Galanin antisense oligonucleotides reduce galanin levels in dorsal root ganglia and induce autotomy in rats after axotomy (original) (raw)
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Annals of the New York Academy of Sciences, 1998
Galanin can normally be detected only in a few dorsal root ganglion (DRG) neurons, but it is dramatically upregulated after peripheral nerve injury in both rat and monkey. Galanin is stored in large dense core vesicles, which after axotomy are often found close to the membrane of afferent nerve endings in the dorsal horn. In the monkey there is an increase in galanin in many nerve terminals in the superficial dorsal horn after axotomy, but such an increase is more difficult to detect in the rat. Galanin is also present in local dorsal horn neurons, where it is upregulated by peripheral inflammation. Both galanin-R1 and galanin-R2 receptor mRNAs are expressed in rat DRGs, mainly in, respectively, large and small DRG neurons. Galanin-R1 receptor mRNA is downregulated in DRG neurons after axotomy, and a small decrease in galanin-R2 receptor mRNA levels can also be seen. After peripheral tissue inflammation galanin-R1 receptor mRNA levels decrease and galanin-R2 receptor mRNA levels increase. The present results show that galanin and galanin receptors are present in sensory and local dorsal horn neurons and are regulated by nerve injury and inflammation. Galanin may therefore be involved in processing of pain information, primarily exerting analgesic effects. Whereas local dorsal horn neurons represent a defense system against inflammatory pain, we have proposed that a second defense system, against neuropathic pain, is intrinsic to DRG neurons.
Neuropeptides, 1998
Peripheral neurons begin to express galanin after axotomy. When neurons in the superior cervical ganglion were axotomized near (about 2 mm) from the ganglion, galanin-like immunoreactivity (IR) was maximal within 72 h. Axotomy of neurons in the middle and inferior cervical ganglion complex (MICG), which could be performed 2 cm from the ganglia, led to an additional galanin increase 7 and 14 days later. This second increase was not accompanied by changes in galanin mRNA or the number of galanin-immunostained neurons. Galanin-IR was detectable in a postganglionic trunk of the MICG 2 days after axotomy. At this time, immunoreactive fibers were only seen near the lesion site, while later they were found throughout the trunk. The data suggest that galanin is actively transported toward the site of nerve crush/transection and that the second increase in galanin-IR found in the MICG may be due to a saturation of the axonal transport system.
Journal of Chemical Neuroanatomy, 2008
Single ligature nerve constriction (SLNC) is a newly developed animal model for the study of neuropathic pain. SLNC of the rat sciatic nerve induces pain-related behaviors, as well as changes in the expression of neuropeptide tyrosine and the Y 1 receptor in lumbar dorsal root ganglia (DRGs) and spinal cord. In the present study, we have analyzed the expression of another neuropeptide, galanin, in lumbar DRGs and spinal cord after different degrees of constriction of the rat sciatic nerve. The nerve was ligated and reduced to 10-30, 40-80 or 90% of its original diameter (light, medium or strong SLNCs). At different times after injury (7, 14, 30, 60 days), lumbar 4 and 5 DRGs and the corresponding levels of the spinal cord were dissected out and processed for galanin-immunohistochemistry. In DRGs, SLNC induced a gradual increase in the number of galanin-immunoreactive (IR) neurons, in direct correlation with the degree of constriction. Thus, after light SLNC, a modest upregulation of galanin was observed, mainly in small-sized neurons. However, following medium or strong SLNCs, there was a more drastic increase in the number of galanin-IR neurons, involving also medium and large-sized cells. The highest numbers of galanin-IR neurons were detected 14 days after injury. In the dorsal horn of the spinal cord, medium and strong SLNCs induced a marked ipsilateral increase in galanin-like immunoreactivity in laminae I-II. These results show that galanin expression in DRGs and spinal cord is differentially regulated by different degrees of nerve constriction and further support its modulatory role on neuropathic pain. # Please cite this article in press as: Coronel, M.F. et al., Differential galanin upregulation in dorsal root ganglia and spinal cord after graded single ligature nerve constriction of the rat sciatic nerve,
Journal of Neurocytology, 1993
Using the indirect immunofluorescence method and in situ hybridization, the localization and levels of immunoreactivities and mRNAs for several neuropeptides were studied in lumbar dorsal root ganglia and spinal cord of untreated monkeys (Macaca mulatta) and after unilateral transection of the sciatic nerve. Immunoreactive galanin, calcitonin gene-related peptide, substance P and somatostatin and their mRNAs were found in cell bodies in dorsal root ganglia of untreated monkeys and on the contralateral side of the monkeys with unilateral sciatic nerve lesion. After axotomy there was a marked decrease in the number of calcitonin gene-related peptide-, substance P-and somatostatin-positive neurons in dorsal root ganglia ipsilateral to the lesion, whereas the number of galanin positive cells strongly increased. A few neuropeptide tyrosine-positive cells were seen in after axotomy, whereas no such neurons were found in controls. No vasoactive intestinal polypeptide-, peptide histidine isoleucine-, cholecystokinin-, dynorphin-, enkephalin-, neurotensin-or thyrotrophin releasing hormone-positive cell bodies were seen in dorsal