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The innate immune regulator STING is a critical sensor of self- and pathogen-derived DNA. DNA sensing by STING leads to the induction of type-I interferons (IFN-I) and other cytokines, which promote immune-cell-mediated eradication of pathogens and neoplastic cells.sup.1,2. STING is also a robust driver of antitumour immunity, which has led to the development of STING activators and small-molecule agonists as adjuvants for cancer immunotherapy.sup.3. Pain, transmitted by peripheral nociceptive sensory neurons (nociceptors), also aids in host defence by alerting organisms to the presence of potentially damaging stimuli, including pathogens and cancer cells.sup.4,5. Here we demonstrate that STING is a critical regulator of nociception through IFN-I signalling in peripheral nociceptors. We show that mice lacking STING or IFN-I signalling exhibit hypersensitivity to nociceptive stimuli and heightened nociceptor excitability. Conversely, intrathecal activation of STING produces robust antinociception in mice and non-human primates. STING-mediated antinociception is governed by IFN-Is, which rapidly suppress excitability of mouse, monkey and human nociceptors. Our findings establish the STING-IFN-I signalling axis as a critical regulator of physiological nociception and a promising new target for treating chronic pain. Studies using mouse and non-human primate models identify the innate immune regulator STING--acting via type I interferons--as a key regulator of nociception, suggesting new targets for the treatment of chronic pain., Author(s): Christopher R. Donnelly [sup.1] , Changyu Jiang [sup.1] , Amanda S. Andriessen [sup.1] , Kaiyuan Wang [sup.1] , Zilong Wang [sup.1] , Huiping Ding [sup.2] , Junli Zhao [sup.1] [...]

Haematopoietic stem cells (HSCs) reside in specialized microenvironments in the bone marrow--often referred to as 'niches'--that represent complex regulatory milieux influenced by multiple cellular constituents, including nerves.sup.1,2. Although sympathetic nerves are known to regulate the HSC niche.sup.3-6, the contribution of nociceptive neurons in the bone marrow remains unclear. Here we show that nociceptive nerves are required for enforced HSC mobilization and that they collaborate with sympathetic nerves to maintain HSCs in the bone marrow. Nociceptor neurons drive granulocyte colony-stimulating factor (G-CSF)-induced HSC mobilization via the secretion of calcitonin gene-related peptide (CGRP). Unlike sympathetic nerves, which regulate HSCs indirectly via the niche.sup.3,4,6, CGRP acts directly on HSCs via receptor activity modifying protein 1 (RAMP1) and the calcitonin receptor-like receptor (CALCRL) to promote egress by activating the G[alpha].sub.s/adenylyl cyclase/cAMP pathway. The ingestion of food containing capsaicin--a natural component of chili peppers that can trigger the activation of nociceptive neurons--significantly enhanced HSC mobilization in mice. Targeting the nociceptive nervous system could therefore represent a strategy to improve the yield of HSCs for stem cell-based therapeutic agents. Stimulation of pain-sensing neurons, which can be achieved in mice by the ingestion of capsaicin, promotes the migration of haematopoietic stem cells from the bone marrow into the blood., Author(s): Xin Gao [sup.1] [sup.2] , Dachuan Zhang [sup.1] [sup.2] , Chunliang Xu [sup.1] [sup.2] , Huihui Li [sup.1] [sup.2] , Kathleen M. Caron [sup.3] , Paul S. Frenette [sup.1] [...]

