A role for extracellular signal-regulated kinases 1 and 2 in the maintenance of persistent mechanical hyperalgesia in ovariectomized mice

• Published in: Neuroscience Vol. 172; no. 1; pp. 483 - 493
• Main Authors: Klinger, M.B, Sacks, S, Cervero, F
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 13.01.2011; Elsevier
• Subjects: Animals; Biological and medical sciences; Disease Models, Animal; estradiol; Estrogens - deficiency; Estrogens - pharmacology; Extracellular Signal-Regulated MAP Kinases - physiology; Female; Fundamental and applied biological sciences. Psychology; Hyperalgesia - enzymology; Hyperalgesia - etiology; Hyperalgesia - physiopathology; Medical sciences; Mice; Mice, Inbred C57BL; mitogen activated protein kinase; Mitogen-Activated Protein Kinase 3 - physiology; Nervous system (semeiology, syndromes); Nervous system as a whole; Neurology; Nociceptors - enzymology; Ovariectomy - adverse effects; p38; pain; Pain Measurement - methods; spinal cord; Spinal Cord - enzymology; Spinal Cord - physiopathology; Vertebrates: nervous system and sense organs; pain; DMSO; extracellular signal-regulated kinases 1 and 2; mitogen activated protein kinase; MAPK; artificial cerebrospinal fluid; mitogen-activated protein kinase; OVX; dimethyl sulfoxide; p38; aCSF; ERK 1/2; spinal cord; ovariectomy; estradiol; Nervous system diseases; Spinal cord; Extracellular signal-regulated protein kinase; Ovariectomy; Enzyme; Transferases; Estrogen; Rodentia; Central nervous system; Mitogen-activated protein kinase; Estradiol; Ovarian hormone; Hyperalgesia; Vertebrata; Mammalia; Pain; Mouse; Animal; Sex steroid hormone
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2010.10.043

Abstract Mitogen-activated protein kinases (MAPKs) are important signaling factors in many cellular processes including cell proliferation and survival during development and synaptic plasticity induced by acute nociception in the adult. There is extensive evidence for the involvement of members of the MAPK family, the extracellular signal-regulated kinases 1 and 2 (ERKs 1/2), in the development of acute inflammatory somatic and visceral pain, but their role in the maintenance of chronic pain states is unknown. We have previously shown that ovariectomy of adult mice (OVX) generates a persistent and estrogen-dependent abdominal hyperalgesic state that lasts for several months and is not related to a persistent nociceptive afferent input. Here we have used OVX mice to study a possible role of ERK 1/2 in the spinal processing of this form of chronic abdominal hyperalgesia. Eight weeks after OVX the mice showed a robust abdominal hyperalgesia and a significant increase in the activation of ERK1/2 in the lumbosacral spinal cord. This enhanced activation was not seen in control and sham-operated mice or in regions of the cord other than lumbosacral in OVX mice. Also, the increased activation of ERK 1/2 observed in OVX mice matched the time course of the hyperalgesic state as no activation was observed at week 1 after OVX when the hyperalgesic state had not yet developed. Administration of slow-release pellets containing 17β-estradiol at week 5 post OVX reversed both the development of the hyperalgesia and the enhanced activation of ERK 1/2, suggesting that this activation, like the hyperalgesic state, was estrogen-dependent. Intrathecal injections of the ERK 1/2 inhibitor U0126 successfully rescued the mice from the abdominal hyperalgesia for up to 24 h after the injection and also reversed the enhanced expression of ERK 1/2. Our study shows, for the first time, activation of ERK 1/2 in the spinal cord matching the time course of an estrogen-dependent chronic hyperalgesic state.