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Scientific evidence supports the notion that migraine pathophysiology involves inherited alteration of brain excitability, intracranial arterial dilatation, recurrent activation, and sensitization of the trigeminovascular pathway, and consequential structural and functional changes in genetically susceptible individuals. Evidence of altered brain excitability emerged from clinical and preclinical investigation of sensory auras, ictal and interictal hypersensitivity to visual, auditory, and olfactory stimulation, and reduced activation of descending inhibitory pain pathways. Data supporting the activation and sensitization of the trigeminovascular system include the progressive development of cephalic and whole-body cutaneous allodynia during a migraine attack. In addition, structural and functional alterations include the presence of subcortical white mater lesions, thickening of cortical areas involved in processing sensory information, and cortical neuroplastic changes induced by cortical spreading depression. Here, we review recent anatomical data on the trigeminovascular pathway and its activation by cortical spreading depression, a novel understanding of the neural substrate of migraine-type photophobia, and modulation of the trigeminovascular pathway by the brainstem, hypothalamus and cortex., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Manganese ion (Mn(2+)) was used as a paramagnetic contrast agent in T1-weighted magnetic resonance imaging (MRI) images. They enter neural cells though voltage-gated calcium channels and are activity-dependently transported along axons and across synapses. The aim of the present study was to investigate the nociceptive medial thalamus projection in rats by activity-dependent manganese-enhanced magnetic resonance imaging (MEMRI). Rats under urethane and α-chloralose anesthesia were microinjected with manganese chloride (MnCl(2), 120mmol/L, iontophoretically with a 5-μA current for 15min) into the right medial thalamus. Innocuous (at a 50-μA intensity for 0.2ms) or noxious (at a 5-mA intensity for 2ms) electrical stimuli were applied through a pair of needles in the left forepaw pads once every 6s for 5h. Enhanced transport of Mn(2+) were found in the anterior cingulate cortex, midcingulate cortex, retrosplenial cortex, ventral medial caudate-putamen, nucleus accumbens, and amygdala in the noxious-stimulated group. Enhancements in the anterior cingulate cortex, midcingulate cortex, ventral medial caudate-putamen, nucleus accumbens, and amygdala, but not the retrosplenial cortex, were attenuated by an intraperitoneal injection of morphine (5mg/kg and 1mg/kg/h, intraperitoneal). These results indicate that a combination of MEMRI with activity-induced manganese-dependent contrast is useful for delineating functional connections in the pain pathway. Noxious stimulation induced enhancement of manganese ion transportation from medial thalamus to cingulate cortex and medial striatum, but not motor cortex. A combination of manganese-enhanced magnetic resonance imaging with activity-dependent contrast is useful for delineating functional connections of the medial pain pathway., (Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Myofascial pain of the temporomandibular region (M-TMD) is a common, but poorly understood chronic disorder. It is unknown whether the condition is a peripheral problem, or a disorder of the central nervous system (CNS). To investigate possible CNS substrates of M-TMD, we compared the brain morphology of 15 women with M-TMD to that of 15 age- and gender-matched healthy controls. High-resolution structural brain and brainstem scans were carried out using magnetic resonance imaging (MRI), and data were analyzed using a voxel-based morphometry approach. The M-TMD group evidenced decreased or increased gray matter volume compared to controls in several areas of the trigeminothalamocortical pathway, including brainstem trigeminal sensory nuclei, the thalamus, and the primary somatosensory cortex. In addition, M-TMD individuals showed increased gray matter volume compared to controls in limbic regions such as the posterior putamen, globus pallidus, and anterior insula. Within the M-TMD group, jaw pain, pain tolerance, and pain duration were differentially associated with brain and brainstem gray matter volume. Self-reported pain severity was associated with increased gray matter in the rostral anterior cingulate cortex and posterior cingulate. Sensitivity to pressure algometry was associated with decreased gray matter in the pons, corresponding to the trigeminal sensory nuclei. Longer pain duration was associated with greater gray matter in the posterior cingulate, hippocampus, midbrain, and cerebellum. The pattern of gray matter abnormality found in M-TMD individuals suggests the involvement of trigeminal and limbic system dysregulation, as well as potential somatotopic reorganization in the putamen, thalamus, and somatosensory cortex., (Copyright 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Peptidergic and nonpeptidergic nociceptive neurons represent parallel yet distinct pathways of pain transmission, but the functional consequences of such specificity are not fully understood. Here, we quantified the progression of peptidergic and nonpeptidergic axon loss within the epidermis in the setting of a dying-back neuropathy induced by diabetes. STZ-induced diabetic MrgD mice heterozygous for green fluorescent protein (GFP) in nonpeptidergic DRG neurons were evaluated for sensitivity to mechanical and noxious thermal and chemogenic stimuli 4 or 8 weeks post-STZ. Using GFP expression in conjunction with PGP9.5 staining, nonpeptidergic (PGP+/GFP+) and peptidergic (PGP+/GFP-) intraepidermal nerve fibers (IENFs) were quantified at each time point. At 4 weeks post-STZ, nonpeptidergic epidermal innervation remained unchanged while peptidergic innervation was reduced by 40.6% in diabetic mice. By 8 weeks post-STZ, both nonpeptidergic innervation and peptidergic innervation were reduced in diabetic mice by 34.1% and 43.8%, respectively, resulting in a 36.5% reduction in total epidermal IENFs. Behavioral deficits in mechanical, thermal, and chemogenic sensitivity were present 4 weeks post-STZ, concomitant with the reduction in peptidergic IENFs, but did not worsen over the next 4 weeks as nonpeptidergic fibers were lost, suggesting that the early reduction in peptidergic fibers may be an important driving force in the loss of cutaneous sensitivity. Furthermore, behavioral responses were correlated at the 4 week time point with peptidergic, but not nonpeptidergic, innervation. These results reveal that peptidergic and nonpeptidergic nociceptive neurons are differentially damaged by diabetes, and behavioral symptoms are more closely related to the losses in peptidergic epidermal fibers.