The encoding of noxious stimuli into action potential firing is largely mediated by nociceptive free nerve endings. Tissue inflammation, by changing the intrinsic properties of the nociceptive endings, leads to nociceptive hyperexcitability and thus to the development of inflammatory pain. Here, we showed that tissue inflammation-induced activation of the mammalian target of rapamycin complex 2 (mTORC2) triggers changes in the architecture of nociceptive terminals and leads to inflammatory pain. Pharmacological activation of mTORC2 induced elongation and branching of nociceptor peripheral endings and caused long- lasting pain hypersensitivity. Conversely, nociceptor-specific deletion of the mTORC2 regulatory protein rapamycin-insensitive companion of mTOR (Rictor) prevented inflammation-induced elongation and branching of cutaneous nociceptive fibers and attenuated inflammatory pain hypersensitivity. Computational modeling demonstrated that mTORC2-mediated structural changes in the nociceptive terminal tree are sufficient to increase the excitability of nociceptors. Targeting mTORC2 using a single injection of antisense oligonucleotide against Rictor provided long-lasting alleviation of inflammatory pain hypersensitivity. Collectively, we showed that tissue inflammation-induced activation of mTORC2 causes structural plasticity of nociceptive free nerve endings in the epidermis and inflammatory hyperalgesia, representing a therapeutic target for inflammatory pain., Introduction Chronic pain is a common (~20% of the world population) debilitating condition that can persist for years, severely affecting the quality of life of affected individuals and their families [...]

Voltage-gated sodium (Na[sub.v]) channels initiate action potentials in most neurons, including primary afferent nerve fibres of the pain pathway. Local anaesthetics block pain through non-specific actions at all Na[sub.v] channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes of these channels and their contributions to chemical, mechanical, or thermal pain. Here we identify and characterize spider (Heteroscodra maculata) toxins that selectively activate the Na[sub.v]1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Na[sub.v]1.1-expressing fibres are modality-specific nociceptors: their activation elicits robust pain behaviours without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibres also express Na[sub.v]1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Na[sub.v]1.1 channels in regulating the excitability of sensory nerve fibres that mediate mechanical pain., Author(s): Jeremiah D. Osteen [1]; Volker Herzig [2]; John Gilchrist [3]; Joshua J. Emrick [1]; Chuchu Zhang [1]; Xidao Wang [4]; Joel Castro [5, 6]; Sonia Garcia-Caraballo [5, 6]; Luke [...]

Nociceptin/orphanin FQ (N/OFQ), the nociceptin opioid peptide (NOP) receptor ligand, increases feeding when injected centrally. Initial data suggest that N/OFQ blocks the development of a conditioned taste aversion (CTA). The current project further characterized the involvement of N/OFQ in the regulation of hunger vs. aversive responses in rats by employing behavioral, immunohistochemical, and real-time PCR methodology. We determined that the same low dose of the NOP antagonist [[Nphe.sup.1]]N/OFQ(1-13)[NH.sub.2] delivered via the lateral ventricle diminishes both N/OFQ-and deprivation-induced feeding. This anorexigenic effect did not stem from aversive consequences, as the antagonist did not cause the development of a CTA. When [[Nphe.sup.1]]N/OFQ(1-13)[NH.sub.2] was administered with LiC1, it moderately delayed extinction of the LiC1-induced CTA. Injection of LiC1 + antagonist compared with LiC1 alone generated an increase in c-Fos immunoreactivity in the central nucleus of the amygdala. The antagonist alone elevated Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, nucleus of the solitary tract, and central nucleus of the amygdala. Hypothalamic NOP mRNA levels were decreased during energy intake restriction induced by aversion, as well as in non-CTA rats food-restricted to match CTA-reduced consumption. Brain stem NOP was upregulated only in aversion. Prepro-N/OFQ mRNA showed a trend toward upregulation in restricted rats (P = 0.068). We conclude that the N/OFQ system promotes feeding by affecting the need to replenish lacking calories and by reducing aversive responsiveness. It may belong to mechanisms that shift a balance between the drive to ingest energy and avoidance of potentially tainted food. food intake; conditioning; hypothalamus; brain stem; amygdala; lithium chloride; NOP receptor; ORLI doi: 10.1152/ajpregu.00556.2009.

