The affective dimension of pain is made up of feelings of unpleasantness and emotions associated with future implications, termed secondary affect. Experimental and clinical studies show serial interactions between pain sensation intensity, pain unpleasantness, and secondary affect. These pain dimensions and their interactions relate to a central network of brain structures that processes nociceptive information both in parallel and in series. Spinal pathways to limbic structures and medial thalamic nuclei provide direct inputs to brain areas involved in affect. Another source is from spinal pathways to somatosensory thalamic and cortical areas and then through a cortico-limbic pathway. The latter integrates nociceptive input with contextual information and memory to provide cognitive mediation of pain affect. Both direct and cortico-limbic pathways converge on the same anterior cingulate cortical and subcortical structures whose function may be to establish emotional valence and response priorities.

https://science.sciencemag.org/content/sci/288/5472/1769.full.pdf

Psychological and Neural Mechanisms of the Affective Dimension of Pain

http://yael-nissan.weebly.com/uploads/5/2/9/2/5292348/the_introduction_to_pain_an_integrative_review_-_millan.pdf

The induction of pain: an integrative review

The purpose of the present investigation was to examine the topographical organization of efferent projections from the cytoarchitectonic divisions of the mPFC (the medial precentral, dorsal anterior cingulate and prelimbic cortices). We also sought to determine whether the efferents from different regions within the prelimbic division were organized topographically. Anterograde transport of Phaseolus vulgaris leucoagglutinin was used to examine the efferent projections from restricted injection sites within the mPFC. Major targets of the prelimbic area were found to include prefrontal, cingulate, and perirhinal cortical structures, the dorsomedial and ventral striatum, basal forebrain nuclei, basolateral amygdala, lateral hypothalamus, mediodorsal, midline and intralaminar thalamic nuclei, periaqueductal gray region, ventral midbrain tegmentum, laterodorsal tegmental nucleus, and raphe nuclei. Previously unreported projections of the prelimbic region were also observed, including efferents to the anterior olfactory nucleus, the piriform cortex, and the pedunculopontine tegmental-cuneiform region. A topographical organization governed the efferent projections from the prelimbic area, such that the position of terminal fields within target structures was determined by the rostrocaudal, dorsoventral, and mediolateral placement of the injection sites. Efferent projections from the medial precentral and dorsal anterior cingulate divisions (dorsomedial PFC) were organized in a similar topographical fashion and produced a pattern of anterograde labeling different from that seen with prelimbic injection sites. Target structures innervated primarily by the dorsomedial PFC included certain neocortical fields (the motor, somatosensory, and visual cortices), the dorsolateral striatum, superior colliculus, deep mesencephalic nucleus, and the pontine and medullary reticular formation. Previously unreported projections to the paraoculomotor central gray area and the mesencephalic trigeminal nucleus were observed following dorsomedial PFC injections. These results indicate that the efferent projections of the mPFC are topographically organized within and across the cytoarchitectonic divisions of the medial wall cortex. The significance of topographically organized and restricted projections of the rat mPFC is discussed in light of behavioral and physiological studies indicating functional heterogeneity of this region.

Topographical organization of the efferent projections of the medial prefrontal cortex in the rat: An anterograde tract-tracing study with Phaseolus vulgaris leucoagglutinin

Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness.

Recent data have emphasized the neurochemically distinct nature of subterritories in the accumbens part of the rat ventral striatum termed the core, shell, and rostral pole. In order to gain a more comprehensive understanding of how afferents are distributed relative to these subterritories, immunohistochemical detection of retrogradely transported Fluoro-Gold was carried out following iontophoretic injections intended to involve selectively one of the subterritories. The data revealed that a number of cortical afferents of the medial shell and core originate in separate areas, i.e., the dorsal peduncular, infralimbic, and posterior piriform cortices (to medial shell) and the dorsal prelimbic, anterior agranular insular, anterior cingulate, and perirhinal cortices (to core). The lateral shell and rostral pole are innervated by cortical structures that also project either to the medial shell or core. The orbital, posterior agranular insular, and entorhinal cortices, hippocampus, and basal amygdala were observed to innervate the accumbens in a topographic manner. Following core injections, strong bilateral cortical labeling was observed. Few labeled cortical cells were observed contralaterally following injections in the medial shell. Intermediate numbers of labeled neurons were observed in contralateral cortices following lateral shell injections. Robust subcortical labeling in a variety of structures in the ventral forebrain, lateral hypothalamus, deep temporal lobe, and brainstem was observed after shell injections, particularly those that involved the caudal dorsomedial extremity of the shell, i.e., its "septal pole." Selective ipsilateral labeling of subcortical structures in the basal ganglia circuitry was observed following injections in the core and, to a lesser extent, lateral shell. It was concluded that a number of afferent systems exhibit varying degrees of segregation with respect to the accumbal subterritories.

