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Regulation of signaling molecules in sensory neurons and spinal cord : Studies on nerve injury models and transgenic mice

By Tie-Jun Shi


Nerve injury may cause neuropathic pain in patients. Similar symptoms can also be seen in some animal models. Evidence from animal studies indicates that neuropathic pain may be associated with changes in expression of neurotransmitters/modulators, and/or other molecules and their receptors in the sensory system, such as dorsal root ganglia (DRGs) and spinal cord. In this study, emphasis is on several neuropeptides, including galanin (GAL), neuropeptide Y (NPY), substance P (SP) and calcitonin generelated peptide (CORP). Also receptors, such as the GALR2 receptor (GALR2) and the NPY Y2 receptor (Y2R) have been analysed. Moreover, several other molecules were included, such as cyclic guanosine monophosphate (cGMP), nitric oxide (NO) as well as three alpha2-adrenoceptor (AR) subtypes(alpha2A-, alpha2Band alpha2C-ARs): Our findings include: 1) a large number of DRG neurons (24%) were lost in mice relatively rapidly (one week) after axotomy, and half of the population after one month. With regard to expression of GAL and NPY after axotomy, a marked difference was observed when using stereological counting method versus profile counting method, demonstrating that the latter method may give erroneous results due to distribution of the peptides in different subpopulations of DRG neurons and due to cell loss with a concomitant shift in DRG neuron size-distribution; 2) studies on GALR2, together with the previously shown regulations of GAL and GALR1, suggest that GALergic mechanisms participate in the complex adaptive responses in DRGs after peripheral injury; 3) under normal conditions NPY may act on Y1- and Y2Rs in, respectively, small and large CGRP-positive DRG neurons in the rat. The Y2R may be an important receptor in somato-sensory neurons, also after axotomy, serving as a presynaptic and/or autoreceptor in rat DRGs, superior cervical ganglia, nodose ganglia and as a presynaptic receptor in monkey DRG neurons; 4) the expression and regulation of GAL and NPY in different neuropathic pain models suggest that endogenous GAL may influence to what extent allodynia develops in the Bennett model; 5) lack of NPY caused exaggerated autotomy behaviour in NPY knock-out (KO) mice. Significant differences in levels of Y I - and Y2R mRNAs were found between KO and wild-type (WT) mice, but they were only moderate, suggesting that the expression, regulation, localization and possible function of Y1 and Y2Rs are not dependent on presence of their endogenous ligand; 6) data from Y1R KO mouse suggest that the Y1R protects DRG neurons against neuron loss induced by peripheral nerve injury. The decreased mechanical threshold may be due to absence of Y1Rs in inter- and/or probable projection neurons in laminae I-IV and/or possibly increased release of CORP and SP in the dorsal horn in the KO as compared to WT mouse; 7) CORP mRNA-positive and immunoreactive neurons were found in mouse spinal dorsal horn This result indicates that CORP is synthesized in local dorsal horn neurons and participates in sensory processing; 8) axotomy, but not inflammation, causes increased levels of cGMP in many lumbar DRG satellite cells. Thus the increase in NOS levels in DRG neurons after axotomy presumably leads to increased NO release, acting on satellite cells. Therefore NO may not only be a neuron-to-neuron but also a neuron-to-glia messenger; 9) the expression of alpha2-ARs in DRGs suggests that the alpha2A-AR represents the most likely candidate in DRG neurons to be involved in transmission of nociceptive information after nerve injury, and presence of three alpha2-AR subtype mRNAs in dorsal hom neurons suggests that also here these receptors are involved in sensory information processing

Topics: Behaviour, cell loss, dorsal root ganglion, immunohistochemistry, in situ hybridization, mRNA, nerve injury, neuropathic pain, neuropeptides, nociception, primary sensory neuron, spinal cord.
Publisher: Institutionen för neurovetenskap / Department of Neuroscience
Year: 2001
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