The gene SCN9A is responsible for three human pain disorders. Non-sense mutations cause a complete absence of pain, whereas activating mutations cause severe episodic pain in paroxysmal extreme pain disorder and primary erythermalgia. This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population. We first genotyped 27 SCN9A SNPs in 578 individuals with a radiographic diagnosis of osteoarthritis and a pain score assessment. A significant association was found between pain score and SNP rs6746030; the rarer A allele was associated with increased pain scores compared to the commoner G allele (P = 0.016). This SNP was then further genotyped in 195 pain-assessed people with sciatica, 100 amputees with phantom pain, 179 individuals after lumbar discectomy, and 205 individuals with pancreatitis. The combined P value for increased A allele pain was 0.0001 in the five cohorts tested (1277 people in total). The two alleles of the SNP rs6746030 alter the coding sequence of the sodium channel Nav1.7. Each was separately transfected into HEK293 cells and electrophysiologically assessed by patch-clamping. The two alleles showed a difference in the voltage-dependent slow inactivation (P = 0.042) where the A allele would be predicted to increase Nav1.7 activity. Finally, we genotyped 186 healthy females characterized by their responses to a diverse set of noxious stimuli. The A allele of rs6746030 was associated with an altered pain threshold and the effect mediated through C-fiber activation. We conclude that individuals experience differing amounts of pain, per nociceptive stimulus, on the basis of their SCN9A rs6746030 genotype. [Na.sub.v]1.7 | nociception | pain | SCN9A | single nucleotide polymorphisms doi: 10.1073/pnas.0913181107

The role of nociceptin and its spinal cord neural pathways in etectroacupuncture (EA)-related inhibition of visceral excitatory reflexes is not clear. Nociceptin/orphanin FQ (N/OFQ) is an endogenous ligand for a G proteincoupled receptor, called the N/OFQ peptide (NOP) receptor, which has been found to be distributed in the spinal cord. The present study investigated the importance of this system in visceral-cardiovascular reflex modulation during EA. Cardiovascular pressor reflex responses were induced by gastric distension in Sprague-Dawley rats anesthetized by ketamine and xylazine. An intrathecal injection of nociceptin (10 nM) at T1-2 attenuated the pressor responses by 35%, similar to the influence of EA at P 5-6 (42% decrease). An intrathecal injection of the NOP antagonist, [N-[Phe.sup.1]] [nociceptin.sub.1-13] N[H.sub.2], partially reversed the EA response. Pretreatment with the opioid receptor antagonist naloxone did not alter the EA-like inhibitory effect of nociceptin on the pressor reflex, whereas a combination of nociceptin receptor antagonist with naloxone completely abolished the EA response. An intrathecal injection of nociceptin attenuated the pressor responses to the electrical stimulation of the rostral ventrolateral medulla by 46%, suggesting that nociceptin can regulate sympathetic outflow. Furthermore, a bilateral microinjection of NOP antagonist into either the dorsal horn or the intermediolateral column at T1 partially reversed the EA inhibitory effect. These results suggest that nociceptin in the spinal cord mediates part of the EA-related modulation of visceral reflex responses. nociceptin/orphanin FQ peptide receptors; pressor response; dorsal horn; intermediolateral column; acupuncture

We recently found that an orally directed stretch of the esophagus activates a neurally mediated relaxation of the lower esophageal sphincter (LES). Goals of our study were to characterize the neural mechanisms responsible for axial and transverse stretch-activated responses in the LES. LES pressure was monitored in anesthetized and artificially ventilated mice. Sutures were placed in the esophagus to exert graded stretch in the longitudinal and transverse directions. Effects of bilateral vagotomy and pharmacological agents on the stretch-activated LES responses were investigated. The relationship between vagally stimulated axial stretch and LES relaxation was also studied. Stretch in the longitudinal and transverse directions caused a dose-dependent LES relaxation and contraction, respectively, that were not affected by bilateral vagotomy and sympathectomy but were blocked by tetrodotoxin. In bilateral vagotomized animals, hexamethonium, atropine, pyridoxalphosphate-6-azophenyl-2',4' disulfonic acid (PPADS), and ondansetron did not block the stretch-activated LES relaxation and contraction. Axial stretch-activated LES relaxation was blocked by nitric oxide inhibitor and transverse stretch-activated LES contraction was blocked by a combination of atropine and substance P antagonist. Electrical stimulation of the vagus nerve induced LES relaxation and axial stretch on the LES, both of which were blocked by rocuronium. Axial and transverse stretch-activated LES relaxation and contraction were present in the W/[W.sup.v] mice that lack interstitial cells of Cajal (ICC). Stretch-activated LES relaxation and contraction are mediated through mechanosensitive neurons located in the myenteric plexus, which involves neither synaptic transmission nor ICC. mechanosensitive neuron; excitatory motor neuron; inhibitory motor neurons

