Acta Derm Venereol 87 night may provide another plausible explanation for the nocturnal exacerbation of pruritus (17). Itch has been reported to be aggravated by ambient heat (2) and it has been suggested that heat can increase itch sensation by its effect on nerve endings (20). Pruritus and pain have a complex interaction, which is only beginning to be elucidated. A reduction in pain can induce itch, while a painful stimuli can reduce it. Furthermore, different opioid receptors have varying effects upon pruritus. Both μ-opioid receptor agonists and κ-opioid receptor antagonists can induce itch while, unsurprisingly, μ-receptor antagonists and κ-receptor agonists can reduce it (21). In addition, it has been shown that patients with atopic dermatitis have a significantly increased concentration of serum β-endorphin compared with controls (22) and that there is a significant down-regulation of μ-opioid receptor expression in the epidermis of such patients (23). Interestingly, β-endorphin has also been reported to be associated with both itch intensity and disease severity in atopic dermatitis patients (18). All of these observations are of relevance given the well-documented circadian rhythm of pain (24). Although the exact pattern of pain perception varies with different disease processes, both human and animal data show that there is a clear circadian rhythm to plasma and brain concentrations of β-endorphin and enkephalins, with peak values always occurring during the activity period (24). One hypothesis accounting for nocturnal pruritus involves a dysfunction of the circadian rhythm releasing different opioids, with peaks occurring during evening hours as opposed to the morning. Interestingly, a dysfunction in the diurnal secretion of melatonin, the principle hormone regulating circadian rhythm, has already been reported in patients with atopic dermatitis (25). One of the most important circadian rhythms in the human body involves the hypothalamus-pituitary axis. Corticosteroid levels are normally at a trough in the evening, meaning the anti-inflammatory effects of this hormone are at a minimum during this time, possibly allowing for an exacerbation of inflammatory skin diseases. Another important circadian rhythm involves the autonomic nervous system (ANS), where parasympathetic tone is increased during the night and sympathetic tone in the morning (26). This circadian rhythm in ANS function has been suggested to play a role in nocturnal asthma (27) and thus may also have a role to play in pruritic exacerbations of atopic dermatitis during the night given the vast overlap between these two disease processes.

Other plausible explanations for nocturnal pruritus may be related to the disruption of the cytokine and prostaglandin (PG) circadian patterns. Interleukin (IL)-2, IL-8 and IL-31 have all been shown to induce itch, while interferon (INF)-γ demonstrated a beneficial effect (28). It has been shown that there is a nocturnal increase in secretion of IL-2 in healthy volunteers, possibly making more susceptible individuals prone to itch (29). With regards to PGs, a diurnal change in secretion from rat diaphyseal bone has been reported (30). Except for prostacyclin, elevated secretion of PGD2, PGE2 and thromboxane B2 occurred during the evening and night hours. Of note, the painful bone conditions of osteoid osteoma (31) and osteolytic metastatic cancer (32) have also shown elevations in PG levels. In addition, it has been suggested that PGD2 and PGE2 accelerate the recovery process of cutaneous barrier disruption caused by mechanical scratching, via specific prostanoid DP1, EP3 and EP4 receptors (33). We postulate that the circadian rhythm of PG is disrupted in …