Cutaneous inflammation differentially regulates the expression and function of Angiotensin-II types 1 and 2 receptors in rat primary sensory neurons.

Neuropathic and inflammatory pain results from cellular and molecular changes in dorsal root ganglion (DRG) neurons. The type-2 receptor for Angiotensin-II (AT2R) has been involved in this type of pain. However, the underlying mechanisms are poorly understood, including the role of the type-1 receptor for Angiotensin-II (AT1R). Here, we used a combination of immunohistochemistry and immunocytochemistry, RT-PCR and in vitro and in vivo pharmacological manipulation to examine how cutaneous inflammation affected the expression of AT1R and AT2R in subpopulations of rat DRG neurons and studied their impact on inflammation-induced neuritogenesis. We demonstrated that AT2R-neurons express C- or A-neuron markers, primarily IB4, trkA, and substance-P. AT1R expression was highest in small neurons and co-localized significantly with AT2R. In vitro, an inflammatory soup caused significant elevation of AT2R mRNA, whereas AT1R mRNA levels remained unchanged. In vivo, we found a unique pattern of change in the expression of AT1R and AT2R after cutaneous inflammation. AT2R increased in small neurons at 1 day and in medium size neurons at 4 days. Interestingly, cutaneous inflammation increased AT1R levels only in large neurons at 4 days. We found that in vitro and in vivo AT1R and AT2R acted co-operatively to regulate DRG neurite outgrowth. In vivo, AT2R inhibition impacted more on non-peptidergic C-neurons neuritogenesis, whereas AT1R blockade affected primarily peptidergic nerve terminals. Thus, cutaneous-induced inflammation regulated AT1R and AT2R expression and function in different DRG neuronal subpopulations at different times. These findings must be considered when targeting AT1R and AT2R to treat chronic inflammatory pain. Cover Image for this issue: doi: 10.1111/jnc.14737.

Changes in the expression of the potassium channels TASK1, TASK3 and TRESK in a rat model of oral squamous cell carcinoma and their relation to malignancy.

OBJECTIVES: Potassium channels have been proposed to promote cancer cell proliferation and metastases. Thus, we investigated the expression pattern of three 2-pore domain potassium channels (K2Ps) TASK1, TASK3 and TRESK in advanced oral squamous cell carcinoma (OSCC), the commonest oral malignancy. DESIGN: We used 4-nitroquinoline-1-oxide (4-NQO) to induce high grade OSCC in male adult rats. We then used immunohistochemistry and Western blotting to study the distribution and expression pattern of TASK1, TASK3 and TRESK in normal versus cancerous tissue. We also examined the expression of ß-tubulin III (ß-tub3), a marker associated with resistance to taxane-based chemotherapy and poor patient prognosis, and its correlation with the K2Ps. Finally, we studied the expression of TASK1, TASK3 and TRESK in human samples of SCC of oral origin. RESULTS: We found that TASK3 was significantly up-regulated whereas TASK1 and TRESK were both significantly down-regulated in advanced, poorly differentiated OSCC. Both, rat and human SCC showed a significant increase in the expression of ß-tub3. Interestingly, the expression of the latter correlated positively and significantly with TASK3 and TRESK but not TASK1 in rat OSCC. Our initial results showed a similar pattern of up and down regulation and correlation with ß-tub3 for these three K2Ps in human SCC. CONCLUSIONS: The changes in expression and the co-localization with a marker of resistance to taxanes like ß-tub3 turn TASK1, TASK3 and TRESK into potentially new prognostic tools and possibly new therapeutic targets for OSCC.

Administration of noradrenaline in the autonomic ganglia modifies the testosterone release from the testis using an ex vivo system.

The male gonad receives nerve fibres from the autonomic ganglionic system. These fibres converge on the testis along two pathways, the superior and the inferior spermatic nerves. The superior spermatic nerve runs from the superior mesenteric ganglion alongside the testicular artery, whereas the inferior spermatic nerve originates in inferior mesenteric ganglion, accompanies the vas deferens and penetrates the inferior pole of the testis. The aim of this work was to evaluate androgen release after the addition of noradrenaline or adrenoreceptor antagonists (propranolol or phentolamine) to the ganglionic compartment. An ex vivo system used in a previous work was incubated in two separate containers, one for the testis and the other for the ganglion. Both organs remain interconnected (as in vivo) by the respective spermatic nerve. When noradrenaline was added to the inferior mesenteric ganglion, testosterone release in the gonad container underwent a progressive and significant increment. Propranolol diminishes and phentolamine increases the androgen release. When using the superior mesenteric ganglion, no changes were observed. These results indicate that the ganglionic stimulation of the autonomic system clearly participates in testosterone release from the testis. This effect depends on the ganglion involved. These results make it evident that not only the classical and well-known hypothalamus-hypophysial axis, but also the peripheral nervous system, via the autonomic ganglia, are directly involved in the endocrine control of the testis.

