Hypothalamus and Nociceptive Pathways

Definition

The hypothalamus is a complex structure that occupies the ventral half of the diencephalon below the thalamus on either side of the third ventricle. It lies just above the pituitary gland responsible for neuroendocrine secretions.

The hypothalamus includes about 40 nuclei of very different shapes and sizes. For simplification, it is generally divided into three medio-lateral zones, periventricular, medial and lateral and four caudo-rostral regions, mammillary, tuberal, anterior and preoptic. Combination of zones and regions permitted the recognition of twelve hypothalamic areas (Simerly 1995).

Neurosecretory neurons are mainly located within the periventricular zone with a particularly high density in the paraventricular nucleus. In addition, another important group of neurosecretory neurons is located in the supraoptic nucleus, a well-individualized nucleus located in the lateral region, on the lateral border of the optic chiasm. The neurosecretory system is subdivided into two parts, 1) magnocellular neurosecretory neurons (oxytocin and vasopressin), which directly innervate the posterior pituitary gland and 2) parvocellular neurosecretory neurons (corticotropin, gonadotropin, growth hormone, thyrotropin releasing hormones, somatostatin, angiotensin II and dopamine), which innervate the median eminence, the hypothalamic hormones being transported to the anterior pituitary gland via the hypophysial portal system (Swanson 1987).

The medial and lateral zones of the hypothalamus are chiefly devoted to the control of autonomic functions (cardiovascular, respiratory, blood fluid balance, energy metabolism, thermoregulatory and digestive) and major basic instinctive behaviors (feeding, drinking, reproductive, flight, defensive and aggressive) including the wakefulness-sleep cycles (Swanson 1987).

Characteristics

The hypothalamus is a fascinating region of the brain, which is much more than a control center for neuroendocrine secretion. Indeed, the hypothalamus is the upper center for autonomic functions and basic behaviors that assure the survival of both the individual and the species. It is easy to understand the role of the hypothalamus when it guarantees an adequate level of homeostasis for autonomic functions needed for survival. It is not so obvious to appreciate the importance of the myriad basic behaviors it generates. Thus, it is basically responsible for most of the motivations that govern our life, such as for example, hunger, the pleasures of eating and satiety, sexual desire, aggressiveness, fear, drowsiness, alertness and numerous other fundamental motivations of life.

Considering these functions, it seems that the hypothalamus should play an important role in the autonomic and motivational components of pain. All the same, the precise role of hypothalamus in different components of pain remains unclear. The only clearly accepted function of the hypothalamus in pain is the neuroendocrine corticotropin response.

In humans, imagery studies indicate that the acute traumatic pain comes with a noticeable activation of the hypothalamus (Hsieh et al. 1996). However, these studies provide neither information about the activation of different hypothalamic nuclei nor data about the role of hypothalamus in pain. In fact until now, most evidence for an involvement of the hypothalamus in nociceptive processing comes from anatomical and c-fos data. Cross-checking these data with the known functions of hypothalamic nuclei, it becomes possible to make hypotheses about the involvement of the hypothalamus in pain.

Nociceptive Afferent Inputs to the Hypothalamus

The hypothalamus has three well-documented sources of nociceptive inputs, the spinal and trigeminal dorsal horn, the parabrachial area and the ventrolateral medulla (Fig. 1).

• Spinal and trigeminal inputs – a number of spinal and trigeminal neurons are labeled after a large injection of retrograde axonal tracer within the hypothalamus. Labeled neurons are located in superficial and, above all, in deep laminae of the dorsal horn i.e. in regions known to be involved in nociceptive processing. Electrophysiological studies indicate that most spino / trigemino-hypothalamic neurons respond to a variety of noxious stimuli (Burstein 1996). These data, which seem to indicate a major nociceptive input to the hypothalamus, are challenged by anterograde axonal tracing studies that show much lower spinal and trigeminal projection upon the hypothalamus (Gauriau and Bernard 2004). Comparative examination of all the studies seems to point to at least a moderate but indisputable nociceptive projection, mainly to the lateral (Fig. 2) but also to the posterior and the paraventricular hypothalamic nuclei.

• Parabrachial inputs (see parabrachial hypothalamic and amygdaloid projections) –the lateral parabrachial area receives a heavy nociceptive input from spinal and trigeminal lamina I nociceptive neurons. The lateral parabrachial area projects heavily to the hypothalamic ventromedial nucleus and extensively to the retrochiasmatic, the median and the ventrolateral preoptic hypothalamus. Although less extensive, a notable projection reaches the dorsomedial, the periventricular, the paraventricular and the lateral nuclei (Fig. 2). Electrophysiological studies indicate that this strong afferent input to the hypothalamus from the parabrachial nucleus is primarily nociceptive (Bernard et al. 1996; Bester et al. 1997).

