Modulation of Pain by the Hypothalamic PituitaryAdrenal Axis

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The hypothalamus is sited at the base of the brain around the third ventricle and above the pituitary stalk, which leads down to the pituitary itself, carrying the hypophyseal portal blood supply. It contains vital centers for functions including appetite, thirst, thermal regulation, and the sleep cycle, and acts as an integrator of many neuroendocrine inputs to control the release of pituitary hormone-releasing factors. Amongst other important influences, it plays a role in the circadian rhythm, menstrual cycle, and responses to stress, exercise, and mood. The pituitary gland is located in the sella turcica at the base of the brain and is around 1 cm in diameter and between 0.5 and 1 g in weight. CRH produced in the hypothalamus induces the release of adrenocorticotropin (ACTH) from specialized cells in the anterior pituitary. This in turn stimulates the release of cortisol from cells in the zona fasciculata and reticularis of the adrenal glands.

The HPA response to stress is a basic adaptive mechanism that modulates the metabolic and cardiovascular responses to it, whether it be acute stress or chronic. The CNS response to stress can modulate pain perception through the control of ANS outflow and activity of the HPA axis (49,65).

CRH has been implicated in the pathophysiology of anxiety. Centrally administered CRH produces several signs of increased anxiety and transgenic mice that overexpress CRH exhibit increased anxiogenic behavior; conversely, central administration of a CRH antagonist produces anxiolytic effects in the rat (66). These effects of CRH are thought to be mediated through actions of CRH on NE systems in the LC. The activity of the NE system has been observed to be increased during stress and anxiety in several animal species, and states of anxiety and fear appear to be associated with an increase in NE release in humans (67). There is anatomical evidence for direct synaptic contact between CRH terminals and dendrites of NE cells in the LC, and both acute and chronic stress increase CRH-like immunoreactivity in the LC (68). Stress increases the turnover of NE in terminal projection areas of the LC (69) and increases extracellular NE in the hippocampus (70). Projection sites of this LC-NE system include the medial PFC (71), PAG, hippocampus, hypothalamus, thalamus, and the nucleus tractus solitarius (NTS) (72,73). The LC has projections to areas such as the amygdala, known to process fear-relevant sensory stimuli, and to the medullary nucleus paragigantocellularis, which receives viscerosensory stimuli relayed by the NTS. Therefore, the LC is well positioned to integrate both external sensory and internal visceral information and influence a wide distribution of stress- and fear-related neural structures, including specific cortical areas.

During stress, the increased secretion of CRH and arginine vasopressin (AVP) into the hypophysial-portal system of the anterior pituitary enhances the synthesis and release of ACTH (Fig. 4), which can be demonstrated in both the cerebrospinal fluid and blood (74,75). Elevated ACTH content in blood, in turn, increases the synthesis and release of adrenal glucocorticoids, which act in synergy with catecholamines to produce lipolysis, glycoge-nolysis, and protein catabolism, resulting in increased blood glucose content, essentially providing a readily available energy source to aid in the stress response. The delivery of energy substrates is enhanced by increased blood flow as a result of glucocorticoid- and catecholamine-induced increases in cardiovascular tone. Prolonged exposure to elevated stress hormones, however, can present a risk. Glucocorticoids and catecholamines promote the suppression of anabolic processes, muscle atrophy, decreased sensitivity to insulin, and a risk of steroid-induced diabetes, hypertension, hyperlipidemia, hypercholesterolemia, arterial disease, amenorrhea, impotency, and the impairment of growth and tissue repair, as well as immunosuppression (76,77). Central CRH systems activate ascending serotonergic and noradrenergic pathways so that under conditions of threat, individuals become hypervigilant.

It is known that inflammatory cytokines, including tumor necrosis factor-a, interleukin-1, and interleukin-6, can stimulate the HPA axis (79,80). CRH is believed to be an important mediator of the central stress response, and indeed animal studies have demonstrated that experimentally induced stress in rats that alters gut motility in a similar pattern to that seen with stress in humans, can be mimicked by intracerebroventricular or intravenous administration of CRH and blocked by a CRH antagonist, a-helical CRH (81). Interestingly,

Mast Cell Crh Stress

Figure 4 (See color insert) The functional anatomy of the hypothalamic-pituitary-adrenal axis. Stress stimulates release of CRH from the hypothalamus, which in turn stimulates the release of ACTH from the anterior pituitary. Cortisol released from the adrenal glands mediates the peripheral effects of this system whilst also providing feedback to higher centers. Abbreviations: CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone. Source: Adapted from Ref. 78.

Figure 4 (See color insert) The functional anatomy of the hypothalamic-pituitary-adrenal axis. Stress stimulates release of CRH from the hypothalamus, which in turn stimulates the release of ACTH from the anterior pituitary. Cortisol released from the adrenal glands mediates the peripheral effects of this system whilst also providing feedback to higher centers. Abbreviations: CRH, corticotropin-releasing hormone; ACTH, adrenocorticotropic hormone. Source: Adapted from Ref. 78.

Gue et al. reported that both stress and the administration of CRH (either centrally or intraper-itoneally) enhanced the number of abdominal cramps evoked by rectal distension in a rat model without affecting rectal compliance, suggesting a role of CRH in visceral hypersensitivity. These effects were also antagonized by a-helical CRH (82). This study also demonstrated that peripheral administration of doxantrazole, a mast cell stabilizer, suppressed stress and CRH-induced rectal hyperalgesia to rectal distension (82). It seems therefore that mast cell mediators are involved in the hypersensitivity response to rectal distension induced by stress. Previous studies have also highlighted the relationship between stress and colonic mast cell degranulation, and the fact that these effects can be reproduced by the administration of CRH (83); rather than, however, the mechanisms by which CRH modulates mast cell function are still unknown.

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