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Projection neurons in lamina I, together with those in laminae III–IV that express the neurokinin 1 receptor (NK1r), form a major route through which nociceptive information reaches the brain. Axons of these cells innervate various targets, including thalamus, periaqueductal gray matter (PAG), and lateral parabrachial area (LPb), and many cells project to more than one target. The aims of this study were to quantify projections from cervical enlargement to PAG and LPb, to determine the proportion of spinothalamic neurons at lumbar and cervical levels that were labelled from PAG and LPb, and to investigate morphological differences between projection populations. The C7 segment contained fewer lamina I spinoparabrachial cells than L4, but a similar number of spino-PAG cells. Virtually all spinothalamic lamina I neurons at both levels were labelled from LPb and between one-third and one-half from PAG. This suggests that significant numbers project to all three targets. Spinothalamic lamina I neurons differed from those labelled only from LPb in that they were generally larger, were more often multipolar, and (in cervical enlargement) had stronger NK1r immunoreactivity. Most lamina III/IV NK1r cells at both levels projected to LPb, but few were labelled from PAG. The great majority of these cells in C7 and over one-fourth of those in L4 were spinothalamic, and at each level some projected to both thalamus and LPb. These results confirm that neurons in these laminae have extensive collateral projections and suggest that different neuronal subpopulations in lamina I have characteristic patterns of supraspinal projection. J. Comp. Neurol. 515:629–646, 2009. © 2009 Wiley-Liss, Inc.

The distribution of cells belonging to the rat spinomesencephalic tract was studied by means of the retrograde transport of fluorescent dyes. Bilateral midbrain injections of cytoplasmic and nuclear tracers were made in order to evaluate the location of ipsilateral, contralateral, or bilaterally projecting cells. Spinal neurons with ascending projections to midbrain and descending propriospinal projections were identified by midbrain and spinal injections of different cytoplasmic labels. The locations of spinomesencephalic tract cells included seven regions of the spinal gray matter: marginal zone, lateral neck of the dorsal horn, nucleus proprius, the region around the central canal, the lateral cervical and spinal nuclei and the ventral horn. Cells projecting to the ipsilateral or contralateral midbrain had similar distributions and were frequently found in clusters with overlapping dendritic fields. Approximately 75% of spinomesencephalic cells projected to the contralateral midbrain. The largest contribution to the spinomesencephalic tract cell population was found in cervical cord segments 1-4. Cells with bilateral projections accounted for nearly 2% of all labeled cells, whereas 5% had both ascending and descending projections. Spinomesencephalic cells were found to have varying dendritic fields and morphology, e.g. fusiform, pyramidal, round/oval, and multipolar. The results of the present study lend further support to the view that the spinomesencephalic tract is a multi-component pathway with varied origins and projection targets.

The responses of 32 spinomesencephalic tract cells to intradermal capsaicin were examined in anesthetized monkeys. Wide dynamic range (n = 20) and nociceptive specific (n = 6) cells showed two types of excitatory responses to intradermal injection of capsaicin. The first excitatory response shown by the majority of wide dynamic range (n = 13) and nociceptive specific (n = 4) cells was consistent with their sensitization by capsaicin. The cells showed an acute and prolonged increase in ongoing activity with capsaicin injection. Responses to mechanical stimuli were substantially increased after capsaicin and an expansion of receptive field was often observed. The responses of the same cells to excitatory amino acid agonists applied locally by iontophoresis also increased. All cells showing sensitization were antidromically activated from periaqueductal gray regions dorsal to the sulcus limitans. Electrical stimulation at these sites did not affect the ongoing or evoked discharges of these cells. The second excitatory response of wide dynamic range (n = 5) and nociceptive specific (n = 1) cells was a novel pattern not consistent with sensitization. These cells nevertheless showed an acute and prolonged increase in background activity after capsaicin injection. Yet, there was no change or a decrease in responses to cutaneous stimuli, no evidence for change in receptive field size and no increase in responses to locally released excitatory amino acids. These cells projected to regions in the periaqueductal gray ventral to the sulcus limitans. Electrical stimulation at these sites produced a decrease in spontaneous activity of the same cell. Low threshold mesencephalic-projecting neurons (n = 6) showed a single inhibitory pattern (n = 4) of responses to capsaicin. The injection produced an acute decrease in spontaneous activity that was sustained for at least 30 min after injection. The responses to cutaneous stimuli and to excitatory amino acids were also substantially reduced. Low threshold cells were found that projected to both dorsal-lateral and ventral-lateral regions of the periaqueductal gray. In summary, three patterns of responses shown by primate spinomesencephalic tract cells to intradermal capsaicin appear dependent on the functional regions of the periaqueductal gray to which they project. These results suggest that inputs of spinomesencephalic tract neurons to the periaqueductal gray may evoke important components of the systemic response to the neurogenic hyperalgesia produced by intradermal capsaicin.

Retrograde transport of the fluorescent tracer Fluorogold was used in combination with immunohistochemical staining for the enzyme glutaminase to identify putative glutamatergic neurons belonging to the rat spinomesencephalic tract. Glutaminase-like staining in spinal projection neurons suggests that the relay of nociceptive information from the spinal cord to midbrain may involve the excitatory amino acid glutamate.