The localization of classical transmitters and neuropeptides within neurons in laminae I–III of the mammalian spinal dorsal horn

116

109

Opioid -and ␦-receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor (NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices and in vivo. ]-enkephalin (DPDPE) (1 M). In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the agonist trans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), deliveredat spinal cord segment L2 using intrathecal catheters. These doses of the and ␦ agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviorally as analgesic.

Section: Introductionmentioning

confidence: 87%

Inhibition by Spinal μ- and δ-Opioid Agonists of Afferent-Evoked Substance P Release

Kondo¹,

Marvizón²,

Song³

et al. 2005

116

109

“…Morphological and functional studies have revealed a tremendous diversity of dorsal horn neurons (Christensen and Perl, 1970;Lima and Coimbra, 1986;Todd and Spike, 1993;Han et al, 1998;Grudt and Perl, 2002;Todd and Koerber, 2006). Diversity of the dorsal horn neurons is further suggested by the expression of neuropeptides, including the opioid-like peptides Dynorphin (DYN) and enkephalin (ENK), the anti-opioid peptide cholecystokinin (CCK), the tachykinin peptides Substance P (SP) and Neurokinin B (NKB), somatostatin (SOM), and others (Marti et al, 1987;Todd and Spike, 1993;Todd and Koerber, 2006;Polgar et al, 2006). Functionally, neuropeptides modulate the transmission of somatic sensory information, particularly those involved with pain perception (Kajander et al, 1990;Xu et al, 1993;Wang et al, 2001;Wiesenfeld-Hallin et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Tlx1 and Tlx3 Coordinate Specification of Dorsal Horn Pain-Modulatory Peptidergic Neurons

Xu¹,

Lopes²,

Qian³

et al. 2008

113

The dorsal spinal cord synthesizes a variety of neuropeptides that modulate the transmission of nociceptive sensory information. Here, we used genetic fate mapping to show that Tlx3 ϩ spinal cord neurons and their derivatives represent a heterogeneous population of neurons, marked by partially overlapping expression of a set of neuropeptide genes, including those encoding the anti-opioid peptide cholecystokinin, pronociceptive Substance P (SP), Neurokinin B, and a late wave of somatostatin. Mutations of Tlx3 and Tlx1 result in a loss of expression of these peptide genes. Brn3a, a homeobox transcription factor, the expression of which is partly dependent on Tlx3, is required specifically for the early wave of SP expression. These studies suggest that Tlx1 and Tlx3 operate high in the regulatory hierarchy that coordinates specification of dorsal horn pain-modulatory peptidergic neurons.

“…Interneuron subtypes can be distinguished on the basis of morphology, neurotransmitter content, and receptor expression (Millan, 1999). For example, neurochemical markers of excitatory interneurons include glutamate, substance P, and vasoactive intestinal peptide, whereas receptors found predominantly in excitatory interneurons in lamina II include the AMPA subtype of ionotropic glutamate receptor (containing GluR2 and GluR3 subunits) and the -opioid receptor (MOR) (Todd and Spike, 1993;Arvidsson et al, 1995;Spike et al, 1998Spike et al, , 2002. At present, little is known about the functional relevance of specific interneuron subtypes.…”

Section: Introductionmentioning

confidence: 99%

Distinct Populations of Spinal Cord Lamina II Interneurons Expressing G-Protein-Gated Potassium Channels

Marker¹,

Luján²,

Colón

et al. 2006

Noxious stimuli are sensed and carried to the spinal cord dorsal horn by A␦ and C primary afferent fibers. Some of this input is relayed directly to supraspinal sites by projection neurons, whereas much of the input impinges on a heterogeneous population of interneurons in lamina II. Previously, we demonstrated that G-protein-gated inwardly rectifying potassium (GIRK) channels are expressed in lamina II of the mouse spinal cord and that pharmacologic ablation of spinal GIRK channels selectively blunts the analgesic effect of high but not lower doses of intrathecal -opioid receptor (MOR) agonists. Here, we report that GIRK channels formed by GIRK1 and GIRK2 subunits are found in two large populations of lamina II excitatory interneurons. One population displays relatively large apparent whole-cell capacitances and prominent GIRK-dependent current responses to the MOR agonist [D-Ala 2 ,N-MePhe 4 ,Gly-ol 5 ]-enkephalin (DAMGO). A second population shows smaller apparent capacitance values and a GIRK-dependent response to the GABA B receptor agonist baclofen, but not DAMGO. Ultrastructural analysis revealed that GIRK subunits preferentially label type I synaptic glomeruli, suggesting that GIRK-containing lamina II interneurons receive prominent input from C fibers, while receiving little input from A␦ fibers. Thus, excitatory interneurons in lamina II of the mouse spinal cord can be subdivided into different populations based on the neurotransmitter system coupled to GIRK channels. This important distinction will afford a unique opportunity to characterize spinal nociceptive circuitry with defined physiological significance.