Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bonding behaviours. Mice lacking secreted oxcytocin ( Oxt −/− , Cd38 −/− ) or its receptor ( Oxtr −/− ) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt −/− and Cd38 −/− , but not Oxtr −/− mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager −/− male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager −/− mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.

The roles of ion channels in sensory neurons were examined in experimental models of muscle pain in the rat. Rats were injected with 50 microl of 4% carrageenan or subjected to an eccentric exercise (ECC) of the gastrocnemius muscle (GM). The Randall-Selitto and von Frey tests were performed on the calves to evaluate mechanical hyperalgesia of the muscle. The changes in expression of four genes and proteins of ion channels in dorsal root ganglia were examined using quantitative PCR and immunohistochemistry, respectively. Effects of antagonists to transient receptor potential (TRP) channels and acid sensing ion channels (ASICs) on the mechanical hyperalgesia induced by carrageenan injection or ECC were evaluated. The mechanical hyperalgesia was observed 6-24h after carrageenan injection and 1-3 days after ECC in the Randall-Selitto test. Infiltrations of the inflammatory cells in the GM were seen in carrageenan-injected animals but not in those subjected to ECC. Expressions of genes and proteins in sensory neurons showed no changes. Intramuscular injection of antagonists to TRPV1 showed an almost complete suppressive effect on ECC-induced muscle hyperalgesia but not a carrageenan-induced one. Antagonists to TRP channels and ASICs showed suppressive effects for both carrageenan- and ECC-induced muscle hyperalgesia. The carrageenan injection and ECC models are useful models of acute inflammatory pain and delayed onset muscle soreness (DOMS), respectively, and the time course and underlying etiology might be different. TRP channels and ASICs are closely related to the development of muscle mechanical hyperalgesia, and TRPV1 is involved in ECC-induced DOMS.

Despite the prevalence of dyspepsia, nonhuman models for study of gastric hyperalgesia are limited. We thus characterized responses to gastric distension (GD) in the absence of and after two different gastric insults. A balloon was surgically placed into the stomach, and electromyographic responses to GD were recorded from the acromiotrapezius muscle at various times after balloon placement. Rats received either 20% acetic acid (HAc) or saline injections into the stomach wall or 0.1% iodoacetamide (IA) in drinking water. Responses to GD were monotonic with increasing distending pressure (10-80 mmHg) and were reproducible from days 3-14 after balloon implantation. Both HAc injection and IA ingestion led to increased responses to GD (i.e., gastric hyperalgesia), which, in the case of HAc, persisted for 60 days after HAc treatment. HAc injection produced ulcers in all treated animals; IA ingestion produced no lesions. Myeloperoxidase activity significantly increased after HAc but not saline injection or IA ingestion. In the awake, unrestrained rat, visceromotor responses to GD are quantifiable, reliable, and reproducible. Significantly enhanced responses to GD were apparent in two models of gastric insult, both of which may be useful for the study of the mechanisms of gastric hyperalgesia.

Intramuscular injection of nerve growth factor (NGF) is known to induce deep-tissue mechanical hyperalgesia. In this study it was hypothesised that daily intramuscular injections of NGF produce a progressive manifestation of soreness, mechanical hyperalgesia, and temporal summation of pain. In a double-blind placebo-controlled design, 12 healthy subjects were injected on 3 days with NGF into the tibialis anterior muscle and with isotonic saline on the contralateral side. Assessments were performed before and after the injections on days 0, 1, and 2, and repeated on days 3, 6, and 10. The self-perceived muscle soreness was assessed on a Likert scale. Computer-controlled pressure algometry was used to assess the pressure pain thresholds (PPTs). Temporal summation of pain after repeated pressure stimulations was assessed by computer-controlled pressure algometry. The pain distribution following painful pressure stimulation was also recorded. Compared with baseline and isotonic saline, the NGF injections caused (P<0.05): (1) progressively increasing soreness scores from 3 hours after the first injection until day 2, after which it remained increased; (2) decreased PPTs at days 1 to 3; (3) facilitated temporal summation of pressure pain at days 1 to 10; and (4) enlarged pressure-induced pain area after the injection on day 1 to day 6. The daily injections of NGF produced a progressive manifestation of muscle soreness, mechanical hyperalgesia, temporal summation of pressure pain, and pressure-induced pain distribution. These data illustrate that the prolonged NGF application affects peripheral and central mechanisms and may reflect process in musculoskeletal pain conditions.

