Thermosensation and the TRPV channel in Rhodnius prolixus

The thermal sense of triatomine bugs, vectors of Chagas disease, is unique among insects. Not only do these bugs exhibit the highest sensitivity to heat known in any animal up to date, but they can also perceive the infrared radiation emitted by the body of their warm-blooded hosts. The sensory basis of this capacity has just started to be unravelled. To shed additional light on our understanding of thermosensation, we initiated an analysis of the genetic basis of the thermal sense in Rhodnius prolixus. We tested the hypothesis that a TRPV (transient receptor potential vanilloid) channel receptor is involved in the evaluation of heat in this species. Two different approaches were adopted. Initially, we analysed the expression of a TRPV candidate for this function, i.e., RproIav, in different tissues. Subsequently, we tested the effects of capsaicin and capsazepine, two molecules known to interact with mammal TRPV1, using three different behavioural protocols for evaluating thermal responses: (1) proboscis extension response (PER), (2) thermopreference in a temperature gradient and (3) spatial learning in an operant conditioning context. Bioinformatic analyses confirmed that the characteristic features typical of the TRPV channel subfamily are found in the RproIav protein sequence. Molecular analysis showed that RproIav is expressed in R. prolixus, not only in the antennae, but also in other body structures bearing sensory organs. Behavioural experiments consistently revealed that capsaicin treated insects are less responsive to heat stimuli and prefer lower temperatures than non-treated insects, and that they fail to orient in space. Conversely, capsazepine induces the opposite behaviours. The latter data suggest that triatomine thermoreception is based on the activation of a TRP channel, with a similar mechanism to that described for mammal TRPV1. The expression of RproIav in diverse sensory structures suggests that this receptor channel is potentially involved in bug thermoreception. This constitutes solid evidence that thermosensation could be based on the activation of TRP receptors that are expressed in different tissues in R. prolixus. Whether RproIav channel is a potential target for the compounds tested and whether it mediates the observed effects on behaviour still deserves to be confirmed by further research.     

Thermosensation: hot findings make TRPNs very cool

TRPV and TRPM proteins have been shown to form temperature-responsive cation channels that act in nociception. Recent work on the mouse ANKTM1 and Drosophila Painless proteins shows that members of a third TRP subfamily, TRPN, also function in thermosensation.     

CPEB3 Deficiency Elevates TRPV1 Expression in Dorsal Root Ganglia Neurons to Potentiate Thermosensation

Cytoplasmic polyadenylation element binding protein 3 (CPEB3) is a sequence-specific RNA-binding protein that downregulates translation of multiple plasticity-related proteins (PRPs) at the glutamatergic synapses. Activity-induced synthesis of PRPs maintains long-lasting synaptic changes that are critical for memory consolidation and chronic pain manifestation. CPEB3-knockout (KO) mice show aberrant hippocampus-related plasticity and memory, so we investigated whether CPEB3 might have a role in nociception-associated plasticity. CPEB3 is widely expressed in the brain and peripheral afferent sensory neurons. CPEB3-KO mice with normal mechanosensation showed hypersensitivity to noxious heat. In the complete Freund''s adjuvant (CFA)-induced inflammatory pain model, CPEB3-KO animals showed normal thermal hyperalgesia and transiently enhanced mechanical hyperalgesia. Translation of transient receptor potential vanilloid 1 (TRPV1) RNA was suppressed by CPEB3 in dorsal root ganglia (DRG), whereas CFA-induced inflammation reversed this inhibition. Moreover, CPEB3/TRPV1 double-KO mice behaved like TRPV1-KO mice, with severely impaired thermosensation and thermal hyperalgesia. An enhanced thermal response was recapitulated in non-inflamed but not inflamed conditional-KO mice, with cpeb3 gene ablated mostly but not completely, in small-diameter nociceptive DRG neurons. CPEB3-regulated translation of TRPV1 RNA may play a role in fine-tuning thermal sensitivity of nociceptors.     

High Concentration of Vitamin E Decreases Thermosensation and Thermotaxis Learning and the Underlying Mechanisms in the Nematode Caenorhabditis elegans

α-tocopherol is a powerful liposoluble antioxidant and the most abundant isoform of vitamin E in the body. Under normal physiological conditions, adverse effects of relatively high concentration of vitamin E on organisms and the underlying mechanisms are still largely unclear. In the present study, we used the nematode Caenorhabditis elegans as an in vivo assay system to investigate the possible adverse effects of high concentration of vitamin E on thermosensation and thermotaxis learning and the underlying mechanisms. Our data show that treatment with 100–200 µg/mL of vitamin E did not noticeably influence both thermosensation and thermotaxis learning; however, treatment with 400 µg/mL of vitamin E altered both thermosensation and thermotaxis learning. The observed decrease in thermotaxis learning in 400 µg/mL of vitamin E treated nematodes might be partially due to the moderate but significant deficits in thermosensation, but not due to deficits in locomotion behavior or perception to food and starvation. Treatment with 400 µg/mL of vitamin E did not noticeably influence the morphology of GABAergic neurons, but significantly decreased fluorescent intensities of the cell bodies in AFD sensory neurons and AIY interneurons, required for thermosensation and thermotaxis learning control. Treatment with 400 µg/mL of vitamin E affected presynaptic function of neurons, but had no remarkable effects on postsynaptic function. Moreover, promotion of synaptic transmission by activating PKC-1 effectively retrieved deficits in both thermosensation and thermotaxis learning induced by 400 µg/mL of vitamin E. Therefore, relatively high concentrations of vitamin E administration may cause adverse effects on thermosensation and thermotaxis learning by inducing damage on the development of specific neurons and presynaptic function under normal physiological conditions in C. elegans.     

