Neuroscience
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Intracerebral microdialysis was employed in awake freely moving rats to investigate the effects of nociceptin/orphanin FQ receptor ligands on glutamate extracellular levels in the substantia nigra pars reticulata. Nociceptin/orphanin FQ, ineffective at 0.1 microM, induced a prolonged stimulation of nigral glutamate levels at 1 and 10 microM (mean effect of 137+/-9 and 167+/-13%, respectively, of basal values). These effects were prevented by the novel nociceptin/orphanin FQ receptor antagonist [Nphe(1)]nociceptin/orphanin FQ(1-13)NH(2) (100 and 300 microM, respectively) but not by the non-selective opioid receptor antagonist naloxone (10 microM). [Nphe(1)]nociceptin/orphanin FQ(1-13)NH(2) (100 microM) inhibited by itself glutamate outflow (maximal reduction to 71+/-4%) while naloxone was ineffective. ⋯ Intranigral perfusion with tetrodotoxin (1 microM) or with the dopamine D(2) receptor antagonist raclopride (1 microM), failed to affect basal glutamate output and prevented the facilitatory effect of nociceptin/orphanin FQ (10 microM). However, perfusion with the GABA(A) receptor antagonist bicuculline (10 microM) increased local glutamate extracellular levels by itself and attenuated the effect of the peptide. Our data suggest that nociceptin/orphanin FQ increases glutamate extracellular levels in the substantia nigra pars reticulata via activation of nociceptin/orphanin FQ receptors located on non-glutamatergic, possibly dopaminergic and GABAergic, neuronal elements.
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Contrary to the classical view of a pre-determined wiring pattern, there is considerable evidence that cortical representation of body parts is continuously modulated in response to activity, behavior and skill acquisition. Both animal and human studies showed that following injury of the peripheral nervous system such as nerve injury or amputation, the somatosensory cortex that responded to the deafferented body parts become responsive to neighboring body parts. Similarly, there is expansion of the motor representation of the stump area following amputation. ⋯ Changes over a longer time likely involve other additional mechanisms such as long-term potentiation, axonal regeneration and sprouting. While cross-modal plasticity appears to be useful in enhancing the perceptions of compensatory sensory modalities, the functional significance of motor reorganization following peripheral injury remains unclear and some forms of sensory reorganization may even be associated with deleterious consequences like phantom pain. An understanding of the mechanism of plasticity will help to develop treatment programs to improve functional outcome.
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Although intrathecal administration of nociceptin, an endogenous ligand of the opioid receptor-like1 receptor, exhibits an antinociceptive effect in various pain models, cellular mechanisms underlying this action are still unknown. Here, we investigated the effects of nociceptin on excitatory and inhibitory synaptic transmission to substantia gelatinosa neurones of an adult rat spinal cord slice with an attached dorsal root by use of the blind whole-cell patch-clamp technique; this was done under the condition of a blockade of a hyperpolarising effect of nociceptin. In about 70% of the neurones examined, nociceptin (1 microM) reduced the amplitude of glutamatergic excitatory postsynaptic currents (EPSCs) which were monosynaptically evoked by stimulating Adelta- or C-afferent fibres; the inhibition of C-fibre EPSCs (50+/-6%, n=11) was larger than that of Adelta-fibre EPSCs (30+/-5%, n=23; P<0.05). ⋯ These results indicate that nociceptin suppresses excitatory but not inhibitory synaptic transmission to substantia gelatinosa neurones through the activation of the opioid receptor-like1 receptor; this action is pre-synaptic in origin. Considering that the substantia gelatinosa is the main part of termination of Adelta- and C-fibres transmitting nociceptive information, the present finding would account for at least a part of the inhibitory action of nociceptin on pain transmission. Nociceptin could inhibit more potently slow-conducting than fast-conducting pain transmission.
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Hypocretin 2 (orexin B) is a hypothalamic neuropeptide thought to be involved in regulating energy homeostasis, autonomic function, arousal, and sensory processing. Neural circuits in the caudal nucleus tractus solitarius (NTS) integrate viscerosensory inputs, and are therefore implicated in aspects of all these functions. We tested the hypothesis that hypocretin 2 modulates fast synaptic activity in caudal NTS areas that are generally associated with visceral sensation from cardiorespiratory and gastrointestinal systems. ⋯ The increase in EPSC frequency persisted in the presence of tetrodotoxin, suggesting a role for the peptide in regulating glutamate release in the NTS by acting at presynaptic terminals. These data suggest that hypocretin 2 modulates excitatory, but not inhibitory, synapses in caudal NTS neurons, including viscerosensory inputs. The selective nature of the effect supports the hypothesis that hypocretin 2 plays a role in modulating autonomic sensory signaling in the NTS.
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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.