HIV associated sensory neuropathy is a common neurological disorder with reported prevalence of 53%. When only small fibers are involved, the diagnosis of neuropathy remains difficult since standard nerve conduction studies generally are unremarkable. We assessed a method to identify small-fiber neuropathy using electrically evoked pain-related potentials and correlated the electrophysiological results with intraepidermal nerve fiber density in patients with HIV associated sensory neuropathy. Nineteen HIV positive patients were investigated for clinically diagnosed peripheral neuropathy with Neuropathy Symptoms Score (NSS)3 and Neuropathy Disability Score (NDS)5. Nine healthy HIV negative control subjects were recruited. We performed standard nerve conduction testing, electrically evoked pain-related potentials and skin biopsy in all participants. Pain-related evoked potentials revealed abnormalities in all HIV positive neuropathy patients, while standard nerve conduction testing was abnormal in eight patients only. Pain-related evoked potential latencies and amplitudes strongly correlated with intraepidermal nerve fiber density. The method of pain-related evoked potential conduction appears to be a sensitive, fast, non-invasive technique for the detection of small-fiber neuropathy and may prove to become a valuable diagnostic asset.

The mechanisms of nociception in the low back are poorly understood, partly because systematic recordings from dorsal horn neurons with input from the low back are largely missing. The purpose of this investigation was to (1) identify spinal segments and dorsal horn neurons receiving input from the low back, (2) test the effect of nerve growth factor (NGF) injected into the multifidus muscle (MF) on the neurons' responsiveness, and (3) study the influence of a chronic MF inflammation on the responses. In rats, microelectrode recordings were made in the segments L2, L3, and L5 to find dorsal horn neurons having input from the low back (LB neurons). In control animals, the proportion of LB neurons in L2 was larger than in L3 and L5. Most LB neurons had a convergent input from several tissues. Injections of NGF into MF increased the proportion of LB neurons significantly. A chronic MF inflammation likewise increased the proportion of LB neurons and the input convergence. The centers of the neurons' receptive fields (RFs) were consistently located 2-3 segments caudally relative to their recording site. The results show that (1) input convergence from various tissues is common for LB neurons, (2) the input from structures of the low back is processed 2-3 segments cranially relative to the vertebral level of the RFs, and (3) the responsiveness of LB neurons is increased during a pathologic alteration of the MF. The above findings may be relevant for some cases of chronic low back pain in patients.

