Irreversible impairment of thermoregulation induced by capsaicin and similar pungent substances in rats and guinea‐pigs
TL;DR: In rats and guinea‐pigs a subcutaneous or intraperitoneal injection of capsaicin, the substance responsible for the pungency of red pepper, produces profound hypothermia associated with skin vasodilatation.
Abstract: 1. In rats and guinea-pigs a subcutaneous or intraperitoneal injection of capsaicin, the substance responsible for the pungency of red pepper, produces profound hypothermia associated with skin vasodilatation.2. After large doses of capsaicin rats and guinea-pigs become insensitive to the hypothermic action of capsaicin. This densensitization is apparently irreversible since it is present months after the capsaicin treatment.3. Capsaicin-desensitized animals are no longer able to protect themselves against overheating but respond with pronounced hyperthermia to high ambient temperatures (32-40 degrees C). Temperature regulation against cold exposure, however, is not impaired.4. They also respond with an enhanced hyperthermia to painful stimuli such as repeated pinching of the tail or repeated introduction of the thermometer probe into the rectum.5. The enhanced hyperthermias are not due to increased heat production but to impairment of the heat dissipating mechanisms, which in rats and guinea-pigs acts mainly through evaporation of saliva, and skin vasodilatation.6. Acylamides with pungent action related to capsaicin such as piperine, caprinoyl-p-aminophenol and propionyl vanillylamide also cause hypothermia followed by desensitization and their efficacy is dependent on their pungency. The non-pungent nonenoyl benzylamide produces neither hypothermia nor desensitization.7. Capsaicin and its related pungent acylamides appear first to stimulate and then to desensitize the hypothalamic warmth detectors. By stimulating them the acylamides evoke reflexly the hypothermic response, whereas after desensitization the protective thermoregulatory reflexes for heat dissipation are no longer activated in response to high ambient temperature and to painful stimuli.
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TL;DR: Sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli and are impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation.
Abstract: The capsaicin (vanilloid) receptor VR1 is a cation channel expressed by primary sensory neurons of the "pain" pathway. Heterologously expressed VR1 can be activated by vanilloid compounds, protons, or heat (>43 degrees C), but whether this channel contributes to chemical or thermal sensitivity in vivo is not known. Here, we demonstrate that sensory neurons from mice lacking VR1 are severely deficient in their responses to each of these noxious stimuli. VR1-/- mice showed normal responses to noxious mechanical stimuli but exhibited no vanilloid-evoked pain behavior, were impaired in the detection of painful heat, and showed little thermal hypersensitivity in the setting of inflammation. Thus, VR1 is essential for selective modalities of pain sensation and for tissue injury-induced thermal hyperalgesia.
3,367 citations
TL;DR: Analysis of TRP channel function and expression has validated the existence of nociceptors as a specialized group of somatosensory neurons devoted to the detection of noxious stimuli and is providing insight into the coding logic of nnociception and how specification of nOCiceptor subtypes underlies behavioral discrimination ofNoxious thermal, chemical, and mechanical stimuli.
Abstract: Nociception is the process whereby primary afferent nerve fibers of the somatosensory system detect noxious stimuli. Pungent irritants from pepper, mint, and mustard plants have served as powerful pharmacological tools for identifying molecules and mechanisms underlying this initial step of pain sensation. These natural products have revealed three members of the transient receptor potential (TRP) ion channel family—TRPV1, TRPM8, and TRPA1—as molecular detectors of thermal and chemical stimuli that activate sensory neurons to produce acute or persistent pain. Analysis of TRP channel function and expression has validated the existence of nociceptors as a specialized group of somatosensory neurons devoted to the detection of noxious stimuli. These studies are also providing insight into the coding logic of nociception and how specification of nociceptor subtypes underlies behavioral discrimination of noxious thermal, chemical, and mechanical stimuli. Biophysical and pharmacological characterization of these...
874 citations
TL;DR: The finding that VR1 is expressed not only in primary sensory neurons but also in several brain nuclei is of great importance in that it places VRs in a much broader perspective than pain perception.
Abstract: The cloned vanilloid receptor VR1 has attracted recent attention as a molecular integrator of painful stimuli on primary sensory neurons. The existence of vanilloid-sensitive neurons in the brain is, however, controversial. In this study, we have used an antibody and a complementary RNA probe to explore the distribution of neurons that express VR1 in rat and in certain areas of human brain. In the rat, we observed VR1-expressing neurons throughout the whole neuroaxis, including all cortical areas (in layers 3 and 5), several members of the limbic system (e.g., hippocampus, central amygdala, and both medial and lateral habenula), striatum, hypothalamus, centromedian and paraventricular thalamic nuclei, substantia nigra, reticular formation, locus coeruleus, cerebellum, and inferior olive. VR1-immunopositive cells also were found in the third and fifth layers of human parietal cortex. Reverse transcription–PCR performed with rat VR1-specific primers verified the expression of VR1 mRNA in cortex, hippocampus, and hypothalamus. In the central nervous system, neonatal capsaicin treatment depleted VR1 mRNA from the spinal nucleus of the trigeminal nerve, but not from other areas such as the inferior olive. The finding that VR1 is expressed not only in primary sensory neurons but also in several brain nuclei is of great importance in that it places VRs in a much broader perspective than pain perception. VRs in the brain (and putative endogenous vanilloids) may be involved in the control of emotions, learning, and satiety, just to name a few exciting possibilities.
811 citations
TL;DR: Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin.
Abstract: This review focuses on the role of the peripheral nervous system in cutaneous biology and disease. During the last few years, a modern concept of an interactive network between cutaneous nerves, the neuroendocrine axis, and the immune system has been established. We learned that neurocutaneous interactions influence a variety of physiological and pathophysiological functions, including cell growth, immunity, inflammation, pruritus, and wound healing. This interaction is mediated by primary afferent as well as autonomic nerves, which release neuromediators and activate specific receptors on many target cells in the skin. A dense network of sensory nerves releases neuropeptides, thereby modulating inflammation, cell growth, and the immune responses in the skin. Neurotrophic factors, in addition to regulating nerve growth, participate in many properties of skin function. The skin expresses a variety of neurohormone receptors coupled to heterotrimeric G proteins that are tightly involved in skin homeostasis and inflammation. This neurohormone-receptor interaction is modulated by endopeptidases, which are able to terminate neuropeptide-induced inflammatory or immune responses. Neuronal proteinase-activated receptors or transient receptor potential ion channels are recently described receptors that may have been important in regulating neurogenic inflammation, pain, and pruritus. Together, a close multidirectional interaction between neuromediators, high-affinity receptors, and regulatory proteases is critically involved to maintain tissue integrity and regulate inflammatory responses in the skin. A deeper understanding of cutaneous neuroimmunoendocrinology may help to develop new strategies for the treatment of several skin diseases.
534 citations
TL;DR: This review summarizes the current understandings of the central circuitry mechanisms that underlie nonshivering thermogenesis in brown adipose tissue, shivering thermogenic in skeletal muscles, thermoregulatory cardiac regulation, heat-loss regulation through cutaneous vasomotion, and ACTH release.
Abstract: Body temperature regulation is a fundamental homeostatic function that is governed by the central nervous system in homeothermic animals, including humans. The central thermoregulatory system also ...
447 citations
Cites background from "Irreversible impairment of thermore..."
...Peripheral or central administration of capsaicin induces hypothermia (54, 62), and administration of TRPV1 antagonists induces hyperthermia (40, 162) by both increasing metabolism and reducing heat loss from the body surface, likely though antagonizing TRPV1 located within abdominal viscera (157)....
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