The patterns of afferent innervation of the core and shell in the “Accumbens” part of the rat ventral striatum: Immunohistochemical detection of retrogradely transported fluoro‐gold

Fibers projecting from several levels of the spinal cord to the diencephalon and telencephalon were labeled anterogradely with Phaseolus vulgaris leucoagglutinin injected iontophoretically. Labeled fibers in the thalamus confirmed projections previously observed. In addition, many labeled fibers were seen in the hypothalamus and in telencephalic areas not generally recognized previously as receiving such projections. In the hypothalamus, these areas included the lateral hypothalamus (including the medial forebrain bundle), the posterior hypothalamic area, the dorsal hypothalamic area, the dorsomedial nucleus, the paraventricular nucleus, the periventricular area, the suprachiasmatic nucleus, and the lateral and medial preoptic areas. In the telencephalon, areas with labeled fibers included the ventral pallidum, the globus pallidus, the substantia innominata, the basal nucleus of Meynert, the amygdala (central nucleus), the horizontal and vertical limbs of the diagonal band of Broca, the medial and lateral septal nuclei, the bed nucleus of the stria terminalis, the nucleus accumbens, infralimbic cortex, and medial orbital cortex. These results suggest that somatosensory, possibly including visceral sensory, information is carried directly from the spinal cord to areas in the brain involved in autonomic regulation, motivation, emotion, attention, arousal, learning, memory, and sensory-motor integration. Many of these areas are associated with the limbic system.

https://www.jneurosci.org/content/jneuro/11/3/852.full.pdf

Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats.

Somatosensory input to the hypothalamus has been thought to ascend via an indirect, multisynaptic pathway. However, we have antidromically identified nociceptive spinal cord neurons that project directly to the lateral hypothalamus in rats. Retrograde tracers injected into the lateral hypothalamus labeled many spinal neurons bilaterally within the marginal zone, the lateral reticulated area, the lateral spinal nucleus, and the area surrounding the central canal. An anterograde tracer injected into these areas of the spinal cord labeled fibers and terminals in the lateral hypothalamus and, surprisingly, in a number of telencephalic areas. These findings demonstrate a direct somatosensory projection from the spinal cord to the hypothalamus and several telencephalic regions.

https://www.jneurosci.org/content/jneuro/7/12/4159.full.pdf

Direct somatosensory projections from the spinal cord to the hypothalamus and telencephalon

We recently demonstrated that large numbers of neurons in the spinal cord of rats project directly to the hypothalamus. In the present study, we used the retrograde tracer Fluoro-Gold (FG) to examine this projection more completely. In the first series ofss studies, we attempted to label the entire population of spinal cord neurons that project to the hypothalamus. Injections that virtually filled the hypothalamus on one side without spreading into any other diencephalic area labeled a large number of neurons (estimated to be more than 9,000 in the case with the most neurons labeled) bilaterally at all levels of the spinal cord. Approximately 60° of the labeled neurons were contralateral to the injection. The greatest number of labeled neurons was found within the deep dorsal horn. Many were also found within the lateral spinal nucleus, the superficial dorsal horn, and the gray matter surrounding the central canal. A small number of labeled cells was located in the intermediate zone and ventral horn of the spinal gray matter. Labeled neurons were distributed bilaterally within the sacral parasympathetic nucleus and trigeminal nucleus caudalis.



Injections of FG restricted to the medial hypothalamus labeled neurons within the spinal cord in a distribution similar to that produced by injections that filled the hypothalamus. However, fewer neurons were labeled in the spinal cord (estimated to be more than 6,200) and trigeminal nucleus caudalis.



Injections of FG restricted to the lateral hypothalamus also labeled fewer neurons (approximately 3,300) than did injections that filled the hypothalamus. In these cases, also, the pattern of labeled neurons within the spinal cord was similar to that produced by injections within either medial or both medial and lateral hypothalamus. However, few neurons were labeled in the sacral parasympathetic nucleus following injections into the lateral hypothalamus.



These findings show the distribution of a large number of spinal cord neurons that project directly to medial or lateral hypothalamic regions that are involved in autonomic, neuroendocrine, and emotional responses to somatosensory stimulation, including painful stimuli.

Cells of origin of the spinohypothalamic tract in the rat.

Evidence that Fluoro-Gold can be transported avidly through fibers of passage.

1. Ninety-six neurons in the lumbar enlargement of urethananesthetized rats were antidromically activated from the contralateral hypothalamus. The antidromic stimulating electrode was moved systema...

Kenneth D. Cliffer

Papers

Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats.

Direct somatosensory projections from the spinal cord to the hypothalamus and telencephalon

Cells of origin of the spinohypothalamic tract in the rat.

Evidence that Fluoro-Gold can be transported avidly through fibers of passage.

Physiological characterization of spinohypothalamic tract neurons in the lumbar enlargement of rats.