CRPS-I consists of post-traumatic limb pain and autonomic abnormalities that continue despite apparent healing of inciting injuries. The cause of symptoms is unknown and objective findings are few, making diagnosis and treatment controversial, and research difficult. We tested the hypotheses that CRPS-I is caused by persistent minimal distal nerve injury (MDNI), specifically distal degeneration of small-diameter axons. These subserve pain and autonomic function. We studied 18 adults with IASP-defined CRPS-I affecting their arms or legs. We studied three sites on subjects' CRPS-affected and matching contralateral limb; the CRPS-affected site, and nearby unaffected ipsilateral and matching contralateral control sites. We performed quantitative mechanical and thermal sensory testing (QST) followed by quantitation of epidermal neurite densities within PGP9.5-immunolabeled skin biopsies. Seven adults with chronic leg pain, edema, disuse, and prior surgeries from trauma or osteoarthritis provided symptom-matched controls. CRPS-I subjects had representative histories and symptoms. Medical procedures were unexpectedly frequently associated with CRPS onset. QST revealed mechanical allodynia (P<0.03) and heat-pain hyperalgesia (P<0.04) at the CRPS-affected site. Axonal densities were highly correlated between subjects' ipsilateral and contralateral control sites (r=0.97), but were diminished at the CRPS-affected sites of 17/18 subjects, on average by 29% (P<0.001). Overall, control subjects had no painful-site neurite reductions (P=1.00), suggesting that pain, disuse, or prior surgeries alone do not explain CRPS-associated neurite losses. These results support the hypothesis that CRPS-I is specifically associated with post-traumatic focal MDNI affecting nociceptive small-fibers. This type of nerve injury will remain undetected in most clinical settings.

Complex regional pain syndromes (CRPS, type I and type II) are devastating conditions that can occur following soft tissue (CRPS type I) or nerve (CRPS type II) injury. CRPS type I, also known as reflex sympathetic dystrophy, presents in patients lacking a well-defined nerve lesion, and has been questioned as to whether or not it is a true neuropathic condition with an organic basis. As described here, glabrous and hairy skin samples from the amputated upper and lower extremity from two CRPS type I diagnosed patients were processed for double-label immunofluorescence using a battery of antibodies directed against neural-related proteins and mediators of nociceptive sensory function. In CRPS affected skin, several neuropathologic alterations were detected, including: (1) the presence of numerous abnormal thin caliber NF-positive/MBP-negative axons innervating hair follicles; (2) a decrease in epidermal, sweat gland, and vascular innervation; (3) a loss of CGRP expression on remaining innervation to vasculature and sweat glands; (4) an inappropriate expression of NPY on innervation to superficial arterioles and sweat glands; and (5) a loss of vascular endothelial integrity and extraordinary vascular hypertrophy. The results are evidence of widespread cutaneous neuropathologic changes. Importantly, in these CRPS type I patients, the myriad of clinical symptoms observed had detectable neuropathologic correlates.

