Opioid receptor signaling via EGF receptor (EGFR) transactivation and ERK/MAPK phosphorylation initiates diverse cellular responses that are cell type-dependent. In astrocytes, multiple opioid receptor-mediated mechanisms of ERK activation exist that are temporally distinctive and feature different outcomes. Upon discovering that chronic opiate treatment of rats down-regulates thrombospondin 1 (TSP1) expression in the nucleus accumbens and cortex, we investigated the mechanism of action of this modulation in astrocytes. TSP1 is synthesized in astrocytes and is released into the extracellular matrix where it is known to play a role in synapse formation and neurite outgrowth. Acute morphine (hours) reduced TSP1 levels in astrocytes. Chronic (days) opioids repressed TSP1 gene expression and reduced its protein levels by opioid receptor and ERK-dependent mechanisms in astrocytes. Morphine also depleted TSP1 levels stimulated by TGF␤1 and abolished ERK activation induced by this factor. Chronic morphine treatment of astrocyte-neuron co-cultures reduced neurite outgrowth and synapse formation. Therefore, inhibitory actions of morphine were detected after both acute and chronic treatments. An acute mechanism of morphine signaling to ERK that entails depletion of TSP1 levels was suggested by inhibition of morphine activation of ERK by a function-blocking TSP1 antibody. This raises the novel possibility that acute morphine uses TSP1 as a source of EGF-like ligands to activate EGFR. Chronic morphine inhibition of TSP1 is reminiscent of the negative effect of opioids on EGFR-induced astrocyte proliferation via a phospho-ERK feedback inhibition mechanism. Both of these variations of classical EGFR transactivation may enable opiates to diminish neurite outgrowth and synapse formation.Astrocytes are the source of a diverse group of molecules that are required for synapse formation, function, and maintenance in neurons (1-7). Thrombospondin (TSP) 3 is a member of the astrocyte-derived intercellular signaling components that have been implicated in synaptogenesis and other neuronal glial interactions of the developing brain (8 -17). In addition, synaptic plasticity and other neuroadaptations involving astrocyte neuron interactions are thought to play a role in reward learning and addiction (18). Some chronic morphine-responsive genes (Homer1, PSD-95, and synaptotagmin1) may subserve the long lived neuronal and behavioral plasticity observed in regions of the mesolimbic reward system, and they are involved in synaptogenesis (19 -26).TSPs are multidomain, multimeric glycoproteins that are secreted into the extracellular matrix of many cells and serve as bridging molecules in cell-cell interactions (27,28). First discovered in platelet ␣-granules and secreted upon platelet activation, the superfamily of TSPs modulate varied functions of cell signaling and cell adhesion in a broad array of cell types. The five TSP genes are expressed in the CNS and peripheral nervous system where they play important roles in neural development. T...

Somatosensation is topographically organized in the primary (S1) and secondary somatosensory cortex (S2), which contributes to identify the region receiving sensory inputs. However, it is still unknown how somatosensory inputs from the oral region, especially nociceptive inputs from the teeth, are processed in the somatosensory cortex. We performed in vivo optical imaging and identified the precise cortical regions responding to electrical stimulation of the maxillary and mandibular dental pulp in rats. Electrical stimulation of the mandibular incisor pulp evoked neural excitation in two areas: the most rostroventral part of S1, and the ventral part of S2 caudal to the middle cerebral artery. Maxillary incisor pulp stimulation initially evoked responses only in the ventral part of S2, although later maximum responses were also observed in S1 similar to mandibular incisor stimulation responses. The maxillary and mandibular molar pulp-responding regions were located in the most ventral S2, a part of which was histologically classified as the insular oral region (IOR). In terms of the initial responses, maxillary incisor and molar stimulation induced excitation in the S2/IOR rostral to the mandibular dental pulp-responding region. Contrary to the spatially segregated initial responses, the maximum excitatory areas responding to both incisors and molars in the mandible and maxilla overlapped in S1 and the S2/IOR. Multielectrode extracellular recording supported the characteristic localization of S2/IOR neurons responding to mandibular and maxillary molar pulp stimulation. The discrete and overlapped spatial profiles of initial and maximum responses, respectively, may characterize nociceptive information processing of dental pain in the cortex.

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There is a particular emphasis on identifying methodological factors that might influence phenotypic effects and account for inconsistencies. The findings are offered empirically to (1) specify the extent of phenotypic diversity among individual DA receptor subtypes and transduction components and (2) indicate relationships between D1, D2, D3, D4 and D5 receptor subtype proteins, associated G alpha(i)/G alpha(s)/G alpha(olf)[G gamma7]-adenylyl cyclase type 5-PKA [RIIbeta]-DARPP-32 signalling cascades and behaviour. The findings are also offered heuristically as a base for such phenotypic comparisons at additional levels of behaviour so that a yet more complete phenotypic profile might emerge.

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