Effects of acute and chronic restraint stress on nitroglycerin-induced hyperalgesia in rats

Nitric oxide (NO) plays an important role in initiation and maintenance of pain, and NO precursor nitroglycerin is able to activate spinal and brain structures involved in nociception. It is also known that acute and chronic stress induce biochemical changes affecting both pain threshold and behaviour, and that the biological pattern of depression can be mimicked in the laboratory using chronic unavoidable stress paradigms (learned helplessness). We, therefore, evaluated the effects of acute and chronic immobilization stress on pain response to nitroglycerin administration in the rat. Pain perception was expressed as the latency of response to a tail-flick test (hot stimulus). Measures were made 1, 2 and 4 h following nitroglycerin (10 mg/kg i.p.) or vehicle. Nitroglycerin caused hyperalgesia after 2 and 4 h (p < 0.05 versus baseline). Acute stress (90 min) induced a clear analgesic state (p < 0.01 versus non-stressed control animals), and nitroglycerin injection was unable to reverse stress-induced analgesia in this setting. By contrast, exposition to chronic immobilization stress (7 days) caused a significant increase in pain response (p < 0.05); in this case, hyperalgesia was shown to be further enhanced by nitroglycerin administration (p < 0.05 versus vehicle). These findings support the view that a condition of chronic stress used in the laboratory to reproduce the biological features of depression can enhance hyperalgesia induced by nitroglycerin administration. These observations may be relevant to pain disorders, and particularly to migraine, since nitroglycerin is able to induce spontaneous-like pain attacks in humans, and an unfavourable migraine outcome (transformation into a chronic daily headache) is associated with chronic stress and comorbid depression.