Search Results (2)

Netrin-1, a chemoattractant expressed by floor plate cells, and one of its receptors (deleted in colorectal cancer) has been associated with pronociceptive actions in a number of pain conditions. Here, we addressed the question of whether spinal TRPC4/C5 or TRPA1 are among the downstream receptors contributing to pronociceptive actions induced by netrin-1. The experiments were performed on rats using a chronic intrathecal catheter for administration of netrin-1 and antagonists of TRPC4/C5 or TRPA1. Pain sensitivity was assessed behaviorally by using mechanical and heat stimuli. Effect on the discharge rate of rostral ventromedial medullary (RVM) pain control neurons was studied in lightly anesthetized animals. Netrin-1, in a dose-related fashion, induced mechanical hypersensitivity that lasted up to three weeks. Netrin-1 had no effect on heat nociception. Mechanical hypersensitivity induced by netrin-1 was attenuated by TRPA1 antagonist Chembridge-5861528 and by the control analgesic compound pregabalin both during the early (first two days) and late (third week) phase of hypersensitivity. TRPC4/C5 antagonist ML-204 had a weak antihypersensitivity effect that was only in the early phase, whereas TRPC4/C5 antagonist HC-070 had no effect on hypersensitivity induced by netrin-1. The discharge rate in pronociceptive ON-like RVM neurons was increased by netrin-1 during the late but not acute phase, whereas netrin-1 had no effect on the discharge rate of antinociceptive RVM OFF-like neurons. The results suggest that spinal TRPA1 receptors and pronociceptive RVM ON-like neurons are involved in the maintenance of submodality-selective pronociceptive actions induced by netrin-1 in the spinal cord. Full article

Mechanical allodynia (pain to normally innocuous tactile stimuli) is a widespread symptom of inflammatory and neuropathic pain. Spinal or medullary dorsal horn (SDH or MDH) circuits mediating tactile sensation and pain need to interact in order to evoke mechanical allodynia. PKCγ-expressing (PKCγ⁺) interneurons and inhibitory controls within SDH/MDH inner lamina II (II_i) are pivotal in connecting touch and pain circuits. However, the relative contribution of GABA and glycine to PKCγ⁺ interneuron inhibition remains unknown. We characterized inhibitory inputs onto PKCγ⁺ interneurons by combining electrophysiology to record spontaneous and miniature IPSCs (sIPSCs, mIPSCs) and immunohistochemical detection of GABA_ARα2 and GlyRα1 subunits in adult rat MDH. While GlyR-only- and GABA_AR-only-mediated mIPSCs/sIPSCs are predominantly recorded from PKCγ⁺ interneurons, immunohistochemistry reveals that ~80% of their inhibitory synapses possess both GABA_ARα2 and GlyRα1. Moreover, nearly all inhibitory boutons at gephyrin-expressing synapses on these cells contain glutamate decarboxylase and are therefore GABAergic, with around half possessing the neuronal glycine transporter (GlyT2) and therefore being glycinergic. Thus, while GABA and glycine are presumably co-released and GABA_ARs and GlyRs are present at most inhibitory synapses on PKCγ⁺ interneurons, these interneurons exhibit almost exclusively GABA_AR-only and GlyR-only quantal postsynaptic inhibitory currents, suggesting a pharmacological specialization of their inhibitory synapses. Full article