Excitatory and inhibitory behavioral responses to the pharmacological stimulation of serotonergic function in dorsalis raphe lesioned rats

La lesion de neuronas 5-HT median te neurotoxinas induce supersensibilidad de receptores 5-HT1 sin afectar el "binding" de receptores 5-HT2. Este modelo fue utilizado en el presente trabajo para analizar el papel de ambos subtipos de receptores 5-HT en el mecanismo de control de las respuestas comportamentales excitatorias e inhibitorias provocadas por la estimulación farmacológica del sistema 5-HT. Las lesiones del rafe dorsales (RD) fueron hechas mediante inyección estereotáxica de ác. kaínico. Treinta días después las ratas RD y sus controles mostraron una actividad basal similar en "testes" de "hole board". Tres días después las ratas RD y sus controles fueron inyectadas ip con fluoxetina (5 y 10 mg/Kg) y 30 m después con 50HTP (15 y 30 mg/Kg). Imediatamente antes y después de cada inyección ip la respuesta excitatoria (síndrome mioclónico) fue evaluada. Las ratas RD y sus controles mostraron similares valores de mioclonías en respuesta a fluoxetina-5-HTP. La respuesta inhibitoria fue investigada en sesiones de "holeboard" a los 30 m de la segunda inyección ip. La lesión del RD potenció el efecto depresor de fluoxetina-5-HTP sobre el comportamiento. En concordancia con la literatura, la lesión del RD produjo una caída del 74.9% de la 5-HT del cerebro anterior y un incremento del 75% en el "bilding" de 3H-5HT en membranas corticales. En conclusión, los componentes de la respuesta excitatoria, que no se modificó por la lesión del RD, estarían relacionados principalmente con receptores 5-HT2. El aumento de la respuesta inhibitoria a la estimulación 5-HT observado en las rata lesionadas en RD estaría vinculado a la supersensibilidad de receptores 5-HT1

Excitatory and inhibitory behavioral responses to the pharmacological stimulation of serotonergic function in dorsalis raphe lesioned rats

La lesion de neuronas 5-HT median te neurotoxinas induce supersensibilidad de receptores 5-HT1 sin afectar el "binding" de receptores 5-HT2. Este modelo fue utilizado en el presente trabajo para analizar el papel de ambos subtipos de receptores 5-HT en el mecanismo de control de las respuestas comportamentales excitatorias e inhibitorias provocadas por la estimulación farmacológica del sistema 5-HT. Las lesiones del rafe dorsales (RD) fueron hechas mediante inyección estereotáxica de ác. kaínico. Treinta días después las ratas RD y sus controles mostraron una actividad basal similar en "testes" de "hole board". Tres días después las ratas RD y sus controles fueron inyectadas ip con fluoxetina (5 y 10 mg/Kg) y 30 m después con 50HTP (15 y 30 mg/Kg). Imediatamente antes y después de cada inyección ip la respuesta excitatoria (síndrome mioclónico) fue evaluada. Las ratas RD y sus controles mostraron similares valores de mioclonías en respuesta a fluoxetina-5-HTP. La respuesta inhibitoria fue investigada en sesiones de "holeboard" a los 30 m de la segunda inyección ip. La lesión del RD potenció el efecto depresor de fluoxetina-5-HTP sobre el comportamiento. En concordancia con la literatura, la lesión del RD produjo una caída del 74.9% de la 5-HT del cerebro anterior y un incremento del 75% en el "bilding" de 3H-5HT en membranas corticales. En conclusión, los componentes de la respuesta excitatoria, que no se modificó por la lesión del RD, estarían relacionados principalmente con receptores 5-HT2. El aumento de la respuesta inhibitoria a la estimulación 5-HT observado en las rata lesionadas en RD estaría vinculado a la supersensibilidad de receptores 5-HT1 (AU)