Molecular and cellular limits to somatosensory specificity

Animals detect environmental changes through sensory neural mechanisms that enable them to differentiate the quality, intensity and temporal characteristics of stimuli. The 'doctrine of specific nervous energies' postulates that the different sensory modalities experienced by humans result of the activation of specific nervous pathways. Identification of functional classes of sensory receptors provided scientific support to the concept that somatosensory modalities (touch, pain, temperature, kinesthesis) are subserved by separate populations of sensory receptor neurons specialized in detecting innocuous and injurious stimuli of different quality (mechanical forces, temperature, chemical compounds). The identification of receptor proteins activated by different physicochemical stimuli, in particular ion channels of the Transient Receptor Potential (TRP) superfamily, has put forward the concept that specificity of peripheral sensory receptor neurons is determined by their expression of a particular "molecular sensor" that confers to each functional type its selectivity to respond with a discharge of nerve impulses to stimuli of a given quality. Nonetheless, recent experimental data suggest that the various molecular sensors proposed as specific transducer molecules for stimuli of different quality are not as neatly associated with the distinct functional types of sensory receptors as originally proposed. First, many ion channel molecules initially associated to the transduction of only one particular form of energy are also activated by stimuli of different quality, implying a limited degree of specificity in their transducing capacities. Second, molecular sensors associated with a stimulus quality and hence to a sensory receptor type and ultimately to a sensory modality may be concomitantly expressed in sensory receptor neurons functionally defined as specific for another stimulus quality. Finally, activation of voltage gated channels involved primarily in nerve impulse generation can also influence the gating of transducing channels, dramatically modifying their activation profile. Thus, we propose that the capacity exhibited by the different functional types of somatosensory receptor neurons to preferentially detect and encode specific stimuli into a discharge of nerve impulses, appears to result of a characteristic combinatorial expression of different ion channels in each neuronal type that finally determines their transduction and impulse firing properties. Transduction channels don't operate in isolation and their cellular context should also be taken into consideration to fully understand their function. Moreover, the inhomogeneous distribution of transduction and voltage-gated channels at soma, axonal branches and peripheral endings of primary sensory neurons influences the characteristics of the propagated impulse discharge that encodes the properties of the stimulus. Alteration of this concerted operation of ion channels in pathological conditions may underlie the changes in excitability accompanying peripheral sensory neuron injuries

Roles of TRPV1 and neuropeptidergic receptors in dorsal root reflex-mediated neurogenic inflammation induced by intradermal injection of capsaicin

<p>Abstract</p> <p>Background</p> <p>Acute cutaneous neurogenic inflammation initiated by activation of transient receptor potential vanilloid-1 (TRPV₁) receptors following intradermal injection of capsaicin is mediated mainly by dorsal root reflexes (DRRs). Inflammatory neuropeptides are suggested to be released from primary afferent nociceptors participating in inflammation. However, no direct evidence demonstrates that the release of inflammatory substances is due to the triggering of DRRs and how activation of TRPV₁receptors initiates neurogenic inflammation via triggering DRRs.</p> <p>Results</p> <p>Here we used pharmacological manipulations to analyze the roles of TRPV₁and neuropeptidergic receptors in the DRR-mediated neurogenic inflammation induced by intradermal injection of capsaicin. The degree of cutaneous inflammation in the hindpaw that followed capsaicin injection was assessed by measurements of local blood flow (vasodilation) and paw-thickness (edema) of the foot skin in anesthetized rats. Local injection of capsaicin, calcitonin gene-related peptide (CGRP) or substance P (SP) resulted in cutaneous vasodilation and edema. Removal of DRRs by either spinal dorsal rhizotomy or intrathecal administration of the GABA_Areceptor antagonist, bicuculline, reduced dramatically the capsaicin-induced vasodilation and edema. In contrast, CGRP- or SP-induced inflammation was not significantly affected after DRR removal. Dose-response analysis of the antagonistic effect of the TRPV₁receptor antagonist, capsazepine administered peripherally, shows that the capsaicin-evoked inflammation was inhibited in a dose-dependent manner, and nearly completely abolished by capsazepine at doses between 30–150 μg. In contrast, pretreatment of the periphery with different doses of CGRP_8–37(a CGRP receptor antagonist) or spantide I (a neurokinin 1 receptor antagonist) only reduced the inflammation. If both CGRP and NK₁receptors were blocked by co-administration of CGRP_8–37and spantide I, a stronger reduction in the capsaicin-initiated inflammation was produced.</p> <p>Conclusion</p> <p>Our data suggest that 1) the generation of DRRs is critical for driving the release of neuropeptides antidromically from primary afferent nociceptors; 2) activation of TRPV₁receptors in primary afferent nociceptors following intradermal capsaicin injection initiates this process; 3) the released CGRP and SP participate in neurogenic inflammation.</p