• Caudal ventrolateral medulla inputs –this reticular region includes the A1 / C1 catecholaminergic neurons and receives nociceptive inputs from both the superficial and the deep laminae of the dorsal horn. The caudal ventrolateral medulla projects extensively to the paraventricular nucleus and, to a lesser extent, to the periventricular, the supraoptic and the median preoptic hypothalamic nuclei (Fig. 2). Here again it was shown that this afferent input contains nociceptive neurons (Burstein 1996; Pan et al. 1999).

Figure 1

Schematic representation, in sagittal sections, of the three main hypothalamic nociceptive inputs: the PBl, the VLM/A1/C1 region and the trigeminal and spinal dorsal horn (mainly the deep laminae). Thick line: extensive nociceptive projection; thin line: medium density nociceptive projection; dotted line: hypothetical nociceptive projection. Abbreviations: A1, A1 noradrenaline cells; C1, C1 adrenaline cells; cc, corpus callosum; Hyp, hypothalamus; NTS, nucleus tractus solitarii; PAG, periaqueductal gray matter; PBl, lateral division of the parabrachial nucleus; Pit, pituitary gland; VLM, ventrolateral medulla.

Figure 2

Summary diagram illustrating, in coronal sections, the location of nociceptive projections within the hypothalamus (1–4, caudal to rostral). The parabrachial “nociceptive” area projects primarily upon the VMH (dark gray) and extensively upon the DM and the perifornical area (1), the RCh and the Pe (2), the rostral Pe and the ventral AH (3) and the AVPO (4) hypothalamic nuclei (gray). Both the parabrachial nucleus and the A1/C1 group within the ventrolateral medulla project to the PVN (2), the SO (3) and the MnPO (4) (black points). Both the parabrachial area and the spinal and trigeminal dorsal horn project to the pLH (1) (horizontal hatching). Abbreviations: 3V, third ventricle; A1/C1 A1, noradrenaline cells, C1, adrenaline cells; ac, anterior commissure; AH, anterior hypothalamic area; Arc, arcuate nucleus; AVPO, anteroventral preoptic nucleus; BST, bed nucleus of stria terminals; DM, dorsal medial nucleus; f, fornix; ic internal capsule; LH, lateral hypothalamus; MnPO, median preoptic nucleus; MPA, medial preoptic area; mt, mammillothalamic tract; opt, optic tract; ox optic chiasm; Pe, periventricular nucleus; pLH, posterior portion of lateral hypothalamus; PVN, paraventricular nucleus; RCh, retrochiasmatic area; SCh, suprachiasmatic nucleus; SO, supraoptic nucleus; sox, supraoptic decussation; VMH, ventromedial hypothalamic nucleus

The nucleus of the solitary tract was also proposed as a nociceptive input for the hypothalamus. However, this nucleus is primarily a center for autonomic / visceral and gustatory information. The role and the importance of solitary tract neurons in conveying nociceptive messages from the spinal cord to the hypothalamus need to be confirmed.

To summarize, anatomical data indicate several hypothalamic subregions that appear to be more specifically involved in nociceptive processing:

• 1. The neuroendocrine group (the paraventricular nucleus and to a lesser extent the periventricular and supraoptic nuclei) that receives nociceptive messages from all the nociceptive sources described above.

• 2. The ventromedial nucleus, the perifornical and the retrochiasmatic areas that receive a very prominent nociceptive input from the parabrachial area.

• 3. The median and ventrolateral preoptic area, the dorsomedial, the lateral and the posterior hypothalamic region, which receive lower but yet substantial nociceptive inputs.

Corroborating the anatomical data closely, it was shown that various painful stimuli evoke c-fos expression in regions receiving nociceptive afferent projections. The strongest c-fos expression was observed in neuroendocrine neurons of the hypothalamus located in the paraventricular, the supraoptic and the periventricular / arcuate nuclei. A substantial c-fos expression is evoked in the posterior, the ventromedial and the dorsomedial nuclei and the retrochiasmatic, the lateral and the anterior regions of the hypothalamus (Rodella et al. 1998; Snowball et al. 2000).

Role of Hypothalamus in Visceromotor Responses to Painful Stimuli

The anatomical data indicate that both parabrachial and A1 / C1 projections to the paraventricular nucleus innervate more densely neurons containing corticotropin releasing hormone as well as magnocellular neurons (that contain vasopressin and oxytocin). Painful stimuli evoke specifically c-fos expression in neurons containing corticotropin releasing hormone, vasopressin and oxytocin at the levels of paraventricular, arcuate and supraoptic nuclei. This neuroendocrine response is specific for these neurohormones; it does not include gonadotropin, growth hormone, and thyrotropin releasing hormones (Pan et al. 1996).

The neuroendocrine component of pain is indisputably under hypothalamic control with well-identified pain pathways to drive it. The role of these neurohormones in pain is not completely understood. It is likely that an increase in the corticotropin hormone axis is important to cope with the dangerous or traumatic situation that comes with pain (mobilization of metabolism and mental energy). Nonetheless, in the case of chronic pain, the stimulation of the corticotropin axis might become deleterious (anxiety, depression, decrease of immunity, neuronal loss). Vasopressin may accompany corticotropin secretion to increase or maintain blood pressure. The role and amount of oxytocin secretion in cases of acute pain remain yet poorly understood.

