Central afferent pathways conveying nociceptive input to the hypothalamic paraventricular nucleus as revealed by a combination of retrograde labeling and c‐fos activation

Abstract

Previous data have shown that noxious thermal stimulation of the hind leg in the anesthetized rat causes c-fos activation in the paraventricular nucleus of the hypothalamus (PVN); in other brain nuclei, including the cathecholaminergic cell groups of the caudal medulla; and in the adenohypophysis. Stimulation was followed by adrenocorticotropic hormone plasma release but did not provoke cardiovascular changes. In the current study, the afferent central pathways conveying the nociceptive input to the PVN were studied throughout the brain by using double labeling for the Fos-protein and the retrograde tracer cholera toxin subunit B (CTb) injected into the PVN. Although double labeling occurred in several hypothalamic nuclei, the periaqueductal gray, the lateral parabrachial area, and the catecholaminergic medullary groups, high rates of double labeling occurred only in the cells of the A1 region of the ventrolateral medulla ( approximately 83% of CTb-labeled cells expressing c-fos). Further triple labeling with tyrosine hydroxylase (TH) revealed that > 80% of the double-labeled cells were TH-immunoreactive. The spinal cord had the usual strong c-fos expression but showed no retrograde labeling from the PVN. Noxious stimulation caused corticosterone plasma release. To ascertain a possible link of spinofugal neurons with the A1 cells, biotinylated dextran amine was injected into the spinal dorsal horn. Numerous anterogradely labeled fibers with bouton-like structures were observed, with the latter apposed to double- and triple-labeled cells in the A1 region. It is suggested that a dysynaptic route relayed in the A1 region conveys the nociceptive somatic input from the spinal cord to the PVN. Noxious stimulation may act as a systemic stressor, activating the hypothalamic-pituitary-adrenal axis.

The adaptive and maladaptive continuum of stress responses – a hippocampal perspective

“…Physiological and psychological stressors activate the brain stem nuclei and the amygdala to induce the release of corticotrophin releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus (Smith et al, 1995;Pan et al, 1999;reviewed in Jankord and Herman, 2008). Hypothalamic CRH then enhances pituitary release of adrenocorticotrophic hormone (ACTH) that stimulates adrenocortical glucocorticoid (GC) secretion (reviewed in Herman and Cullinan, 1997).…”

Trigeminohypothalamic and Reticulohypothalamic Tract Neurons in the Upper Cervical Spinal Cord and Caudal Medulla of the Rat

“…Traditionally, A1 neurons have been viewed as playing an important role in the reflex control of hormonal secretion from hypothalamic neurons in response to hemodynamic, gastrointestinal, and respiratory stimuli (Cunningham and Sawchenko 1991;Randle et al 1986;Swanson 1987;Willoughby et al 1987); sensory information they receive through the nucleus of the solitary tract (Loewy 1990). The finding that hypothalamic projecting neurons in this region convey nociceptive information that originates in multiple organs indicates their potential involvement in the initiation of endocrine responses to noxious stimuli as well; a consideration that was brought up recently by Pan and colleagues using the Fos technique (Pan et al 1999).…”

“…To be in a position to integrate somatosensory and visceral information with endocrine and autonomic responses, hypothalamic neurons must receive somatosensory and visceral inputs. The afferent inputs that the hypothalamus receives from brain stem nuclei, such as the parabrachial nuclei (Cechetto et al 1985;Saper and Loewy 1980;Slugg and Light 1994), nucleus of the solitary tract (Menetrey and Basbaum 1987;Ricardo and Koh 1978), periaqueductal gray (Beitz 1982;Eberhart et al 1985;Lima and Coimbra 1989;Liu 1983), and caudal ventrolateral medulla (Lima et al 1991;Sawchenko and Swanson 1981), and the identification of neurons in these nuclei that respond to noxious and innocuous somatosensory and visceral stimulation (Bernard and Besson 1990;Kannan et al 1986;Pan et al 1999;Person 1989;Zhang et al 1992) contributed to the notion that somatosensory signals reach the hypothalamus through several polysynaptic pathways.…”

Is neuropathic pain caused by the activation of nociceptive‐specific neurons due to anatomic sprouting in the dorsal horn?

“…Whereas the homeostatic changes evoked by painful stimuli are adaptive and essential when pain is of an acute, nociceptive character, they may be detrimental during conditions of chronic pain (Sawchenko et al, 1996). The activation of parabrachial neurons by low-threshold mechanoreceptors shown by Bester et al could be involved in the autonomic disturbances elicited by persistent pain (Ren and Dubner, 1999), although direct spinal inputs to the ventrolateral medulla (Craig, 1995;Pan et al, 1999) and to the hypothalamus and other limbic forebrain regions (Burstein, 1996) are probably also important.…”