To validate a laser-based method to measure thermal nociception in dairy cows (e.g., for the use in studies on stress-induced analgesia), we performed three experiments to observe the behavioral responses to a computer-controlled C[O.sub.2] laser beam applied to the skin on the caudal aspect of the metatarsus. In Exp. 1, effects of power output (0, 1.3, 1.8, 2.2, 2.4 and 2.6 W) on nociceptive responses were examined using 18 dairy cows kept and tested in tie stalls. Increasing the power output affected the latencies to respond (decreasing latencies, P [less than or equal to] 0.01), types of response (less nonresponding and more kicking, P < 0.0001), and behavior during (increasing frequency of tail flicking, P = 0.003) and between single laser exposures (increasing frequency of kicking, P = 0.02). Therefore, behavioral responses to a laser stimulus seem to be a valid measure of nociception in dairy cows. Repeatability within 15 rain was investigated in Exp. 2 using n = 36 dairy cows kept and tested in tie stalls and a power output of 1.8 W. The variables' latency to move the exposed leg and frequency of tail flicking during laser exposure showed the highest level of repeatability (0.50 and 0.38, respectively). However, retesting at t=15 min led to increased responses in terms of shorter latencies to respond (P [less than or equal to] 0.05), increased kicking (P = 0.05), and tail flicking (P = 0.02), which probably can be explained by sensitization. Effects of power output (1.0 vs. 1.8 W) and skin condition (naked vs. intact) were examined in Exp. 3 on 11 group-housed dairy cows, tested just outside their home pen. Increasing the power output and shaving off hair led to increased responses as seen by shorter latencies to respond (P < 0.0001), less nonresponding (P < 0.0001), and increased kicking (P = 0.0003), as well as reduced intra- and interindividual variability (P [less than or equal to] 0.04). In conclusion, the results of these experiments suggest that behavioral responses to laser stimulation are a valid and reliable measure of nociception in dairy cows, especially when applied on naked skin, both in the home environment and just outside a group pen. The fact that repeated testing in itself at t = 15 min led to increased responses means that the test will be a conservative measure of stress-induced analgesia. Key Words: Behavior, Dairy Cows, Heat, Laser Radiation, Pain

The present study investigated whether activation of presynaptic N-methyl-D-aspartate (NMDA) receptors in the spinal cord produces a retrograde nociceptor sensitization (hypernociception) to mechanical nonnoxious stimulus. By using an electronic version of the von Frey hair test (pressure meter), s.c. intraplantar administration of prostaglandin [E.sub.2] (PG[E.sub.2]) (50-400 [micro]g per paw) evoked a dose-related ipsilateral paw hypernociception. In contrast, intrathecal (i.t.) administration of NMDA (5-80 ng) and PG[E.sub.2] (15-150 ng) evoked dose-related bilateral paw hypernociception. The s.c. intraplantar administration of dipyrone (80-320 [micro]g per paw) or morphine (3 and 9 [micro]g per paw), usually used to antagonize peripheral PG[E.sub.2] (100 ng per paw), induced hypernociception and also antagonized the ipsilateral (without affecting the contralateral) paw hypernociception induced by i.t. injections of NMDA (40 ng) or PG[E.sub.2] (50 ng). These doses of drugs did not modify the basal mechanical sensitivity of control paws. This result shows that intraspinal NMDA or PG[E.sub.2] produces sensitization of the primary sensory neuron in response to mechanical stimulation. In a second series of experiments it was shown that the i.t. treatment with NaV1.8 (SNS/PN3) sodium channel antisense oligodeoxynucleotides, but not mismatch oligodeoxynucleotides, decreased the mRNA expression of sodium tetrodotoxin-resistant channels on the dorsal root ganglia and abolished the mechanical hypernociception induced by i.t. administration of NMDA. Thus, our results support the suggestion that glutamate release in the spinal cord during inflammation causes retrograde hypernociception of nociceptors associated with sodium tetrodotoxin-resistant channels in primary nociceptive sensory neurons.

