Postnatal development of ectopic sensory fibers containing endomorphin-2 in the white matter of the spinal cord of a transgenic mouse expressing nerve growth factor in oligodendrocytes.
Transgenic mice ectopically expressing nerve growth factor in oligodendrocytes have high levels of nerve growth factor immunoreactivity in the white matter of the spinal cord from birth until 2 months of age. The nerve growth factor over-expression leads to the appearance of ectopic substance P containing sensory fibers in the white matter of the spinal cord that persist throughout the life of the animal. These transgenic mice have been found to display hypersensitivity to a thermal stimulus following a sensitizing pinch stimulus known to release endogenous substance P. Surprisingly, this hypersensitivity is completely reversed following the administration of morphine, to the extent that transgenic mice become less sensitive to pain than the wild type mice given morphine. Endomorphin-2, an endogenous opioid peptide, has been found co-localized with substance P in primary sensory fibers in the spinal cord. In this study, we show that the ectopic fibers also express endomorphin-2, and describe the postnatal development of such expression, as detected by immunocytochemistry. We confirmed that endomorphin-2 expression starts later in the postnatal period than substance P. Surprisingly, transgenic animals had delayed appearance of endomorphin-2 in the superficial dorsal horn, compared with wild type, and expressed particularly high levels of endomorphin-2 immunoreactivity in the ectopic fibers from postnatal days 10-30, coinciding with the peak of nerve growth factor expression in oligodendrocytes. Endomorphin-2 immunoreactivity was still readily detected in ectopic fibers of 120-day-old animals. Furthermore, we detected immunoreactivity for the mu-opioid receptor in the ectopic fibers, where it was co-localized with endomorphin-2 immunoreactivity. In the superficial dorsal horn, there were no apparent differences in the distribution and intensity of mu-opioid receptor immunoreactivity between wild type and transgenic animals. Taken together, these data could provide an explanation for the enhanced effect of opioid analgesics in transgenic mice, when compared with control mice, as well as provide the basis for studies of the postnatal development of the hyperalgesia and allodynia demonstrated by these animals.
Dorfman
H N
HN
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Bailey
A L
AL
St Louis
M
M
Zadina
J E
JE
Ribeiro-da-Silva
A
A
D000818:Animals; D000831:Animals, Newborn; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D020932:Nerve Growth Factor / Q000096:biosynthesis*; D009475:Neurons, Afferent / Q000378:metabolism*; D009836:Oligodendroglia / Q000378:metabolism*; D009842:Oligopeptides / Q000096:biosynthesis*; D010146:Pain / Q000503:physiopathology*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism*; D013373:Substance P / Q000096:biosynthesis
D009842:Oligopeptides; D017450:Receptors, Opioid, mu; D013373:Substance P; C105294:endomorphin 2; D020932:Nerve Growth Factor