%0 Journal Article %~ Pubmed %A Fioretti, Bernard %A Catacuzzeno, Luigi %A Sforna, Luigi %A Gerke-Duncan, Michelle B %A van den Maagdenberg, Arn Mjm %A Franciolini, Fabio %A Connor, Mark %A Pietrobon, Daniela %T Trigeminal ganglion neuron subtype-specific alterations of CaV2.1 calcium current and excitability in a Cacna1a mouse model of migraine. %B The Journal of Physiology %D 2011 %V %N %P %@ 1469-7793 %X Familial hemiplegic migraine type-1 (FHM1), a monogenic subtype of migraine with aura, is caused by gain-of-function mutations in CaV2.1 (P/Q-type) calcium channels. The consequences of FHM1 mutations on the trigeminovascular pathway that generates migraine headache remain largely unexplored. Here we studied the calcium currents and excitability properties of two subpopulations of small diameter trigeminal ganglion (TG) neurons from adult wild-type (WT) and R192Q FHM1 knockin (KI) mice: capsaicin-sensitive neurons without T-type calcium currents (CS) and capsaicin-insensitive neurons characterized by the expression of T-type calcium currents (CI-T). Small TG neurons retrogradely labelled from the dura are mostly CS neurons, while CI-T neurons were not present in the labelled population. CS and CI-T neurons express CaV2.1 channels with different activation properties, and the CaV2.1 channels are differently affected by the FHM1 mutation in the two TG neuron subtypes. In CI-T neurons from FHM1 KI mice there was a larger P/Q-type current density following mild depolarizations, a larger action potential (AP)-evoked calcium current and a longer AP duration when compared to CI-T neurons from WT mice. In striking contrast, the P/Q-type current density, voltage dependence and kinetics were not altered by the FHM1 mutation in CS neurons. Also unaltered were the excitability properties of mutant CS neurons. Congruently, the FHM1 mutation did not alter depolarization-evoked CGRP release from the dura mater, while CGRP release from the trigeminal ganglion was larger in KI compared to WT mice. Our findings suggest that the facilitation of peripheral mechanisms of CGRP action, such as dural vasodilation and nociceptor sensitization at the meninges, does not contribute to the generation of headache in FHM1. %Z FOR Codes: 110902 %0 Journal Article %~ Pubmed %A Thornton, Peter D J %A Gerke, Michelle B %A Plenderleith, Mark B %T Histochemical localisation of a galactose-containing glycoconjugate expressed by sensory neurones innervating different peripheral tissues in the rat. %B Journal of the peripheral nervous system : JPNS %D 2005 %V 10 %N 1 %P 47-57 %@ 1085-9489 %X The plant lectin Bandeiraea simplicifolia I-isolectin B4 (BSI-B4) identifies a galactose-containing, membrane-associated glycoconjugate expressed by a discrete subpopulation of unmyelinated primary sensory neurones in the rat. We have previously suggested that BSI-B4 selectively binds to primary sensory neurones that innervate the skin. However, in that study, the tracer diamidino yellow was applied to the cut ends of peripheral nerves to identify neurones innervating particular target tissues. In this study, we have avoided axotomy by retrogradely labelling primary sensory neurones from peripheral tissues using the carbocyanine dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbacyanine perchlorate (DiI). DiI was injected into the plantar skin, gastrocnemius muscle, and pyloric region of the stomach in rats. Corresponding ganglia were sectioned, incubated in BSI-B4 conjugated to fluorescein isothiocyanate, and examined with a fluorescence microscope. DiI-labelled cells were identified by red fluorescence within the cytoplasm, whereas cells binding BSI-B4 displayed green fluorescence associated with the plasma membrane and Golgi apparatus. Quantitative analysis revealed that 36.2% of cutaneous neurones, 7.6% of muscle neurones, and 6.8% of visceral neurones expressed the BSI-B4-binding site, indicating that a small but significant proportion of small-diameter primary sensory neurones innervating muscle and viscera also express BSI-B4-binding sites. %Z FOR Codes: 110906 %0 Journal Article %~ Pubmed %A Bagley, Elena E %A Gerke, Michelle B %A Vaughan, Christopher W %A Hack, Stephen P %A Christie, MacDonald J %T GABA transporter currents activated by protein kinase A excite midbrain neurons during opioid withdrawal. %B Neuron %D 2005 %V 45 %N 3 %P 433-45 %@ 0896-6273 %X Adaptations in neurons of the midbrain periaqueductal gray (PAG) induced by chronic morphine treatment mediate expression of many signs of opioid withdrawal. The abnormally elevated action potential rate of opioid-sensitive PAG neurons is a likely cellular mechanism for withdrawal expression. We report here that opioid withdrawal in vitro induced an opioid-sensitive cation current that was mediated by the GABA transporter-1 (GAT-1) and required activation of protein kinase A (PKA) for its expression. Inhibition of GAT-1 or PKA also prevented withdrawal-induced hyperexcitation of PAG neurons. Our findings indicate that GAT-1 currents can directly increase the action potential rates of neurons and that GAT-1 may be a target for therapy to alleviate opioid-withdrawal symptoms. %Z FOR Codes: 110903 %0 Journal Article %~ Pubmed %A Gerke, M B %A Plenderleith, M B %T Ultrastructural analysis of the central terminals of primary sensory neurones labelled by transganglionic transport of bandeiraea simplicifolia I-isolectin B4. %B Neuroscience %D 2004 %V 127 %N 1 %P 165-75 %@ 0306-4522 %X In this study the ultrastructural appearance of primary sensory neurones labelled by the injection of the plant lectin Bandeiraea simplicifolia I-isolectin B(4) (BSI-B(4)) into a peripheral nerve has been examined in the rat. Electron microscopy of the somata of retrogradely labelled neurones showed the lectin to be associated with the inner surface of cytoplasmic vesicles, supporting the premise that the uptake of BSI-B(4) into sensory neurones is by the process of receptor-mediated endocytosis. Light and electron microscopic analysis of the spinal