Results demonstrate that the calcium-sensing protein DREAM is involved in pain processing. Mutants lacking this protein respond poorly to acute thermal, mechanical, and visceral pain as well as to chronic neuropathic and inflammatory pain.

G protein-coupled receptors (GPCRs), also know as mrgs, are expressed in nociceptive sensory neuron populations. Data suggest that mrgs may be involved in the regulation of nociceptor development and function and pain modulation.

Ion channels form a diverse and sophisticated collection of membrane-bound proteins. They are influenced by many endogenous compounds and physiological stimuli and modulate neuronal activity. It is thus unsurprising that they provide attractive targets for the design of novel therapeutics. In this article, recent ion channel research and its relevance to modulation of sensory transmission is assessed. In pain research, specific blockade or activation of ion channels has long been considered a desired route for identification of analgesics. Historically, this has proven difficult to attain due to the incidence of side-effects associated with most ion-channel modulators. The recent discovery of several novel classes of ion channels, each of which has a specific distribution and role in sensory processing and nociception, has provided a plethora of targets for pharmaceutical intervention with the promise of an improved therapeutic index.

Much research has been undertaken in the field of pain in an attempt to find an effective treatment. Insights into the underlying mechanisms of pain have been gained from studies using preclinical animal models (acute stimuli, post-tissue injury and peripheral nerve injury) and evaluating their similarity with the human condition. In this article, these pain models are summarized and the mechanisms of pain discussed in relation to spinal processing. In the context of this research the therapeutic potential of novel analgesics is highlighted as the future looks forward to the many possibilities that the targeted spinal delivery of drugs can bring.

Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

The heart rate response to gastric distension, the participation of vagal and sympathetic sensory afferents, adrenergic and cholinergic neural pathways, and the effects of capsaicin on this response in anesthetized rats were investigated. Findings showed that unmyelinated, capsaicin-sensitive vagal afferents are important to the pseudoaffective cardioautonomic response to a noxious gastric stimulus.

Ion channels of nociception, pain perception, are discussed. Nociceptors are first among the cells in the series of neurons leading to the pain sensation.All of their essential functions depend on ion channels. The capsaicin receptor and its possible role in themosensation is of interest as are ATP- and proton -gated channels and nociceptor-specific sodium ion channels.

A study was conducted to investigate the effect of rectal distensions on a somatic nociceptive flexion RIII reflex as part of additional research on human visceral sensations and viscerasomatic interactions. Results indicate that rectal distensions in humans induce different effects on the RIII nociceptive flexion reflex based on the location of recording and the mode of distension. Further, these different modes of distension appear to activate two functionally distinct types of rectal mechanoreceptor.

Substance P is released in the spinal cord in response to painful stimuli, but its role in nociceptive signaling remains unclear. When a conjugate of substance P and the ribosome-inactivating protein saporin was infused into the spinal cord, it was internalized and cytotoxic to lamina I spinal cord neurons that express the substance P receptor. This treatment left responses to mild noxious stimuli unchanged, but markedly attenuated responses to highly noxious stimuli and mechanical and thermal hyperalgesia. Thus, lamina I spinal cord neurons that express the substance P receptor play a pivotal role in the transmission of highly noxious stimuli and the maintenance of hyperalgesia., A subpopulation of dorsal root ganglion neurons synthesize (1) and transport (2) substance P (SP) to the spinal cord, where it is released upon noxious stimulation of the innervated peripheral [...]

