Since the first published description of central pain, over 120 years ago,42,43
numerous hypotheses have been proposed to explain its pathophysiology.6,18,44,45
Many were disproved with time, and many remain controversial. Fortunately, despite the clinical variability in presentation and variability in size, location and causes of spinal cord injury, there is general agreement on a number of pathophysiological factors:
Many of the earliest reported cases of central pain are based on pain caused by damage or injury to the thalamus.43,46,47
As a result, thalamic abnormalities were thought to be required for development of pain and the condition was referred to for decades by the misleading term “thalamic pain”. Research since that time has established that central pain can result from damage to any structure along the afferent spinothalamocortical pathway that conveys pain and temperature information.18,48–52
This pathway includes: The spinothalamic tract (STT) in the spinal cord and brainstem; thalamic nuclei that receive STT input, including the posterior thalamus (PO), the mediodorsal thalamus (MD) and the ventroposterior complex (VP); the internal capsule; and cortical areas such as the primary (S1) and second (S2) somatosensory cortices.53,54
Damage to the spinothalamocortical pathway is, in fact, necessary for central pain development. There are no documented cases of pain resulting from central nervous system lesions that spare it, such as lesions involving only the dorsal column-medial lemniscal pathway.44
Consistent with an obligatory role for the STT is the finding that essentially all central pain patients have altered pain and temperature sensation, while abnormalities of tactile sensation occur in only a subset of patients.18,49,55
Unfortunately, the consensus appears to end there as there are several hypotheses regarding the mechanisms of central pain.
Most of our knowledge regarding molecular, cellular and physiological changes following spinal cord injury comes from studies performed in animal models of spinal cord injury pain. Hyperalgesia and pain following spinal cord injury can result from maladaptive plastic changes throughout the neural axis. In the spinal cord there are massive changes following injury that include: Ischemia, necrosis, deafferentation, re-organization and sprouting in primary afferents, the activation of astrocytes and glia and the release of inflammatory mediators and neurotoxic excitatory amino acids in the extracellular space.35,56–58
These changes have far reaching consequences that compromise the normal function of not only the surrounding local neurons but also their distant targets within the central nervous system. Indeed, the delayed onset of pain and the diffuse localization of painful symptoms suggest that the pathophysiology does not reflect only direct effects at the denervated spinal segments. Rather, these features strongly suggest the occurrence of maladaptive plasticity in supraspinal structures at which inputs from various body parts converge. Consistent with this notion, it has been shown repeatedly that spinal cord injury is associated with increased activity, increased spike bursts and changes in glial activation in the thalamus.40,59–61
However, the mechanism by which these central maladaptive changes occur requires more study.
One hypothesis that remains in favor, almost a century since it was first formulated, is that central pain results from abnormally suppressed inhibition in the thalamus47
however, the site of operation of this dis-inhibition remains unknown.18,44
For example, it has been argued that the medial lemniscal pathway normally inhibits the spinothalamic system, and that this inhibition is suppressed in central pain. It has been proposed that either descending cortical inputs or ascending spinal inputs to the thalamus are involved in this dis-inhibition.47,62
A more recent elaboration of the Head and Holmes hypothesis47
posits that the disinhibition results from a loss of the discriminative thermosensory representation in the central nervous system.63 This “thermosensory disinhibition hypothesis” assumes that pain is relayed from the spinal cord through independent thalamic pain/temperature nuclei that serve as specific relays in the ascending pain system. However, this viewpoint is controversial and remains unresolved.
Loss of inhibition has also been implicated in the pathogenesis of central pain and is thought to alter the firing properties of thalamic neurons, rendering them more likely to produce spontaneous and evoked bursts of action potentials.64,65
However, some have argued that the incidence and properties of these bursts in central pain do not differ significantly than in controls.66
In sum, remaining unknown are the mechanisms for the engagement of inhibition, the source of this inhibition, and the specific nuclei affected.