Acute myocardial infarction and coronary vasospasm associated with the ingestion of cayenne pepper pills in a 25-year-old male

Capsaicin, one of the major active components of cayenne pepper pills, is an over-the-counter substance with sympathomimetic activity used commonly by young individuals for weight loss. Here we report the case of a previously healthy young male who developed severe chest pain after using cayenne pepper pills for slimming and sustained an extensive inferior myocardial infarction. Electrocardiography combined with a bedside transthoracic echocardiogram confirmed the diagnosis of acute myocardial infarction. The patient denied using illicit substances, and he had no risk factors for coronary artery disease. His medication history revealed that he had recently started taking cayenne pepper pills for slimming. A subsequent coronary angiogram revealed patent coronary arteries, suggesting that the mechanism was vasospasm. We postulate that the patient developed acute coronary vasospasm and a myocardial infarction in the presence of this known sympathomimetic agent. This case highlights the potential danger of capsaicin, even when used by otherwise healthy individuals

Increased function of pronociceptive TRPV1 at the level of the joint in a rat model of osteoarthritis pain

Objectives Blockade of transient receptor potential vanilloid 1 (TRPV1) with systemic antagonists attenuates osteoarthritis (OA) pain behaviour in rat models, but on-target-mediated hyperthermia has halted clinical trials. The present study investigated the potential for targeting TRPV1 receptors within the OA joint in order to produce analgesia. Methods The presence of TRPV1 receptors in human synovium was detected using western blotting and immunohistochemistry. In a rat model of OA, joint levels of an endogenous ligand for TRPV1, 12- ydroxyeicosatetraenoic acid (12-HETE), were quantified using liquid chromatography-tandem mass spectrometry (LCMS/MS). Effects of peripheral administration of the TRPV1 receptor antagonist JNJ-17203212 on afferent fibre activity, pain behaviour and core body temperature were investigated. Effects of a spinal administration of JNJ-17203212 on dorsal horn neuronal responses were studied. Results We demonstrate increased TRPV1 immunoreactivity in human OA synovium, confirming the diseased joint as a potential therapeutic target for TRPV1-mediated analgesia. In a model of OA pain, we report increased joint levels of 12-HETE, and the sensitisation of joint afferent neurones to mechanical stimulation of the knee. Local administration of JNJ- 17203212 reversed this sensitisation of joint afferents and inhibited pain behaviour (weight-bearing asymmetry), to a comparable extent as systemic JNJ- 17203212, in this model of OA pain, but did not alter core body temperature. There was no evidence for increased TRPV1 function in the spinal cord in this model of OA pain. Conclusions Our data provide a clinical and mechanistic rationale for the future investigation of the therapeutic benefits of intra-articular administration of TRPV1 antagonists for the treatment of OA pain

Sumatriptan causes parallel decrease in plasma calcitonin gene-related peptide (CGRP) concentration and migraine headache during nitroglycerin induced migraine attack

Sumatriptan-induced changes in plasma calcitonin gene-related peptide (CGRP) concentration and headache intensity were investigated in 19 female migraineurs during nitroglycerin-induced migraine attack. Sumatriptan nasal spray was administered 120 min after the onset of the attack. Blood samples were obtained immediately before and 60 min after sumatriptan administration. In those subjects whose migraine attack improved considerably 60 min after the treatment the plasma CGRP concentration decreased significantly (P<0.05). In contrast, plasma CGRP concentration failed to change in patients whose headache did not improve. In addition, plasma CGRP concentrations showed significant positive correlations with the headache scores both 60 and 120 min after sumatriptan administration (P<0.05). According to our results plasma CGRP concentration decreases parallel to headache intensity during sumatriptan treatment and this decrease in CGRP predicts effectiveness of antimigraine drug therapy. This supports that one of the main effects of triptans is to decrease CGRP release

Neural Immune Communication in the Control of Host-Bacterial Pathogen Interactions in the Gastrointestinal Tract

The orchestration of host immune responses to enteric bacterial pathogens is a complex process involving the integration of numerous signals, including from the nervous system. Despite the recent progress in understanding the contribution of neuroimmune interactions in the regulation of inflammation, the mechanisms and effects of this communication during enteric bacterial infection are only beginning to be characterized. As part of this neuroimmune communication, neurons specialized to detect painful or otherwise noxious stimuli can respond to bacterial pathogens. Highlighting the complexity of these systems, the immunological consequences of sensory neuron activation can be either host adaptive or maladaptive, depending on the pathogen and organ system. These are but one of many types of neuroimmune circuits, with the vagus nerve and sympathetic innervation of numerous organs now known to modulate immune cell function and therefore dictate immunological outcomes during health and disease. Here, we review the evidence for neuroimmune communication in response to bacterial pathogens, and then discuss the consequences to host morbidity and mortality during infection of the gastrointestinal tract