There are some conspicuous differences between the sensibilities of cutaneous and visceral tissues: (1) Direct trauma, which readily produces pain when applied to the skin, is mostly without effect ill healthy visceral tissue. (2) Pain that arises from visceral tissues is initially often poorly localised and diffuse. (3) With time, visceral pains are often referred to more superficial structures. (4) The site of referred pain may also show hyperalgesia. (5) In disease states, the afflicted viscera may also become hyperalgesic. In this target article, 1 consider to what extent differences in the physiology, anatomy, and chemistry of peripheral processing systems explain these different sensibilities. In almost every aspect, there are subtle differences in the properties of the processing mechanisms for cutaneous and visceral information. These may arise because of distinct developmental cues operating in the. two domains Many of the differences between -visceral and cutaneous afferents are quantitative rather than qualitative. The quantitative differences, for example ill the density of afferent innervation, can be large. The quantitative differences ill the numbers of afferents alone may be a sufficient explanation for some aspects of the differential sensibility, for example, the poor localisation of sensation and the apparent insensitivity to focal yet tissue-damaging stimuli. In addition, the few clear qualitative differences apparent ill the innervations of the two tissue types may be of special importance. That the encoding of visceral nociceptive events may occur by an intensity mechanism rather than a specificity mechanism could be the key difference in viscerosensory and somatosensory processing.

Research shows that cacitonin gene-related peptide (CGRP) is critical to the visceral afferent nerve sensitization from gastrointestinal origin. Studies on colorectal distension-induced visceral pain using conscious rats indicate that CGRP actively stimulates abdominal contractions caused by colorectal distension. Experimental evidence suggests that CGRP promotes nociceptive transmission.

The intraureter pressure points of rats exhibiting artificial ureteric calculosis was quantified to determine the effects of calculosis on ureter motility. Partial obstruction of the ureter via injection of dental cement increased the amplitude of phasic contractions and baseline pressure in rats due to ureteral calculosis. On the other hand, complete obstruction of the ureter by tight ligation totally eliminated phasic motility. Furthermore, hypermotility evoked by the presence of stone in the ureter also stimulated nociceptive afferents.

The role of N-methyl-D-aspartate (NMDA)-type glutamate receptors on the release of substance P from primary afferent nociceptors was established by analyzing the results following injection of NMDA on the cerebrospinal spinal fluids of rat spinal cord. Results revealed that presynaptic NMDA receptors positively influence the the primary afferent terminal like any typical autoreceptor and acts antagonistically with endogenous opioids.

The effects of abdominal ischemia on the intestinal motility and activation of gastrointestinal afferents were analyzed in anesthetized cats. Anesthetized cats exposed to 15 minutes of abdominal ischemia exhibited impaired gastrointestinal motility and intraluminal pressure. However, ischemia did not alter the single-unit activity of C fiber afferents in the stomach, jejunum, duodenum and colon.

The abdominal muscle contractions of rats were analyzed after the intraperitoneal injection of acetic acid to determine the role of calcitonin gene-related peptides (CGRP) in the sensory afferents on visceral pain. Acetic acid-induced gastric emptying in rats was inhibited by the administration of RP-67580 indicating the role of neurokinin 1 receptors in mediating the release of CGRP due to peritoneal irritation. Furthermore, visceral and abdominal pain was inhibited by the administration of CGRP-receptor agonists.

