Receptors In Human Spinal Cord Research Articles

GDNF, RET and GFRalpha-1-3 mRNA expression in the developing human spinal cord and ganglia.

The identification of endogenous neurotrophic factors and their receptors in human spinal cord is important not only to understand development, but also in the consideration of possible future therapies for neurodegenerative disorders and trauma. Using in situ hybridization, the expression of glial cell line-derived neurotrophic factor (GDNF), neurturin (NTN), persephin (PSP), GFRalpha-1, GFRalpha-2, GFRalpha-3 and RET mRNA in human fetal spinal cord was studied. Strong GDNF mRNA hybridization signal, presumably restricted to Clarke's nucleus, was detected in the thoracic spinal cord. mRNA encoding GFRalpha-1 was expressed in the entire spinal cord gray matter with particularly high expression in the ventral horn. GFRbeta-1 was also expressed more weakly in dorsal root ganglia. NTN and persephin mRNA were not detected in either the fetal spinal cord or the dorsal root ganglia. mRNA coding for GFRalpha-2, however, was found in most cells of the spinal cord gray matter. A strong expression of GFRalpha-3 mRNA was detected in dorsal root ganglia cells and Schwann cells. The transducing receptor RET was expressed strongly in motorneurons and dorsal root ganglion neurons. We conclude that basic features concerning the role of the GDNF family of ligands and their receptors revealed in rodents applies to humans.

α 1-Adrenergic receptors in human spinal cord: specific localized expression of mRNA encoding α 1-adrenergic receptor subtypes at four distinct levels

α 1-Adrenergic receptors (α 1ARs) are important in lower urinary tract syndromes such as benign prostatic hypertrophy and bladder irritability. Spinal cord α 1ARs have been postulated to play a role in modulating these diseases, yet α 1AR subtype (α 1a, α 1b, α 1d) neuronal localization in human spinal cord has not been described. We therefore tested the hypothesis that α 1AR subtype distribution varies according to specific spinal cord tract and level. In situ hybridization was performed to identify cell bodies containing α 1AR subtype mRNA at four levels of human spinal cord (cervical enlargement, thoracic, lumbar, sacral). α 1AR mRNA is present in ventral gray matter only (ventral>dorsal; sacral>lumbar=thoracic>cervical). Signaling cell bodies were detected in anterior horn motor neurons at all levels; dorsal nucleus of Clarke and intermediolateral columns in cervical enlargement, thoracic and lumbar spinal cord regions; and parasympathetic nucleus in sacral spinal cord. Although all three α 1AR subtypes are present throughout human spinal cord, α 1d mRNA predominates overall. If confirmed at a protein level, these findings may contribute to the development of new therapeutic strategies in the treatment of several human diseases.

Analysis of NMDA receptors in the human spinal cord.

NMDA receptors in postmortem human spinal cord were analyzed using [3H]MK-801 ligand binding and immunoblotting with NMDA receptor subunit-specific antibodies. The average KD for [3H]MK-801 binding was 1.77 nM with a Bmax of 0.103 pmol/mg. The EC50 for stimulation of -3H-MK-801 binding with L-glutamate was 0.34 microM. None of these parameters were affected by postmortem intervals up to 72 h. Immunoblotting of native NMDA receptors showed that NR1, NR2A, NR2C, and NR2D subunits could all be found in the human spinal cord of which NR1 was preferentially located to the dorsal half. Immunoprecipitation of solubilized receptors revealed that NR1, NR2C, and NR2D subunits coprecipitated with the NR2A subunit, indicating that native human spinal cord NMDA receptors are heteroligimeric receptors assembled by at least three different receptor subunits. These results provide a basis for the development of drugs selectively aimed at spinal cord NMDA receptors for the future treatment of spinal cord disorders.

No protective effect of the NMDA antagonist memantine in experimental spinal cord injuries.

