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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 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

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.

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.

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 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.

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.

A review of existing studies on the psychological and physiological aspects of induced pain is presented. The methods employed in pain stimulation, the mechanisms involved and the nature of induced pain are discussed. In addition, the threshold levels of pain and the methods of pain measurement are assessed. The role of nociceptors in the discharge of pain and its effects on pain sensation are also discussed.

The pain thresholds of normal individuals without diabetes or esophageal disorders were analyzed by utilizing the graded intraesophageal balloon distension (IEBD) technique. Analysis of pain thresholds in normal individuals indicated the presence of higher pain threshold to IEBD in subjects aged 65-87 years old compared to 18-57-year-olds. Furthermore, gender did not influence the decrease in visceral pain sensation among aging subjects.

Research demonstrates that nociceptin and its receptor are present and functional in human peripheral blood neutrophils facilitating interaction between neural and immune tissues. Data indicate that nociceptin elicits cellular responses such as protein phosphorylation and modulation of intracellular cAMP levels.

Research shows that ANKTM1 belongs to the TRP channel of specialized neurons involved in temperature sensing. It is one in the subset of nociceptive sensory neurons in which it is coexpressed with the capsaicin/heat receptor. Data indicate that the ANKTM1 is a cold-activated channel protein.