root ganglia of any of the groups studied. In the dorsal horn of the spinal cord all peptide immunoreactivities described above, except thyrotropin releasing hormone, were found in varying numbers of nerve fibres with a similar distribution in untreated monkeys and in the contralateral dorsal horn in monkey with unilateral sciatic nerve lesion. Two cholecystokinin antisera were used directed against the C-and N-terminal portions, respectively, showing a distinctly different distribution pattern in the dorsal horn. Somatostatin-and dynorphin-like immunoreactivities were also observed in small neurons in the dorsal horn. No certain effect of axotomy on these interneurons could be seen. However, marked changes were observed after this type of lesion for some peptide containing fibres in the ipsilateral dorsal horn. Thus, there was a marked increase in galanin-like immunoreactivity, whereas calcitonin gene-related peptide-, substance P-, somatostatin-, peptide histidine isoleucine neurotensin-and cholecystokinin-like immunoreactivities decreased. No changes could be observed in neuropeptide tyrosine or enkephalin-positive fibres. The present results demonstrate marked ganglionic and transganglionic changes in peptide levels after peripheral axotomy. When compared to published results on the effect of axotomy on peptides in dorsal root ganglia and spinal cord of rat, both similarities and differences were encountered. Thus, in contrast to rat there was no marked upregulation of vasoactive intestinal polypeptide/peptide histidine isoleucine or neuropeptide tyrosine after axotomy in the monkey, whereas galanin was increased in both species. Both in monkey and rat, calcitonin gene-related peptide, substance P and somatostatin decreased. The decrease in neurotensin, peptide histidine isoleucine, and 'genuine' cholecystokinin seen in monkey after axotomy has not been reported in the rat. Experimental studies on rat suggest that galanin may be an endogenous analgesic compound, active particularly after peripheral nerve lesions. We have therefore recently proposed that galanin agonists may be used in treatment of chronic pain, and the present demonstration that galanin is regulated in a similar fashion in a primate gives further support to the proposal to test galanin as an analgesic in human.
Neuroscience Letters, 1999
Partial sciatic nerve ligation (PSNL) is a widely used model for the study of neuropathic pain. However, there is little information on neuropeptide expression in primary sensory neurons after PSNL. We examined galanin (GAL) mRNA expression in L4 and L5 dorsal root ganglion (DRG) neurons of adult rats after PSNL. We found that 4 and 14 days after PSNL the percentages of GAL mRNA positive neurons were significantly increased in the ipsilateral DRG compared to the contralateral side. Using combined retrograde fluorescent dye tracing and in situ hybridization, we found that 47% of the injured neurons and 10% of the spared neurons were GAL mRNA positive. Since only 2-3% of neurons in the contralateral uninjured DRG were GAL mRNA positive, PSNL induced up-regulation of GAL mRNA in both injured and spared DRG neurons.
Neuroscience Letters, 1997
Using in situ hybridization, we studied galanin-R2 receptor (GAL-R2-R) mRNA in rat lumbar 5 dorsal root ganglia (DRGs) at different time points after peripheral tissue inflammation and sciatic nerve transection (axotomy). About 25% of all normal DRG neuron profiles were GAL-R2-R mRNA-positive, and the majority was of the small type. In normal DRGs GAL-R2-R mRNA often ( ≈ 80%) colocalized with CGRP mRNA and sometimes ( ≈ 20%) with GAL-R1-R mRNA. There was a strong increase in the number and labeling intensity of GAL-R2-R mRNA-positive neuron profiles after peripheral tissue inflammation with a peak at 3 days, as well as a long-lasting decrease after axotomy. These results, together with the previously shown regulation of GAL and the GAL-R1-R, suggest that GALergic mechanisms participate in complex adaptive responses in DRGs after inflammation and nerve injury.
Galanin expression in adult human dorsal root ganglion neurons: initial observations
Neuroscience, 2003
Human dorsal root ganglia (DRGs) were obtained during various procedures and processed for single and double in situ hybridisation using oligonucleotide probes complementary to three peptide mRNAs. Some postmortem ganglia were also analysed. In donor (unlesioned) DRGs 12.5% of the neuron profiles (NPs) were galanin mRNA-positive (mRNA ؉), 47.5% calcitonin gene-related peptide (CGRP) mRNA ؉ and 32.7% substance P mRNA ؉. The corresponding percentages for cervical/thoracic DRGs from patients suffering from severe brachial plexus injury were 32.8%, 57.4% and 34.5%, respectively. In these DRGs a high proportion of the galanin mRNA ؉ NPs contained CGRP mRNA and substance P mRNA. In DRGs from a patient with migraine-like pain a comparatively small proportion expressed galanin, whereas in DRGs from a herpes zoster patient galanin mRNA ؉ NPs were comparatively more frequent. The results from human postmortem DRGs revealed only weak peptide mRNA signals. The present results demonstrate that galanin is expressed in DRGs not only in a number of animal species including monkey as previously shown, but also in a considerable proportion of human DRG neurons, often together with CGRP and substance P, and mostly in small neurons. Thus, galanin may play a role in processing of sensory information, especially pain, in human DRGs and dorsal horn. However, to what extent a similarly dramatic upregulation of galanin expression can be seen after peripheral nerve lesion in man, as has been reported for rat, mouse and monkey, remains to be analysed.