The dorsolateral striatum (DLS) receives excitatory inputs from both sensory and motor cortical regions. In the neocortex, sensory responses are affected by motor activity, however, it is not known whether such sensorimotor interactions occur in the striatum and how they are shaped by dopamine. To determine the impact of motor activity on striatal sensory processing, we performed in vivo whole-cell recordings in the DLS of awake mice during the presentation of tactile stimuli. Striatal medium spiny neurons (MSNs) were activated by both whisker stimulation and spontaneous whisking, however, their responses to whisker deflection during ongoing whisking were attenuated. Dopamine depletion reduced the representation of whisking in direct-pathway MSNs, but not in those of the indirect-pathway. Furthermore, dopamine depletion impaired the discrimination between ipsilateral and contralateral sensory stimulation in both direct and indirect pathway MSNs. Our results show that whisking affects sensory responses in DLS and that striatal representation of both processes is dopamine- and cell type-dependent.

Background and Purpose: Paclitaxel produces a chemotherapy‐induced peripheral neuropathy that persists in 50–60% of cancer patients upon treatment. Evidence from animal models suggests an axonopathy of peripheral A‐ and C‐type fibres that affects their excitability. However, direct effects of paclitaxel on sensory neuron excitability and sexual dimorphism remain poorly understood.Experimental Approach: We used a long‐lasting (10 days in vitro) primary culture of rat dorsal root ganglion (DRG) neurons to investigate the time course effect of paclitaxel on the electrical activity of IB4(−) and IB4(+) sensory neurons of female and male adult Wistar rats.Key Results: Paclitaxel strongly and reversibly stimulated spontaneous activity and augmented action potential tonic firing in IB4(−) and IB4(+) neurons in both sexes, peaking at 48 h post‐treatment and virtually disappearing at 96 h. Paclitaxel decreased the current rheobase for action potential firing by reducing and accelerating the after‐hyperpolarization phase. Molecularly, paclitaxel modulated Na⁺ and K⁺ ion currents. Particularly, the drug significantly augmented the function of Na_v1.8, TRPV1 and TRPM8 channels. Furthermore, paclitaxel increased Na_v1.8 and TRPV1 expression at 48 h post‐treatment. Notably, we observed that female DRG neurons appear more sensitive to paclitaxel sensitization than their male counterparts.Conclusions and Implications: Our data indicate that paclitaxel similarly potentiated IB4(−) and IB4(+) electrogenicity and uncover a potential sex dimorphism in paclitaxel‐induced chemotherapy‐induced peripheral neuropathy. Our in vitro, pre‐clinical, chemotherapy‐induced peripheral neuropathy paradigm provides a tool for studying the dynamics and underlying molecular mechanisms contributing to nociceptor sensitization in peripheral neuropathies and for testing desensitizing compounds.

Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties, whereas it has no effect on the TRPM8 nor TRPV1 channels. The possibility of replacing a phenyl ring by an adamantyl ring opens new avenues in other fields of medicinal chemistry.