Single, teased fiber recordings were made from the decentralized right cervical vagus nerve (hyponodal) of the rat. A total of 67 afferent fibers that responded to gastric distension (GD) were studied: 9 fibers were stimulated by phasic balloon GD, 58 by more natural fluid GD. All balloon GD-responsive fibers had resting activity (3.1 imp/s), and 57/58 fluid GD responsive fibers had resting activity (1.3 imp/s). All balloon GD-responsive fibers exhibited a dynamic response to phasic distension followed by slow adaptation, whereas fluid GD-responsive fibers exhibited increasing responses as intragastric pressure increased, followed typically by slow adaptation. Responses to graded GD were studied in all fibers, and all gave increasing responses to increasing pressures (5-60 mmHg). Thresholds for response varied between 0 and 18 mmHg. Mean response thresholds for two durations of fluid GD (30 and 60 s) were 5.6 and 3.9 mmHg; the mean response threshold to phasic balloon GD (30 s duration) was 5.3 mmHg. The potential sensitizing effect of platelet activating factor (PAF, 50 or 100 ng. kg(-1). min(-1) for 20 min) infused into the gastric artery was studied in 20 fibers. Fifteen fibers exhibited an increase in spontaneous activity; intragastric pressure also slightly increased during PAF infusion. The increase in activity produced by PAF was attenuated in the presence of the PAF receptor antagonist WEB 2086. After PAF-induced acute inflammation of the stomach, three of five fibers studied did not exhibit any change in response to graded GD. The present study characterized distension-sensitive afferent fibers in the right cervical vagus innervating the stomach of the rat by balloon GD and fluid GD. The results document that all distension-sensitive gastric vagal afferent fibers encoded the intensity of GD, but none had response thresholds in what might be considered the noxious range. PAF infusion activated mechanosensitive gastric vagal afferent fibers, but acute inflammation produced by PAF did not sensitize responses to GD.

Splanchnic nerve fibers innervating the stomach were studied in anesthetized rats; 997 fibers in the T(9) or T(10) dorsal roots were identified by electrical stimulation of the splanchnic nerve. Thirty-one fibers responded to gastric distension. Extrapolated response thresholds ranged between 0 and 53 mmHg; seven fibers had thresholds for response > or =30 mmHg. Thermo- and/or chemosensitivity was tested in 18 of the 31 fibers. Four of twelve fibers responded to intragastric perfusion of heated saline; none of eight fibers tested responded to perfusion of cold saline. Infusion of glucose, L-arginine, or potassium oleate produced no change in resting activity. Intragastric instillation of 12% glycerol or an inflammatory soup (bradykinin 10(-5) M, PGE(2) 10(-5) M, serotonin 10(-5) M, histamine 10(-5) M, and KCl 10(-3) M) and prior heat stimulation sensitized responses to distension. The results reveal the presence of low- and high-threshold mechanosensitive fibers in the splanchnic innervation of the stomach. These fibers have the ability to sensitize, and they likely contribute to pain and altered sensations that can arise from the stomach.

Single-fiber recordings were made from the decentralized right cervical vagus nerve (hyponodosal) of the rat. A total of 56 afferent fibers that responded to gastric distension (GD) were studied: 6 fibers were stimulated by phasic balloon GD, 50 by fluid GD. All fibers gave increasing responses to increasing pressures of GD (5-60 mmHg). The effects of mu-opioid (morphine), delta-opioid (SNC80), and kappa-opioid (EMD61,753, U62,066) receptor agonists were tested on responses of afferent fibers to GD. Morphine, administered systemically over a broad dose range (10 microg to 31 mg/kg, cumulative), had no effect on either resting activity or responses of vagal afferent fibers to GD. Similarly, the delta-opioid receptor agonist SNC80 (0.05-3.2 mg/kg) did not affect resting activity or responses to GD. In contrast, cumulative intra-arterial doses of the kappa-opioid receptor agonist EMD61,753 or U62,066 dose dependently attenuated afferent fiber responses to GD. Doses producing inhibition to 50% of the control response to GD of EMD61,753 (8.0 mg/kg) and U62,066 (8.8 mg/kg) did not differ. The effect of U62,066 was moderately attenuated by a nonselective dose (4 mg/kg) of naloxone hydrochloride; the kappa-opioid receptor-selective antagonist nor-BNI (20 mg/kg) was ineffective. These results demonstrate that kappa-, but not mu- or delta-opioid receptor agonists modulate visceral sensation conveyed by vagal afferent fibers innervating the stomach. Given that kappa-opioid receptor agonists effects were only modestly antagonized by naloxone and not at all by nor-BNI, the results point to a novel site of action.

No abstract