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[Background]: The vasculature function is mainly regulated by the autonomic nervous system. Importantly, the sensory-motor nervous system also innervates peripheral vessels and has the capacity to modulate vascular tone. Here we investigated the effects of electrical stimulation of a mixed nerve trunk on blood flow in deep arteries and muscle perfusion. Our hypothesis is that stimulation of a mixed nerve can modify blood flow., [Methods]: Twenty-nine healthy participants were included into a randomized-crossover and blinded clinical trial. Each subject received a placebo and two percutaneous peripheral nerve stimulation (pPNS) protocols on the median nerve: Pain Threshold continuous Low Frequency (PT-cLF) and Sensory Threshold burst High Frequency (ST-bHF). Blood flow was then assessed bilaterally using Power Doppler Ultrasonography at the main arteries of the arm, and blood perfusion at the forearm muscles. Afterwards, blood flow was quantified using a semi-automatized software, freely shared here., [Results]: Placebo, consisting in needle insertion, produced an immediate and generalized reduction on peak systolic velocity in all arteries. Although nerve stimulation produced mainly no effects, some significant differences were found: both protocols increased the relative perfusion area of the forearm muscles, the ST-bHF protocol prevented the reduction in peak systolic velocity and TAMEAN of the radial artery produced by the control protocol and PT-cLF produced a TAMEAN reduction of the ulnar artery., [Conclusions]: Therefore, the arterial blood flow in the arm is mainly impervious to the electrical stimulation of the median nerve, composed by autonomic and sensory-motor axons, although it produces mild modifications in the forearm muscles perfusion.

The role of TRPA1 in the thermosensitivity of the corneal cold thermoreceptor nerve endings was studied in young and aged mice. The contribution of the TRPA1-dependent activity to basal tearing and thermally-evoked blink was also explored. The corneal cold thermoreceptors' activity was recorded extracellularly in young (5-month-old) and aged (18-month-old) C57BL/6WT (WT) and TRPA1-/- knockout (TRPA1-KO) mice at basal temperature (34 °C) and during cooling (15 °C) and heating (45 °C) ramps. The blink response to cold and heat stimulation of the ocular surface and the basal tearing rate were also measured in young animals using orbicularis oculi muscle electromyography (OOemg) and phenol red threads, respectively. The background activity at 34 °C and the cooling- and heating-evoked responses of the cold thermoreceptors were similar in WT and TRPA1-KO animals, no matter the age. Similar to the aged WT mice, in the young and aged TRPA1-KO mice, most of the cold thermoreceptors presented low frequency background activity, a low cooling threshold, and a sluggish response to heating. The amplitude and duration of the OOemg signals correlated with the magnitude of the induced thermal change in the WT but not in the TRPA1-KO mice. The basal tearing was similar in the TRPA1-KO and WT mice. The electrophysiological data suggest that the TRPA1-dependent nerve activity, which declines with age, contributes to detecting the warming of the ocular surface and also to integrating the thermally-evoked reflex blink.

Corneal cold nerve endings are crucial structures in the maintenance of the ocular surface due to their ability to detect cold and humidity changes, thereby regulating cold-evoked blink reflex and tearing flow. However, despite their physiological relevance, their functional organization remains poorly understood. Optopharmacological agents allow modulation of neural activity acting on native ion channels without requiring exogenous gene expression. Amongst them, photo-isomerizable small molecules (photoswitches) have been shown to confer light-sensitivity to a variety of neurons at the central nervous system (1). Nevertheless, there is no direct evidence on whether photoswitches can modulate electrical activity of neural structures located far away from the neuron cell body, such as peripheral nerve terminals. Here, we show that DENAQ, a photochromic potassium channel blocker, enters guinea-pig corneal cold sensory nerve endings primarily through P2X channels. Subsequently, DENAQ produces a robust decrease in spontaneous nerve terminal activity and sensitizes cold-evoked responses of the cold thermoreceptors upon light irradiation. Moreover, DENAQ photo-modulates electrical activity of the orbicularis oculi muscle associated with cold-evoked blink reflex in rats. Small molecules acting as chemical photoswitches may be potentially useful as drugs for patients with corneal ectopic nerve activity, such as in dry- eye and ocular neuropathic pain.

Free nerve endings are key structures in sensory transduction of noxious stimuli. In spite of this, little is known about their functional organization. Transient receptor potential (TRP) channels have emerged as key molecular identities in the sensory transduction of pain-producing stimuli, yet the vast majority of our knowledge about sensory TRP channel function is limited to data obtained from in vitro models which do not necessarily reflect physiological conditions. In recent years, the development of novel optical methods such as genetically encoded calcium indicators and photo-modulation of ion channel activity by pharmacological tools has provided an invaluable opportunity to directly assess nociceptive TRP channel function at the nerve terminal.