Abstract
Nitric oxide (NO) is an important molecule involved in nociceptive processing in the central nervous system. The release of NO within the spinal cord has long been implicated in the mechanisms underlying exaggerated pain sensitivity, and administration of NO donors can induce hyperalgesia. To elucidate the supraspinal mechanism responsible for NO-induced nociceptive hypersensitivity, we investigated the modulation of protein kinase C (PKC) and downstream effectors following treatment with the NO donors nitroglycerin and sodium nitroprusside. Both compounds induced a prolonged cold allodynia and heat hyperalgesia, increased levels of c-Fos and IL-1β, and activated NF-κB within periaqueductal grey matter and thalamus. Simultaneously, an increased expression and phosphorylation of PKC γ and ε were detected. To clarify the cellular mechanism involved in the NO-induced hypernociception, we examined the expression of transcription factors that act as PKC downstream effectors. A dramatic hyperphosphorylation of CREB and STAT1 was observed. The i.c.v. administration of the PKC blocker calphostin C prevented the NO-induced hypernociception, the hyperphosphorylation of CREB and STAT1, and partially reduced NF-κB activation. Conversely, the increase of IL-1β was unmodified by calphostin C. These results suggest the relevance of cerebral PKC-mediated CREB and STAT1 activation in the NO donor-induced nociceptive behavior.
Highlights
Nitric oxide (NO) is a molecule importantly involved in pain processing within central nervous system
To elucidate the supraspinal mechanism responsible for NO-induced nociceptive hypersensitivity, we investigated the modulation of protein kinase C (PKC) and downstream effectors following treatment with the NO donors nitroglycerin and sodium nitroprusside
It has been speculated that activation of cGMP-dependent protein kinase I, in turn, is the major effector of NO-dependent cGMP synthesis in the spinal cord [12, 13] and that the pronociceptive effects of the NO are mediated by activation of cGKI [14, 15]
Summary
Nitric oxide (NO) is a molecule importantly involved in pain processing within central nervous system. A major signaling mechanism of NO in spinal nociceptive processing initiates with activation of NO sensitive guanylyl cyclase and subsequent cGMP production [10, 11]. It has been speculated that activation of cGMP-dependent protein kinase I (cGKI), in turn, is the major effector of NO-dependent cGMP synthesis in the spinal cord [12, 13] and that the pronociceptive effects of the NO are mediated by activation of cGKI [14, 15]. The possible activation of targets different from cGKI has been postulated on the bases of data showing the lack of antagonism of the pronociceptive effect of an NO donor by the cGKI inhibitor [8]. To the spinal mechanisms, little is known on the supraspinal events modulated by NO
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