Pain differs from other sensations in many respects. Primary pain-sensitive neurons respond to a wide variety of noxious stimuli, in contrast to the relatively specific responses characteristic of other sensory systems, and the response is often observed to sensitize on repeated presentation of a painful stimulus, while adaptation is typically observed in other sensory systems. In most cases the cellular mechanisms of transduction and sensitization in response to painful stimuli are not understood. We report here that application of pulses of noxious heat to a subpopulation of isolated primary sensory neurons rapidly activates an inward current. The ion channel activated by heat discriminates poorly among alkali cations. Calcium ions both carry current and partially suppress the current carried by other ions. The current is markedly increased by bradykinin, a potent algogenic nonapeptide that is known to be released in vivo by tissue damage. Phosphatase inhibitors prolong the sensitization caused by bradykinin, and a similar sensitization is caused by activators of protein kinase C. We conclude that bradykinin sensitizes the response to heat by activating protein kinase C.

Electrical and mechanical stimulations of the lower esophagus was conducted in patients with C6 and C7 spinal injuries to evaluate nerve injury-related impairments in esophageal nociception. Balloon distention in the lower esophagus elicited pain in patients with C6 or C7 spinal injuries. The patients also exhibited normal subjective sensation of pain in response to varied evoked potentials after esophageal ballon distension compared to control subjects. However, specific impairments of receptor nerve units caused subtle changes in sensory threshold and cerebral evoked potentials.

Glutamate is an important neurotransmitter in spinal nociceptive pathways. In rats, glutamate is activated by an early gene that is induced by increased neuronal activity from the lower urinary tract (LUT). Expression of this early gene, designated c-fos, is increased by chemical activation of the LUT. Experiments performed on rats show that spinal processing of nociceptive input from the LUT is mediated by glutaminergic receptors such as N-methyl-D-aspartic acid and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid.

The role of somatostatin and etorphine in adrenal and autonomic function in the cat was investigated. Microinjections of somatostatin in 100 pmol dose into laminae I-II of trigeminal subnucleus caudalis caused increases in catecholamine release and adrenal blood flow, but had no effect when injected into laminae III-IV. No effect was observed when the drugs were delivered in 500 pmol dose into laminae I-II but caused a slight increase in renal blood flow and peripheral concentrations of norepinephrine when injected into laminae III-IV. It was concluded that somatostatin and etorphine act by different mechanisms during nociception.

Internal and external adenosine do not affect the activation of ischemically sensitive cardiac sympathetic afferent (ISA) nerve endings, which are involved in the pain of angina pectoris. Single-unit activity of ISA from the left thoracic sympathetic chain was observed during 5 minutes of myocardial ischemia in cats which received adenosine and an adenosine A1 receptor agonist. Activity of ISA did not increase with adenosine. Dipyridamole and aminophylline also produced no change.

Lipoxygenase products such as leukotriene B4 (LTB4) interact with stereospecific receptors to reduce and dihydroxyeicosa tetraenoic acid sensitizes the response of abdominal visceral afferent to ischemia. In anesthetized cats, single-unit activity of abdominal visceral C fiber afferent from the right thoracic sympathetic chain was observed. The data also indicate that the augmented response of afferents to abdominal ischemia after inhibition of 5-lipoxygenase is partially independent of shunting to the 15-lipoxygenase or the cycloxygenase system.

Chronic pain, which is associated with prolonged tissue damage or injuries to the peripheral or central nervous system, results from a number of complex changes in nociceptive pathways. These include alterations of cell phenotype and changes in the expression of proteins such as receptors, transmitters and ion channels, as well as modifications of neural structure, for example, cell loss, nerve regeneration and synaptic reorganizations. The resultant increase in neural excitability can be reduced with receptor-selective drugs that block peripheral or central chemical mediators or that control ectopic activity or cellular phenotype changes. In this article, Andy Dray, Laszlo Urban and Anthony Dickenson focus on some current mechanistic aspects of chronic pain imposed by inflammation and peripheral neuropathy, and review in particular the molecular changes involving the pharmacology of nociceptive pathways since these have important implications for the management of pain.