We have investigated the effect of memantine, a clinically used NMDA receptor antagonist, in two experimental animals models of spinal cord injury. The lesions were laser-induced photothrombosis to induce focal spinal cord ischemia and clip compression to mimic traumatic spinal cord injury. Pre- or posttreatment of rats with a dose of memantine (20 mg/kg ip) previously shown to be neuroprotective in cerebral ischemia, failed to affect both the neurological and morphological outcome of ischemic spinal cord injury. Likewise, memantine had no effects on neurological and morphological outcome after experimental traumatic injury. In view of the regional heterogeneity of NMDA receptors, the affinity of memantine for spinal cord NMDA receptors was also determined by studying displacement of [3H] (+)-5-methyl-10,11-dihydro-5-H-dibenzo[a,d]cyclohepten-5-10-imine (MK-801) to rat and human spinal cord homogenates. We found that memantine had an affinity for NMDA receptors in the spinal cord (Ki = 0.58 microM) that was significantly lower compared to that of the cerebral cortex (Ki = 0.23 microM) and that the affinity for NMDA receptors in human spinal cord was even lower. We conclude that in view of available data, memantine should not be chosen for clinical studies on neuroprotection in spinal cord injuries and that the lack of protective effect is most likely due to insufficient affinity of memantine for spinal cord NMDA receptors.

Insulin-like growth factor-1 receptors in human spinal cord: changes in amyotrophic lateral sclerosis.

Neurotrophic factors are important for neuronal survival and maintenance in the adult nervous system. The regional distribution of insulin-like growth factor-1 (IGF-1) receptors in human spinal cords from controls and amyotrophic lateral sclerosis (ALS) patients was studied by immunohistochemistry and quantitative autoradiography. When comparing 125I-IGF-1 binding in the different spinal levels of normal spinal cord the same distribution pattern was found in which the binding was highest in the central canal > dorsal horn > ventral horn > white matter. In the ALS cases although a general upregulation of IGF-1 receptors was observed throughout the spinal cord, significant increases were observed in the cervical and sacral segments compared to controls. IGF-1 receptor immunoreactivity showed a similar pattern to that for 125I-IGF-1 binding, with immunoreactivity being found in the gray matter of the spinal cord and enhanced immunoreactivity occuring in ALS patients compared to controls. In agreement with the distribution of IGF-1 receptors, IGF-1 immunoreactivity was found within the gray matter of the spinal cord. The cartography of IGF-1 receptors in the normal spinal cord as well as the change of these receptors in diseased spinal cord may be of importance in future treatment strategies of ALS.

Autoradiographic localisation of NMDA, quisqualate and kainic acid receptors in human spinal cord

The phencyclidine (PCP) binding site of the N- methyl- d-aspartate receptor, the kainic acid (KA) receptor and the quisqualate (QA) receptor were visualised, using autoradiography in the human spinal cord and the distributions compared with that of benzodiazepine (BDZ) receptors and substance P (SP). All of the receptor types, and SP, were concentrated in lamina II of the dorsal horn, consistent with physiological data indicating that glutamate is a neurotransmitter of primary afferent terminals in the spinal cord.

Autoradiographic localization of thyrotropin-releasing hormone (TRH) receptors in human spinal cord.

Thyrotropin-releasing hormone (TRH) exerts many effects upon spinal cord function in animals, and may also play a role in human spinal cord function. We have used the technique of quantitative autoradiography to anatomically localize specific receptors for TRH within human spinal cord. Highest concentrations of TRH receptors were localized within lamina II, the substantia gelatinosa. A moderate density of TRH receptors was found in lamina IX, the motor neurons of the anterior horn. Low levels of TRH receptors were noted throughout the remainder of the gray matter of the human spinal cord, and no TRH receptors were localized within white matter. This anatomic distribution of TRH receptors within the human spinal cord is consistent with the localization of endogenous TRH and the effects of exogenously applied TRH in animal studies. These results suggest that any effects of TRH on human spinal cord function may be mediated by TRH receptors.