The transmission of nociceptive information occurs along non-myelinated, or thinly myelinated, primary afferent axons. These axons are generally classified as peptidergic (CGRP-expressing) or non-peptidergic (IB4-binding), although there is a sub-population that is both CGRP-positive and IB4-binding. During neuronal development and following injury, trophic factors and their respective receptors regulate their survival and repair. Recent reports also show that the carbohydrate-binding protein galectin-1 (Gal1), which is expressed by nociceptive primary afferent neurons during development and into adulthood, is involved in axonal pathfinding and regeneration. Here we characterize anatomical differences in dorsal root ganglia (DRG) of Gal1 homozygous null mutant mice (Gal1(-/-)), as well as behavioural differences in tests of nociception. Gal1(-/-) mice have a significantly reduced proportion of IB4-binding DRG neurons, an increased proportion of NF200-immunoreactive DRG neurons, increased depth of central terminals of IB4-binding and CGRP-immunoreactive axons in the dorsal horn, and a reduced number of Fos-positive second order neurons following thermal (cold or hot) stimulation. While there is no difference in the total number of axons in the dorsal root of Gal1(-/-) mice, there are an increased number of myelinated axons, suggesting that in the absence of Gal1, neurons that are normally destined to become IB4-binding instead become NF200-expressing. In addition, mice lacking Gal1 have a decreased sensitivity to noxious thermal stimuli. We conclude that Gal1 is involved in nociceptive neuronal development and that the lack of this protein results in anatomical and functional deficits in adulthood.

The disinhibition hypothesis of post-stroke central pain (CPSP) suggests that 'the excessive response (dysesthesia/hyperalgesia/allodynia) is accompanied by a em leader loss of sensation' resulting from a lesion of a 'lateral nucleus' of thalamus or of 'cortico-thalamic paths' [Brain 34 (1911) 102]. One recent elaboration of this hypothesis proposes a submodality specific relationship, such that injury to a cool-signaling lateral thalamic pathway disinhibits a nociceptive medial thalamic pathway, thereby producing both burning, cold, ongoing pain and cold allodynia. The current study quantitatively evaluated the sensory loss and sensory abnormalities to discern submodality relationships between these sensory features of CPSP. The present results were statistically tested within individuals so that sensory loss and sensory abnormality are directly related by occurrence in the same individual. The results demonstrate that individuals with CPSP and normal tactile detection thresholds experience tactile allodynia significantly more often than those with tactile hypoesthesia. Most patients (11/13) exhibited hypoesthesia for the perception of cool stimuli, but few of these (2/11) showed cold allodynia. The most dramatic case of cold allodynia occurred in a patient who had a normal detection threshold for cold. Individuals with cold hypoesthesia, strictly contralateral to the cerebro-vascular accident (CVA or stroke), were often characterized by the presence of burning, cold, ongoing pain, and by the absence, not the presence, of cold allodynia. Overall, these results in CPSP suggest that tactile allodynia occurs in disturbances of thermal/pain pathways that spare the tactile-signaling pathways, and that cold hypoesthesia is neither necessary nor sufficient for cold allodynia.

In this study extracellular recordings of nociceptive dorsal horn neurones driven by electrical stimulation of the sciatic nerve were performed in intact urethane-anaesthetized Sprague-Dawley rats. Spikes 0-40, 40-250 and 250-800 ms after stimulus were defined as A- and C-fibre responses and post-discharge, respectively, and the effect of 200 microg capsaicin (8-methyl-N-vanillyl-6-noneamide) injected into the contralateral gastrocnemius-soleus muscle was investigated. In most cells tested, regardless of the size or location of their receptive fields, the injection of capsaicin caused a clear inhibition of the electrically evoked C-fibre responses. In animals with intact descending pathways the mean C-fibre response was inhibited to 51% of baseline 15 min after injection of capsaicin. In contrast, when capsaicin was given during cold block of the spinal cord between the brainstem and the site of recording in the dorsal horn, the same response was inhibited to 91% of baseline. A significant interaction between cold block and capsaicin was detected. We conclude that stimulation of capsaicin-sensitive afferents in the deep tissue in the hind limb can inhibit the electrically evoked C-fibre responses in the dorsal horn by activating inhibitory descending projections from higher centres. The model presented here may be an important tool for further investigations of the endogenous descending antinociceptive system.