pain syndrome (CPS) is a debilitating condition that affects a large number of patients with a primary lesion or dysfunction in the CNS. Despite its discovery over a century ago, the pathophysiological processes underlying the development and maintenance of CPS are poorly understood. We recently demonstrated that activity in the posterior thalamus (PO) is tightly regulated by inhibitory inputs from zona incerta (ZI). Here we test the hypothesis that CPS is associated with abnormal inhibitory regulation of PO by ZI. We recorded single units from ZI and PO in animals with CPS resulting from spinal cord lesions. Consistent with our hypothesis, the spontaneous firing rate and somatosensory evoked responses of ZI neurons were lower in lesioned animals compared with sham-operated controls. In PO, neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses to noxious and innocuous stimuli applied to the hindpaw and to the face. These changes were not associated with increased afferent drive from the spinal trigeminal nucleus or changes in the ventroposterior thalamus. Thus CPS can result from suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus.

A limitation of animal models of central pain is their inability to recapitulate all clinical characteristics of the human condition. Specifically, many animal models rely on reflexive measures of hypersensitivity and ignore, or cannot assess spontaneous pain, the hallmark characteristic of central pain in humans. Here, we adopt a conditioned place preference paradigm to test if animals with lesions in the anterolateral quadrant of the spinal cord develop signs consistent with spontaneous pain. This paradigm relies on the fact that pain relief is rewarding to animals, and has been used previously to show that animals with peripheral nerve injury develop tonic pain. With the use of two analgesic treatments commonly used to treat patients with central pain (clonidine infusion and motor cortex stimulation), we demonstrate that analgesic treatments are rewarding to animals with spinal cord lesions but not sham operated controls. These findings are consistent with the conclusion that animals with spinal cord injury suffer from tonic pain.

Sex differences in endogenous pain modulation were tested in healthy volunteers (32 men, 30 women). Painful contact heat stimuli were delivered to the right leg alone, and then in combination with various electrical conditioning stimuli delivered to the left forearm. Four conditioning protocols were applied to each subject in separate sessions: mild, nonpainful (control); distracting; stressfulyet-nonpainful; strongly painful. Thermal stimuli were rated on visual analog scales for pain intensity (INT) and unpleasantness (UNP). Distracting and painful conditioning stimuli significantly reduced heat pain INT and UNP ratings for both sexes, with significantly larger distraction effects on INT ratings for men than women (p=0.004). No sex differences in pain-evoked hypoalgesia were detected (p>0.05). The stress protocol did not consistently reduce heat pain ratings, possibly because the protocol was not sufficiently stressful to activate endogenous modulatory systems. Regression analysis revealed that the magnitude of pain-evoked hypoalgesia was predicted by the perceived distraction (p=0.003) and stress (p=0.04) produced by the painful conditioning stimulation, providing evidence that distraction and stress contribute to pain-evoked hypoalgesia. However, the contribution of stress to pain-evoked hypoalgesia differed by sex (p=0.02), with greater perceived stress associated with greater hypoalgesia in men and the opposite trend in women, suggesting sex differences in the mechanisms underlying pain-evoked hypoalgesia. This study provides indirect evidence that multiple neural mechanisms are involved in endogenous pain modulation and suggests that sex-specific aspects of these systems may contribute to greater pain sensitivity and higher prevalence of many chronic pain conditions among women.

This study examined within-and across-session consistency of visual analog scale (VAS) pain intensity and unpleasantness ratings of contact heat stimuli in 64 subjects (32 male). Subjects participated in four sessions over 14 days, with three stimulus series per session. Two levels of painful heat (pain-lo: rated 40, and pain-hi: rated 70 on a 0-100 VAS) were delivered in randomized order during each series, with temperatures selected on an individual subject basis to equalize pain perception across subjects. Across-session ratings declined by the fourth session for both pain levels (p=0.01). Within-session ratings declined by the third series for both pain levels (p<0.001). While significant, changes in across-and within-session ratings were of small magnitude. Comparison of coefficients of variation (CV) for across-and within-session ratings revealed that pain-lo ratings were more variable than pain-hi ratings (p<0.001). Across-and within-session CVs were highly correlated for each pain level (pain-lo p<0.001; pain-hi p=0.001), suggesting that variability of VAS ratings is a characteristic of individual subjects over both short and long time scales. Across-and within-session CVs were significantly negatively correlated with individual ratings of the stimuli, but were not correlated with demographic or psychosocial factors. Furthermore, sex did not impact consistency of ratings, demonstrating that neither sex is more variable in ratings than the other over time. Taken together, these findings suggest that VAS ratings of painful contact heat are relatively stable over time but the variability of these ratings is significantly impacted by the perceived intensity of the stimulus.

Central pain syndrome (CPS) is a debilitating and chronic pain condition that results from a lesion or dysfunction in the CNS. The pathophysiological mechanisms underlying CPS are poorly understood. We recently demonstrated that CPS is associated with suppressed inputs from the inhibitory nucleus zona incerta to the posterior thalamus (PO). As a consequence, activity in PO is abnormally increased in CPS. Because the perception of pain requires activity in the cerebral cortex, CPS must also involve abnormal cortical activity. Here we test the hypothesis that CPS is associated with increased activity in the primary somatosensory cortex (SI), a major projection target of PO that plays an important role in processing sensory-discriminative aspects of pain. We recorded activity of single units in SI in rats with CPS resulting from spinal cord lesions. Consistent with our hypothesis, SI neurons recorded from lesioned rats exhibited significantly higher spontaneous firing rates and greater responses evoked by innocuous and noxious mechanical stimulation of the hindpaw compared with control rats. Neurons from lesioned rats also showed a greater tendency than controls to fire bursts of action potentials in response to noxious stimuli. Thus, the excruciatingly painful symptoms of CPS may result, at least in part, from abnormally increased activity in SI.