Neuroscience
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Effects of C-fiber activation on type I slowly adapting mechanoreceptor responses were investigated in a rat in vitro nerve-skin preparation using controlled mechanical stimuli. Two changes in behavior were evoked by antidromic C-fiber stimulation: (1). The type I response to mechanical stimuli was modulated in a graded fashion by antidromic C-fiber activation. ⋯ Immunohistochemical staining revealed both substance P- and calcitonin gene-related peptide-like immunoreactivity in small unmyelinated nerve fibers entering the touch dome. These results support the concepts that (1). the type I slowly adapting mechanoreceptor in rat receives input from nociceptive terminals within the touch dome. (2). The function of type I slowly adapting mechanoreceptors is modulated by axon reflex activation of nociceptor terminals, which may play a role in altering the type I response during states of mechanical allodynia and have paracrine and autocrine influences on maintenance of touch dome structure.
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Nitric oxide synthase is expressed abundantly in the spinal cord, and nitric oxide (NO) has been shown to play important roles in the central mechanism of inflammatory hyperalgesia. However, the expression and function of the NO receptor, soluble guanylate cyclase, is not fully understood in this processing at the spinal cord level. In the present study, we report that the soluble guanylate cyclase alpha(1) subunit but not the beta(1) subunit was expressed in rat spinal cord, particularly in the dorsal horn. ⋯ During formalin-induced long-lasting inflammation, we found that the expression of the alpha(1) subunit of soluble guanylate cyclase was dramatically increased in the lumbar spinal cord on the second and fourth days after formalin injection into the dorsal side of a hind paw. Intraperitoneal pretreatment with an N-methyl-D-aspartate (NMDA) receptor antagonist, dizocilpine maleate (MK-801), and a neuronal NO synthase inhibitor, 7-nitroindazole, not only significantly blocked formalin-induced secondary thermal hyperalgesia but also suppressed formalin-produced increase in the alpha(1) subunit of soluble guanylate cyclase in the spinal cord. The present results indicate that peripheral inflammation not only initially activates but also later up-regulates soluble guanylate cyclase expression via the NMDA receptor-NO signaling pathway, suggesting that soluble guanylate cyclase might be involved in the central mechanism of formalin-induced inflammatory hyperalgesia in the spinal cord.
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One of us showed previously [Cuajungco and Lees (1998) Brain Res. 799, 188-129] that nitric oxide injected into the cerebrum in vivo causes zinc staining to appear in the somata of neurons and suggested that this staining of somata might be accompanied by a depletion (release) of zinc from axon terminals. In the present study, we confirm earlier results and report that there is a dramatic loss (apparent release) of histologically reactive zinc from the boutons of zinc-containing axons induced by infusion of nitric oxide into the brain in vivo. Rats were anesthetized with halothane and a cannula was inserted into the hippocampus. ⋯ Two hours after infusion, N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ) staining for zinc in the brains revealed that sperminenitric oxide, but not control (spermine only) produced up to 95% depletion of zinc staining from the zinc-containing boutons. TSQ-positive neurons were also conspicuous throughout injection sites, in both the cerebral cortex and in the cerebellar cortex, where the Purkinje neurons were especially vivid, despite the scarcity of zinc-containing axonal boutons. It is suggested that the TSQ-stainable zinc in somata might represent intracellular stores mobilized from within or permeating extracellular stores.
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Protein phosphorylation is a major mechanism for regulation of N-methyl-D-aspartate (NMDA) receptor function. The NMDA receptor 1 subunit (NR1) is phosphorylated by protein kinase A (PKA) on serine 890 and 897. We have recently reported that there is enhanced phosphorylation of NR1 on serine 897 in dorsal horn and spinothalamic tract (STT) neurons after intradermal injection of capsaicin (CAP) in rats [Zou et al. (2000) J. ⋯ However, the proportion of p-NR1-LI STT cells in deep laminae was unchanged unless the PKC inhibitor, chelerythrine chloride, was co-administered with H89. Combined with our previous findings, the present results indicate that NR1 in spinal dorsal horn neurons, including the superficial dorsal horn STT cells, is phosphorylated following CAP injection and that this phosphorylation is due to the action of PKA. However, the phosphorylation of deep STT cells involves both PKA and PKC.
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Classical fear conditioning is believed to result from potentiation of conditioned synaptic inputs in the basolateral amygdala. That is, the conditioned stimulus would excite more neurons in the central nucleus and, via their projections to the brainstem and hypothalamus, evoke fear responses. However, much data suggests that extinction of fear responses does not depend on the reversal of these changes but on a parallel NMDA-dependent learning that competes with the first one. ⋯ Depotentiation of previously potentiated synapses did not revert the modification in paired pulse facilitation, suggesting that LTP is associated with presynaptic alterations, but that LTD and depotentiation depend on postsynaptic changes. Taken together, our results suggest that basolateral synapses onto intercalated neurons can express NMDA-dependent LTP and LTD, consistent with the possibility that intercalated neurons are a critical locus of plasticity for the extinction of conditioned fear responses. Ultimately, these plastic events may prevent conditioned amygdala responses from exciting neurons of the central nucleus, and thus from evoking conditioned fear responses.