cord revealed transganglionically transported lectin in unmyelinated axons in the dorsolateral funiculus and axon terminals concentrated mainly within lamina II of the dorsal horn. Detailed analysis of 1377 of these axon terminals revealed that the majority were glomerular in shape and surrounded by up to 14 other unlabelled profiles. These findings suggest that primary sensory neurones which transganglionically transport BSI-B(4) have a synaptic ultrastructure similar to that which has been previously reported for unmyelinated primary sensory neurones. Moreover, it appears that the axon terminals of these neurones are subjected to extensive modulation. Examination of the vesicle content of lectin labelled axon terminals revealed that the majority contained small agranular vesicles while large granular vesicles were observed only occasionally. These findings support the suggestion that the populations of neurones expressing binding sites for BSI-B(4) are fairly distinct from those containing neuroactive peptides. In conclusion, the results of the current study suggest that the lectin BSI-B(4) can be used as a histological marker for a subpopulation of small diameter primary sensory neurones and provide further evidence for the potential of this lectin as a useful tool in the study of pain. %0 Journal Article %~ Pubmed %A Gerke, Michelle B %A Plenderleith, Mark B %T Analysis of the unmyelinated primary sensory neurone projection through the dorsal columns of the rat spinal cord using transganglionic transport of the plant lectin Bandeiraea simplicifolia I-isolectin B4. %B Journal of the Neurological Sciences %D 2004 %V 221 %N 1-2 %P 69-77 %@ 0022-510X %X We have examined the projection of unmyelinated primary sensory neurones through the dorsal columns of the rat spinal cord using transganglionic transport of the plant lectin Bandeiraea simplicifolia I-isolectin B4. A small volume of the lectin was injected into the sciatic nerve of anaesthetised rats to label the central terminals of nociceptive primary sensory neurones. Following a survival period of 7 days, transverse and longitudinal sections of the superficial dorsal horn, dorsolateral funiculus and the dorsal columns from spinal segments L4 through to T13 were screened for lectin transport using light and electron microscopy. Longitudinal sections of the thoraco-lumbar region of spinal cord were also examined for lectin binding. Light and electron microscopy revealed transganglionically transported and bound lectin in the superficial dorsal horn and dorsolateral funiculus of the L3 and L4 segments of spinal cord. However, no lectin transport or binding was observed within the dorsal columns at any level of spinal cord examined. From these results, we suggest that the unmyelinated neurones within the dorsal columns do not express the binding site for BSI-B4 and, as such, may be responsible for visceral rather than cutaneous sensation. In line with the theories regarding a postsynaptic dorsal column pathway, these results suggest that nociceptors that bind BSI-B4 are not involved in a direct ascending projection through the dorsal columns. %0 Journal Article %~ Pubmed %A Gerke, M B %A Duggan, A W %A Xu, L %A Siddall, P J %T Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury. %B Neuroscience %D 2003 %V 117 %N 3 %P 715-22 %@ 0306-4522 %X Pain and allodynia following spinal cord injury are poorly understood and difficult to treat. Since there is evidence that supraspinal mechanisms are important in such pain, we have studied the role of the thalamus in an experimental model of spinal injury. Extracellular recordings were obtained from neurones of the thalamic nucleus ventralis postero-lateralis (VPL) in normal rats and those which had sustained a contusive spinal cord injury to the thoraco-lumbar junction 7 days previously. Behavioural testing with von Frey hairs established that 11 spinally injured rats showed exaggerated vocal responses to normally innocuous mechanical stimulation (allodynia) whereas eight were non-allodynic. Thalamic VPL neurones in spinally injured rats (both allodynic and non-allodynic) exhibited a dysrhythmia in that a significantly higher proportion fired spontaneously in an oscillatory mode when compared with neurones in uninjured rats. Thus this dysrhythmia was linked to spinal injury, not to allodynia. The evoked responses of VPL thalamic neurones to brushing the skin, however, were significantly elevated in allodynic rats when compared with those in uninjured rats and neuronal afterdischarges to these stimuli (which were absent in uninjured rats) were more common in allodynic than in non-allodynic rats. We have previously reported that a proportion of spinal neurones in allodynic spinally injured rats show increased evoked responses and afterdischarges following brushing the skin and hence the enhanced thalamic responses may reflect a greater spinal input. In view of the increasing evidence that thalamo-cortical rhythmical firing is linked to sensorimotor and cognitive brain functions, we propose that pain following brushing the skin results from an exaggerated spinal input being processed by a dysrhythmic thalamus. Thus both spinal and thalamic mechanisms may be important in the genesis of pain and allodynia following spinal cord injury. %Z FOR Codes: 110999 %0 Journal Article %A Gerke, MB %A Plenderleith, MB %T Distribution of binding sites for the plant lectin Ulex europaeus agglutinin I on primary sensory neurones in seven different mammalian species %B Histochemical Journal %D 2002 %C Van Godewijckstraat 30, Dordrecht, Netherlands, 3311 Gz %I Kluwer Academic Publ %V 34 %N %P 79-84 %@ 0018-2214 %X %0 Journal Article %A Gerke, MB %A Plenderleith, M %T Analysis of the Distribution of Binding Sites for the Plant Lectin Bandeiraea simplicifolia I-Isolectin B4 on Primary Sensory Neurones in Seven Mammalian Species %B Anatomical Record %D 2002 %C Div John Wiley & Sons Inc,605 Third Ave, New York, Ny, 10158-0012 %I Wiley-Liss %V 268 %N %P 105-114 %@ 0003-276X %X