Importantly, psychological stress (immobilization, anxiety, and fear) acts on the corticotropin axis of the hypothalamus via limbic projections (bed nucleus of the stria terminalis, prefrontal cortex) different from those described for nociceptive stimuli (physical stress).

Numerous paraventricular neurons (chiefly in a dorsal position) are not neuroendocrine cells but provide descending projections to the brainstem and the spinal cord. Although the paraventricular nucleus provides the more extensive set of descending projections, other hypothalamic nuclei also receiving nociceptive messages send similar descending projections, namely the periventricular, the retrochiasmatic area, the dorsomedial, the dorsal, the perifornical and the lateral hypothalamic areas. These hypothalamic neurons project to the periaqueductal gray matter, the parabrachial area, the solitary tract, the motor vagus, the ambiguous nuclei and the ventrolateral medulla in the brainstem. In the spinal cord, they project chiefly to the sympathetic preganglionic column (Saper 1995). These hypothalamic neurons are adequately placed to drive both the sympathetic and the parasympathetic components of pain. They might, in connection with brainstem neurons, increase or decrease blood pressure and cardiac frequency and modify circulatory territory, according to the nature of the painful stimuli.

Role of Hypothalamus in Behavioral Response to Painful Stimuli

Several hypothalamic nuclei, which receive an extensive nociceptive input, play an important role in motivational components of pain.

The first group, including the ventromedial and the dorsomedial nuclei, the perifornical and the retrochiasmatic areas, is markedly involved in defensive-aggressive behavior. This group of nuclei projects extensively to the periaqueductal gray matter, each nucleus targeting a specific quadrant. The periaqueductal gray matter appears to be a major hypothalamic descending output to mediate aggressive-defensive behavior. Each nucleus of this hypothalamic group receives an extensive nociceptive input from the lateral parabrachial area, the ventromedial hypothalamic nucleus receiving the heaviest input. The ventromedial nucleus has been involved in aggressive-defensive behavior. Stimulation applied in this nucleus induces vocalization, attack, escape, piloerection, mydriasis and micturition that resemble the pseudo-affective reactions induced by noxious stimuli (Bester et al. 1997; Swanson 1987). Recently, the dorsomedial portion of the ventromedial nucleus has been shown to be responsible for the vocalization induced by painful electrical shock applied to the tail (Borszcz 2002). The ventromedial nucleus has also been involved in feeding behavior (it has long been considered as the “satiety center") and regulation of energy metabolism (Swanson 1987). Recently, the ventromedial hypothalamic nucleus has thus been proposed to be responsible for the anorexia induced by migraine (Malick et al. 2001). Pain should act on appetite via a parabrachio-ventromedial CCKergic link. Leptin receptors, which are abundant in this hypothalamic nucleus, might also participate in the loss of appetite. Finally, stimulation applied within the ventromedial nuclei produces an analgesia, which is also probably mediated via the periaqueductal output. Thus, it appears that the medial zone of the tuberal (posterior) and the anterior hypothalamus is responsible for the defensive-aggressive and feeding motivational component of pain.

The second group, including the median and the anteroventral preoptic hypothalamic nuclei, is involved in osmotic / blood fluids balance regulation and sleep promoting / thermoregulation functions. These nuclei also receive a substantial nociceptive input from the lateral parabrachial area. The influence of nociceptive input upon the neurons of this hypothalamic region is less clear. It might alter drinking behavior, vasopressin secretion, falling asleep and the thermoregulation set point according to the nature of the nociceptive aggression (Saper et al. 2001; Swanson 1987).

The posterior portion of the lateral hypothalamus receives a diffuse but substantial nociceptive input directly from the deep laminae of the dorsal horn and indirectly via the internal lateral parabrachial nucleus. The role of the lateral hypothalamus in nociceptive processing remains obscure because this hypothalamic region was involved in a myriad functions, such as feeding behavior (it has long been considered to be a “feeding center"), drinking behavior and cardiovascular and visceral regulation, as well as in wakefulness and anti-nociceptive and rewarding mechanisms. However, the recent discovery that narcolepsy can be induced by lack of orexin / hypocretin (a peptide located in the neurons of lateral hypothalamus), indicates that the lateral hypothalamus is probably markedly involved in the wakefulness mechanism (Saper 2001). One role of nociceptive inputs upon neurons of the posterior lateral hypothalamus could be to trigger awakening.

Conclusion

Bringing together anatomical and functional data, the hypothalamus appears as a key center for most visceromotor (neuroendocrine, autonomic response) and motivational (aggressive-defensive reactions, ingestive behaviors, wakefulness, antinociception) components of pain. It yet remains to check experimentally the actual role of hypothalamic subregions and / or neuromodulators in the genesis of different components of pain. Anatomical data also indicate that hypothalamic functions are probably strongly modulated by the upper limbic structures (notably the extended amygdala and the cingulate / prefrontal cortex), which are also involved in the emotional appreciation of pain.