Neuropathic Pain After Spinal Cord Injury: Challenges and Research Perspectives

Abstract

Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that remains difficult to treat because underlying mechanisms are not yet fully understood. In part, this is due to limitations of evaluating neuropathic pain in animal models in general, and SCI rodents in particular. Though pain in patients is primarily spontaneous, with relatively few patients experiencing evoked pains, animal models of SCI pain have primarily relied upon evoked withdrawals. Greater use of operant tasks for evaluation of the affective dimension of pain in rodents is needed, but these tests have their own limitations such that additional studies of the relationship between evoked withdrawals and operant outcomes are recommended. In preclinical SCI models, enhanced reflex withdrawal or pain responses can arise from pathological changes that occur at any point along the sensory neuraxis. Use of quantitative sensory testing for identification of optimal treatment approach may yield improved identification of treatment options and clinical trial design. Additionally, a better understanding of the differences between mechanisms contributing to at- versus below-level neuropathic pain and neuropathic pain versus spasticity may shed insights into novel treatment options. Finally, the role of patient characteristics such as age and sex in pathogenesis of neuropathic SCI pain remains to be addressed.

Keywords: Operant tests; animal models; glia.; quantitative sensory testing; spinal disinhibition.

Fig. 1

Operant conditioning tests for evaluation of SCI pain. (A) Place-escape avoidance paradigm (PEAP) pits aversion to light against aversion to a putatively noxious stimulus such as tactile, cold, or heat. In this test, the painful stimulus is presented in (for mechanical stimuli) or makes up the flooring of (for thermal stimuli) only the dark side of the chamber, whereas in the light chamber the stimulus is applied to a potentially nonpainful body region or not at all. (B) Increased time spent in the light side of the chamber is indicative of aversion to the sensory stimulus, suggesting that the rat perceived it as being painful [33]. (C) In the Mechanical Conflict Avoidance System, a light chamber is connected to a dark chamber by noxious flooring consisting of spikes that can be raised to different heights. When the light is turned on, the rat crosses the floor to reach the dark chamber. Rats with pain exhibit a longer latency to exit the light chamber and begin crossing the noxious flooring [35]. (D) Conditioned place preference (CPP) testing can also use a light/dark chamber setup [42], or two neutrally lit chambers with distinctive flooring and walls [36]. In conditioning trials, the dark side of the chamber is paired with vehicle administration, whereas the light side of the chamber is paired with administration of a drug that may alleviate pain. Chamber preference is evaluated during a subsequent session when the drug is not administered. (E) Increased time spent in the light side of the chamber indicates that the subject experienced pain relief in response to drug administration

Fig. 2

Reactive astrogliosis contributes to SCI pain. (A) Astrocytes at and below the lesion level upregulate expression of GFAP and p-p38 MAPK, indicators of reactive gliosis [ , , 62, 101, 103, 104]. (B) Concomitant increases in the astrocyte-specific gap junction protein, connexin-43 (CX-43), could increase connectivity between adjacent astrocytes [37]. (C) Reduced expression of glutamate transporter, GLT-1 [105], would be expected to lead to decreased reuptake of glutamate. (D) Increased upregulation of aquaporin-4 (AQP4) is observed for up to 9 months, but only in rats that develop below-level hypersensitivity [101]. AQP4 is a water transport channel predominantly found in astrocytic foot processes that regulate the blood–brain barrier and may mediate pain behavior by causing astrocyte swelling that results in glutamate release [106]

Fig. 3

KCC2 downregulation in the dorsal versus ventral spinal cord has different behavioral outcomes. Under normal conditions, expression of KCC2 on dorsal horn and motor neurons maintains the neuronal chloride gradient such that activation of ionotropic GABA_A receptors results in neuronal inhibition (Sham). Reduction or loss of KCC2 expression leads to a build-up of intraneuronal chloride that reduces the inhibitory potential of GABA_A receptors [116]. Selective loss of KCC2 in dorsal horn neurons results in disinhibition of sensory neurons that contributes to ongoing SCI pain by enhancing spinal responses to peripheral inputs (SCI Pain) [115]. Selective loss of KCC2 in the ventral horn results in disinhibition of motor neurons that can cause amplification of spinal reflex responses and spasticity (Spasticity) [117, 118]. If global changes in KCC2 expression occur following SCI, both neuropathic pain and spasticity could develop