Type 1 Cannabinoid Receptor-Containing Axons Innervate Hypophysiotropic Thyrotropin-Releasing Hormone-Synthesizing Neurons

Hypophysiotropic TRH-synthesizing neurons of the hypothalamic paraventricular nucleus (PVN) have a critical role in the regulation of the energy homeostasis through control of the hypothalamic-pituitary-thyroid axis. Recently, endocannabinoids have been shown to exert inhibitory effects on TRH neurons via the type 1 cannabinoid receptor (CB1). To understand the anatomical basis for this regulatory mechanism, we determined whether CB1 is contained in axons innervating hypophysiotropic TRH neurons using a recently developed antiserum against the C-terminal portion of mouse CB1. CB1-immunoreactive axons densely innervated the parvicellular subdivisions of the PVN where the hypophysiotropic TRH neurons are located. By double-labeling immunocytochemistry, CB1-immunoreactive varicosities were observed in juxtaposition to the vast majority of TRH neurons in the PVN. At the ultrastructural level, CB1-immunoreactivity was observed in the preterminal portion of axons establishing both symmetric and asymmetric synaptic specializations with the perikarya and dendrites of TRH neurons in the PVN. These data demonstrate that CB1 is abundantly present in axons that are in synaptic association with hypophysiotropic TRH neurons, indicating an important role for endocannabinoids in the regulation of the hypothalamic-pituitary-thyroid axis. The presence of both symmetric and asymmetric type CB1 synapses on TRH neurons in the PVN suggests that endocannabinoids may influence both excitatory and inhibitory inputs of these neurons

Involvement of the Endocannabinoid System in Metabolism and Fertility

Involvement of the endocannabinoid system in metabolism and fertilit

Soft Law as a New Mode of Governance: A Legal Perspective

After a brief review of the history and typology of soft law in public international law, we approach the concept deductively. We reject the binary view and subscribe to the continuum view. Building on the idea of graduated normativity and on the prototype theory of concepts, we submit that soft law is in the penumbra of law. It can be distinguished from purely political documents more or less readily, depending on its closeness to the prototype of law. Insights gained by the study of public international soft law are relevant to EC and EU soft law despite some differences between those legal orders. European soft law is created by institutions, Member States, and private actors. The legal effects of soft law acts can be clustered according to their relation to hard law. Both practical and normative considerations motivate reliance on soft law. An examination of the soft legal consequences of a disregard of soft law shows that compliance control mechanisms for hard and soft international law are converging. Moreover, some factors of compliance are independent of the theoretical hardness or softness of a given norm. In a legal policy perspective, the proliferation of soft law carries both dangers and benefits. Especially soft acts with a lawplus function do not weaken the respective regimes, but perfect them