Search

CCL2 chemokine and its receptor CCR2 may contribute to neuropathic pain development. We tested the hypothesis that injury to peripheral nerves triggers CCL2 release from afferents in the dorsal horn spinal cord (DHSC), leading to pronociceptive effects, involving the production of proinflammatory factors, in particular. Consistent with the release of CCL2 from primary afferents, electron microscopy showed the CCL2 immunoreactivity in glomerular boutons and secretory vesicles in the DHSC of naive rats. Through the ex vivo superfusion of DHSC slices, we demonstrated that the rate of CCL2 secretion was much lower in neonatal capsaicin-treated rats than in controls. Thus, much of the CCL2 released in the DHSC originates from nociceptive fibers bearing TRPV1 (transient receptor potential vanilloid 1). In contrast, high levels of CCL2 released from the DHSC were observed in neuropathic pain animal model induced by chronic constriction of the sciatic nerve (SN-CCI). The upregulated expression of proinflammatory markers and extracellular signal-regulated kinase (ERK) 1/2 pathway activation (ERK1/2 phosphorylation) in the DHSC of SN-CCI animals were reversed by intrathecal administration of the CCR2 antagonist INCB3344 (N-[2-[[(3S,4S)-1-E4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexyl]-4-ethoxy-3-pyrrolidinyl]amino]- 2-oxoethyl]-3-(trifluoromethyl)benzamide). These pathological pain-associated changes in the DHSC were mimicked by the intrathecal injection of exogenous CCL2 in naive rats and were prevented by the administration of INCB3344 or ERK inhibitor (PD98059). Finally, mechanical allodynia, which was fully developed 2 weeks after SN-CCI in rats, was attenuated by the intrathecal injection of INCB3344. Our data demonstrate thatCCL2has the typical characteristics of a neuronal mediator involved in nociceptive signal processingandthat antagonists of its receptor are promising agents from treating neuropathic pain. [ABSTRACT FROM AUTHOR]

Neuronal networks originating in the hypothalamic arcuate nucleus (Arc) play a fundamental role in controlling energy balance. In the Arc, neuropeptide Y (NPY)-producing neurons stimulate food intake, whereas neurons releasing the proopiomelanocortin (POMC)-derived peptide α-melanocyte-stimulating hormone (α-MSH) strongly decrease food intake. There is growing evidence to suggest that apelin and its receptor may play a role in the central control of food intake, and both are concentrated in the Arc. We investigated the presence of apelin and its receptor in Arc NPY- and POMC-containing neurons and the effects of apelin on α-MSH release in the hypothalamus. We showed, by immunofluorescence and confocal microscopy, that apelin-immunoreactive (IR) neuronal cell bodies were distributed throughout the rostrocaudal extent of the Arc and that apelin was strongly colocalized with POMC, but weakly colocalized with NPY. However, there were numerous NPY-IR nerve fibers close to the apelin-IR neuronal cell bodies. By combining in situ hybridization with immunohistochemistry, we demonstrated the presence of apelin receptor mRNA in Arc POMC neurons. Moreover, using a perifusion technique for hypothalamic explants, we demonstrated that apelin-17 (K17F) increased α-MSH release, suggesting that apelin released somato-dendritically or axonally from POMC neurons may stimulate α-MSH release in an autocrine manner. Consistent with these data, hypothalamic apelin levels were found to be higher in obese db/db mice and fa/fa Zucker rats than in wild-type animals. These findings support the hypothesis that central apelin is involved in regulating body weight and feeding behavior through the direct stimulation of α-MSH release.

Recent observations suggest that besides their role in the immune system, chemokines have important functions in the brain. There is a great line of evidence to suggest that chemokines are a unique class of neurotransmitters/neuromodulators, which regulate many biological aspects as diverse as neurodevelopment, neuroinflammation and synaptic transmission. In physiopathological conditions, many chemokines are synthesized in activated astrocytes and microglial cells, suggesting their involvement in brain defense mechanisms. However, when evoking chemokine functions in the nervous system, it is important to make a distinction between resting conditions and various pathological states including inflammatory diseases, autoimmune or neurodegenerative disorders in which chemokine functions have been extensively studied. We illustrate here the emergent concept of the neuromodulatory/neurotransmitter activities of neurochemokines and their potential role as a regulatory alarm system and as a group of messenger molecules for the crosstalk between neurons and cells from their surrounding microenvironment. In this deliberately challenging review, we provide novel hypotheses on the role of these subtle messenger molecules in brain functions leading to the evidence that previous dogmas concerning chemokines should be reconsidered., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

Apelin is a bioactive peptide recently identified as the endogenous ligand of the human orphan G protein-coupled receptor APJ. The presence of apelin-immunoreactive nerve fibers, together with the detection of apelin receptor mRNA in the parvocellular part of the paraventricular nucleus and the stimulatory action of apelin on corticotropin-releasing hormone release, indicate that apelin modulates adrenocorticotropin (ACTH) release via an indirect action on the hypothalamus. However, a direct action of apelin in the anterior pituitary cannot be excluded. Here, we provided evidence for the existence of an apelinergic system within the adult male rat pituitary gland. Double immunofluorescence staining indicated that apelin is highly coexpressed in the anterior pituitary, mainly in corticotrophs (96.5 +/- 0.3%) and to a much lower extent in somatotropes (3.2 +/- 0.2%). Using in situ hybridization combined with immunohistochemistry, a high expression of apelin receptor mRNA was also found in corticotrophs, suggesting a local interaction between apelin and ACTH. In an ex vivo perifusion system of anterior pituitaries, apelin 17 (K17F, 10(-6) M) significantly increased basal ACTH release by 41%, whereas apelin 10 (R10F, 10(-6) M), an inactive apelin fragment, was ineffective. In addition, K17F but not R10F induced a dose-dependent increase in K(+)-evoked ACTH release, with maximal increase being observed for a 10(-6) M concentration. Taken together, these data outline the potential role of apelin as an autocrine/paracrine-acting peptide on ACTH release and provide morphological and neuroendocrine basis for further studies that explore the physiological role of apelin in the regulation of anterior pituitary functions.

Apelin, a neuropeptide recently identified as the endogenous ligand for the G protein-coupled receptor APJ, is highly concentrated in brain structures involved in the control of body fluid homeostasis including the supraoptic (SON) and paraventricular (PVN) hypothalamic nuclei. To clarify the implication of apelin in the regulation of water balance, we sought to determine whether apelin colocalized with arginine vasopressin (AVP) in the rat SON and PVN. We also investigated the effects of water deprivation on the levels of apelin within these two nuclei by comparison with those of AVP. Using dual immunolabeling confocal microscopy, we found that a large proportion of apelin-immunoreactive neurons colocalized AVP within both the SON and PVN, but that the two peptides were segregated within distinct subcellular compartments inside these cells. Both the number and labeling intensity of magnocellular apelin-immunoreactive cells increased significantly after 24- or 48-h dehydration, whereas the number and labeling density of AVP-immunoreactive neurons significantly decreased. The dehydration-induced increase in apelin immunoreactivity was markedly diminished by central injection of a selective vasopressin-1 receptor antagonist. Conversely, the effect of dehydration was mimicked by a 16-min intracerebroventricular infusion of AVP, again in a vasopressin-1 receptor antagonist-reversible manner. These results provide additional evidence for the involvement of the neuropeptide apelin in the control of body fluid homeostasis. They further suggest that the dehydration-induced release of AVP from magnocellular hypothalamic neurons may be responsible for the observed increase in immunoreactive apelin levels within the same neurons and thus that the release of one peptide may block that of another peptide synthesized in the same cells.