title: Regionally selective activation of ERK and JNK in morphine paradoxical hyperalgesia: a step toward improving opioid pain therapy.
abstract: In addition to analgesia, opioid agonists may increase pain sensitivity under different conditions varying dose and administration pattern. While opioid hyperalgesia induced by tolerance and withdrawal is largely studied, little is known on the mechanisms underlying ultra-low dose morphine hyperalgesia. This pronociceptive response appears to play an opposing role in morphine analgesia and might have clinical relevance. Ultra-low dose morphine elicited thermal hyperalgesia through activation of μ opioid receptors. To elucidate the intracellular mechanism of morphine nociceptive behaviour, we investigated the mitogen-activated protein kinase (MAPK), crucial pathways in pain hypersensitivity. The catalytic activity of extracellular signal-regulated kinase (ERK), p38, c-Jun-N-terminal kinase (JNK), upstream modulators and transcription factors was investigated in the mouse periaqueductal grey matter (PAG), thalamus and prefrontal cortex by western blotting. Ultra-low dose morphine intensively increased pERK1 contents in the PAG and cortex and, to a lesser extent, increased cortical ERK2 and JNK phosphorylation. No involvement of p38 was detected. Morphine exposure also increased phosphorylation of cortical c-Jun whereas levels of phosphorylated cAMP response element-binding protein (CREB) remained unmodified. Blockade of protein kinase C (PKC) prevented increases in phosphorylation showing a PKC-dependent mechanism of activation. Pharmacological inhibitors of PKC, ERK, and JNK activity prevented morphine hyperalgesia. No modulation of MAPK and transcription factors' activity was detected in the thalamus. These results support the concept that selective activation of ERK and JNK on descending pathways plays an important role in ultra-low dose morphine hyperalgesia. The modulation of these signalling processes might improve pain management with opiate analgesics.
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale G. Pieraccini 6, I-50139, Florence, Italy.
authors.forename: Maria Domenica
authors.initials: MD
authors.lastname: Sanna
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale G. Pieraccini 6, I-50139, Florence, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Ghelardini
authors.affiliation: Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmacology, University of Florence, Viale G. Pieraccini 6, I-50139, Florence, Italy. Electronic address: nicoletta.galeotti@unifi.it.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Galeotti
mesh_terms: D000818:Animals; D050882:CREB-Binding Protein / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced* / Q000188:drug therapy / Q000201:enzymology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D009294:Narcotics / Q000494:pharmacology*; D010487:Periaqueductal Gray / Q000187:drug effects / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000187:drug effects / Q000201:enzymology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011897:Random Allocation; D017450:Receptors, Opioid, mu / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013788:Thalamus / Q000187:drug effects / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D009294:Narcotics; D017450:Receptors, Opioid, mu; D009020:Morphine; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D011493:Protein Kinase C; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Hyperalgesia; MAPK; Morphine; Pain; Protein kinase C