulting in an increase in the number of spinal cord segments activated along with increases in reported pain intensity (Bosma et al., 2015, 2016). This shows repeated stimulation can change the number of neurons activated in response to each stimulus as well.

Neuropathic pain also appears to cause a scaling response within the spinal cord. The area of activation within the spinal cord measured with functional MRI increased after simulated nerve pain (Rempe et al., 2014, 2015), consistent with findings from animal studies assessing cellular changes occurring during central sensitization (Quinn et al., 2010). This suggests that the number of spinal cord segments activating in response to a stimulus may increase in the presence of central sensitization.

Technology allowing researchers to directly link spinal cord neural activity with subjective perception of pain is not currently available; however, some inferences can be made from a study of patients with carpal tunnel syndrome. Even with electrodiagnostic findings consistent with median nerve compression only, one third of patients experienced symptoms beyond the expected median nerve distribution. Such symptoms were correlated with changes in pain threshold and temporal summation consistent with central sensitization (Zanette et al., 2010). Significant overlap of symptom distribution is also seen when comparing patients with C6 and C7 nerve root impingement (Rainville et al., 2016). These symptoms are likely not due to changes in spinal cord activation alone, but the patterns are consistent with the functional MRI studies cited above.

Results of functional MRI studies also suggest the possibility of bilateral spinal cord activation in response to a unilateral peripheral input given adequate time and stimulus intensity. One example is the bilateral symptoms and multiple limb involvement in almost half of all patients with Complex Regional Pain Syndrome (van Rijn et al., 2011). Similarly, bilateral motor changes can occur in carpal tunnel syndrome without bilateral change in electrodiagnostic results (Fernández-de-Las-Penãs et al., 2020). Determining the source of symptoms can therefore be challenging when relying on distribution alone, as the painful area may appear to span multiple nerve distributions or be present bilaterally, even if the original pain generator or injury did not.

3. Why does diagnostic imaging often not match pain symptoms?

Current diagnostic imaging cannot capture changes in spinal cord stimulus processing because many of these mechanisms occur on a cellular level. In addition to neuron behavior changes mentioned above, changes in circuity of the DH after repeated nociceptive input may also impact the pain experience.

The DH relies on inhibitory control from interneurons to downscale noxious information (Kuner and Flor, 2017). However, animal models of prolonged neuropathic pain show that activation of these interneurons through repeated stimulation by primary afferent neurons can cause them to die (Inquimbert et al., 2018). Additionally, persistent stimulation may cause peripheral neurons normally conveying light touch to instead relay noxious information by creating synapses with nociceptive DH neurons (Todd, 2010; Zhu et al., 2018) or change their chemical signature to resemble nociceptive neurons (Waller et al., 2016).

It is possible that cellular changes within the DH prime the DH to receive nociceptive information. Both interneuron death and changes to normally non-nociceptive neurons could amplify the nociceptive signal at the DH and increase the amount of nociceptive signal ultimately relayed to the brain. It would then stand to follow that a person with these changes would be more likely to experience recurrent pain. While the recurrent nature of some orthopedic conditions such as low back pain (Machado et al., 2017) seems to be consistent with this idea, there are no studies examining this in humans,so while this relationship is possible, it is not proven.

4. How do processes in the spinal DH affect clinical practice?

The processes outlined in this commentary highlight serious limitations in the way musculoskeletal pain sources are often diagnosed and treated.

The utility of dermatomal distributions in determining symptom origin is challenged by the dynamic way spinal activation may fluctuate depending on stimulus intensity, prior stimulation, and the presence and extent of central sensitization (Bosma et al., 2015, 2016; Rempe et al., 2014, 2015; Weber et al., 2016). Pain location may indicate how much the nervous system has changed in response to noxious stimuli rather than what peripheral nerves or spinal nerve roots are injured and may explain the variance in many dermatomal maps (Lee et al., 2008).

To determine specific changes in sensation or sensitivity to noxious stimuli, Quantitative Sensory Testing (QST), which tests single aspects of sensation, may be used. Mechanical pain threshold and pressure pain threshold are easily assessed using weighted filaments or a pressure algometer, respectively (Rolke et al., 2006). QST also assesses the presence of temporal summation (Rolke et al., 2006; Waller et al., 2016). These values can be compared to age-based norms or measured over time to track progress (Rolke et al., 2006; Waller et al., 2016) and may help determine if a patient is experiencing secondary hyperalgesia to give an estimate of amplification occurring in the central nervous system. While this testing cannot isolate the specific location of signal amplification, the information gained from these tests may still guide treatment by quantifying sensory changes (Rolke et al., 2006).

Bilateral DH activation in response to noxious input (Rempe et al., 2015; Weber et al., 2016) creates a possible explanation for some bilateral symptoms. As input to the DH increases and is maintained over time, the bilateral DH activation may create a bilateral symptom presentation. Thus, if a unilateral stimulus was of adequate intensity or persisted long enough, functional changes within the spinal cord DH due to that specific stimulus could lead to the experience of bilateral pain. This is of direct relevance to physical therapy treatment. Bilateral symptoms could be a result of a single peripheral driver and require addressing this driver to improve.

Summary

The spinal cord is a key player in the dynamic response of the nervous system to nociceptive input and deserves to be considered within the pain experience beyond concepts of facet joint irritation or disc herniation. Understanding of how the spinal cord contributes to nociceptive processing allows a therapist to view their patient’s symptoms in the context of the nervous system’s multi-level nociceptive processing and fully appreciate the limitations of diagnostic techniques often used in the clinic. Of specific importance are the diagnostic limitations of dermatomal testing and the outdated belief that all bilateral symptoms must be addressed with interventions aimed at the spine to improve if they are mediated by the nervous system.

While all aspects of the Biopsychosocial Pain Model should be considered, biological factors considered during evaluation must include nervous system changes leading to or resulting from persistent pain, including those at the spinal DH. Understanding the mechanisms contributing to pain can help clinicians better understand their patients’ experience by moving beyond “pain is in the brain” and including the entire nervous system in pain neuroscience.