Brain mechanisms of pain affect and pain modulation

Recent animal studies reveal ascending nociceptive and descending modulatory pathways that may contribute to the affective-motivational aspects of pain and play a critical role in the modulation of pain. In humans, a reliable pattern of cerebral activity occurs during the subjective experience of pain. Activity within the anterior cingulate cortex and possibly in other classical limbic structures, appears to be closely related to the subjective experience of pain unpleasantness and may reflect the regulation of endogenous mechanisms of pain modulation.     

Mechanosensation and pain

The ability of cells to detect and transduce mechanical stimuli impinging on them is a fundamental process that underlies normal cell growth, hearing, balance, touch, and pain. Surprisingly, little research has focused on mechanotransduction as it relates to the sensations of somatic touch and pain. In this article we will review data on the wealth of different mechanosensitive sensory neurons that innervate our main somatic sense organ the skin. The role of different types of mechanosensitive sensory neurons in pain under physiological and pathophysiological conditions (allodynia and hyperalgesia) will also be reviewed. Finally, recent work on the cellular and molecular mechanisms by which mechanoreceptive sensory neurons signal both innocuous and noxious sensation is evaluated in the context of pain.     

Arthritis and pain. Future targets to control osteoarthritis pain

Clinical presentation of osteoarthritis (OA) is dominated by pain during joint use and at rest. OA pain is caused by aberrant functioning of a pathologically altered nervous system with key mechanistic drivers from peripheral nerves and central pain pathways. This review focuses on symptomatic pain therapy exemplified by molecular targets that alter sensitization and hyperexcitability of the nervous system, for example, opioids and cannabinoids. We highlight opportunities for targeting inflammatory mediators and their key receptors (for example, prostanoids, kinins, cytokines and chemokines), ion channels (for example, NaV1.8, NaV1.7 and CaV2.2) and neurotrophins (for example, nerve growth factor), noting evidence that relates to their participation in OA etiology and treatment. Future neurological treatments of pain appear optimistic but will require the systematic evaluation of emerging opportunities.     

Glutamate receptors and pain

Pain is an important survival and protection mechanism for animals. However, chronic/persistent pain may be differentiated from normal physiological pain in that it confers no obvious advantage. An accumulating body of pharmacological, electrophysiological, and behavioral evidence is emerging in support of the notion that glutamate receptors play a crucial role in pain pathways and that modulation of glutamate receptors may have potential for therapeutic utility in several categories of persistent pain, including neuropathic pain resulting from injury and/or disease of central (e.g., spinal cord injury) or peripheral nerves (e.g., diabetic neuropathy, radiculopathy) and inflammatory or joint-related pain (e.g., rheumatoid arthritis, osteoarthritis). This review focuses on the role of glutamate receptors, including both ionotropic (AMPA, NMDA and kainate) and metabotropic (mGlu1-8) receptors in persistent pain states with particular emphasis on their expression patterns in nociceptive pathways and their potential as targets for pharmacological intervention strategies.     

Neck and shoulder pain

Neck and shoulder pains are presenting or incidental symptoms in a large variety of conditions. There may be similarities in the anatomicophysiological mechanism of pain production and in the clinical picture in many of these conditions. Many of the vague and refractory cases of neck and shoulder pain and of migraine may be due to cervical disc disease. Scalenus anticus syndrome and cardiac disease can be diagnosed or differentiated from cervical disc syndrome only by thorough investigation. Proper treatment of neck and shoulder pain is dependent upon correct diagnosis through complete history, physical examination and laboratory tests, as described in this presentation.     

TRP channels and pain

Since the molecular identification of the capsaicin receptor, now known as TRPV1, transient receptor potential (TRP) channels have occupied an important place in the understanding of sensory nerve function in the context of pain. Several TRP channels exhibit sensitivity to substances previously known to cause pain or pain-like sensations; these include cinnamaldehyde, menthol, gingerol, and icillin. Many TRP channels also exhibit significant sensitivity to increases or decreases in temperature. Some TRP channels are sensitized in vitro by the activation of other receptors such that these channels may be activated by processes, such as inflammation that result in pain. TRP channels are suggested to be involved in processes as diverse as sensory neuron activation events, neurotransmitter release and action in the spinal cord, and release of inflammatory mediators. These functions strongly suggest that specific and selective inhibition of TRP channel activity will be of use in alleviating pain.     

Nociceptor activation and pain

This paper reviews advances in our knowledge on the physiological properties of human nociceptors and their capacity to signal pain. Conventional microneurography was used in combination with intraneural microstimulation in subjects who estimated the magnitude of pain from nociceptor stimulation. The experimental evidence favours the notion that C polymodal nociceptors can provide a peripheral neuronal basis for determination of heat pain threshold and also an essential peripheral code for suprathreshold magnitude judgments of heat pain. Furthermore, sensitized C polymodal nociceptors can contribute to hyperalgesia after a mild heat injury to hairy skin. Temporal summation is documented for dull, delayed C fibre pain, which is different in quality and less accurately projected than the fast, sharp pain from high-threshold A delta nociceptors. A segmental organization is shown for projected and referred pain from deep structures. Examples are given of central inhibition of pain by a prostaglandin synthetase inhibitor, and by physical manoeuvres such as vibration and cooling. Recent reports on microneurographic findings after nerve injury indicate that the technique may be useful for future studies on pathophysiological pain mechanisms.