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Complementary modulation of somatic inhibition by opioids and cannabinoids.

ABSTRACT: Somatic inhibition, which is critical for determining the spike output of principal cells, is mediated by two physiologically distinct classes of GABAergic interneurons called basket cells. In the hippocampus, despite both targeting the somatic membrane of CA1 pyramidal cells, these two classes of basket cells are active at different times. Differential modulation of these two types of basket cells could hence be important for regulating the activity patterns of CA1 pyramidal cells at very specific periods during ongoing activity. Indeed, cannabinoids selectively suppress the output of one class of basket cell. Whether opioids, another major modulator of inhibition in the hippocampus, also selectively suppress somatic inhibition is not known. Here, we show that basket cells are selectively modulated by either opioids or cannabinoids, but not both. We also find that basket cells are integrated into specific inhibitory subnetworks that are themselves under differential control of opioids and cannabinoids. Furthermore, because the two interneuron types are activated at different times, opioids and cannabinoids suppress different epochs of inhibition. This cell-type specific sensitivity to neuromodulators allows for a fine control of the temporal structure of hippocampal activity.

SUBMITTER: Glickfeld LL

PROVIDER: S-EPMC3505026 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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Complementary modulation of somatic inhibition by opioids and cannabinoids.

Glickfeld Lindsey L LL Atallah Bassam V BV Scanziani Massimo M

The Journal of neuroscience : the official journal of the Society for Neuroscience 20080201 8

Somatic inhibition, which is critical for determining the spike output of principal cells, is mediated by two physiologically distinct classes of GABAergic interneurons called basket cells. In the hippocampus, despite both targeting the somatic membrane of CA1 pyramidal cells, these two classes of basket cells are active at different times. Differential modulation of these two types of basket cells could hence be important for regulating the activity patterns of CA1 pyramidal cells at very speci ...[more]

PMID: 18287499

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Project description:ObjectiveInhibition of hedgehog (HH) signaling prevents cartilage degeneration and promotes repair in animal models of osteoarthritis (OA). This study, undertaken in OA models and in human OA articular cartilage, was designed to explore whether kappa opioid receptor (KOR) modulation via the inhibition of HH signaling may have therapeutic potential for achieving disease-modifying activity in OA.MethodsPrimary human articular cartilage and synovial tissue samples from patients with knee OA undergoing total joint replacement and from healthy human subjects were obtained from the National Disease Research Interchange. For in vivo animal studies, a partial medial meniscectomy (PMM) model of knee OA in rats was used. A novel automated 3-dimensional indentation tester (Mach-1) was used to quantify the thickness and stiffness properties of the articular cartilage.ResultsInhibition of HH signaling through KOR activation was achieved with a selective peptide agonist, JT09, which reduced HH signaling via the cAMP/CREB pathway in OA human articular chondrocytes (P = 0.002 for treated versus untreated OA chondrocytes). Moreover, JT09 markedly decreased matrix degeneration induced by an HH agonist, SAG, in pig articular chondrocytes and cartilage explants (P = 0.026 versus untreated controls). In vivo application of JT09 via intraarticular injection into the rat knee joint after PMM surgery significantly attenuated articular cartilage degeneration (60% improvement in the tibial plateau; P = 0.021 versus vehicle-treated controls). In JT09-treated rats, cartilage content, structure, and functional properties were largely maintained, and osteophyte formation was reduced by 70% (P = 0.005 versus vehicle-treated controls).ConclusionThe results of this study define a novel mechanism for the role of KOR in articular cartilage homeostasis and disease, providing a potential unifying mechanistic basis for the overlap in disease processes and features involving opioid and HH signaling. Moreover, this study identifies a potential novel therapeutic strategy in which KOR modulation can improve outcomes in patients with OA.

Dataset Information

Complementary modulation of somatic inhibition by opioids and cannabinoids.

Publications

Complementary modulation of somatic inhibition by opioids and cannabinoids.

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