Greta Ågren

Repeated massage-like stimulation induces long-term effects on nociception: contribution of oxytocinergic mechanisms.

Massage‐like stroking induces acute antinociceptive effects that can be reversed by an oxytocin antagonist, indicating activation of oxytocin on endogenous pain controlling systems. We now demonstrate an increase in hindpaw withdrawal latencies (HWLs), in response to thermal and mechanical stimuli, which was present after six treatments of massage‐like stroking every other day and which continued to increase through the remaining seven treatments. Repeated massage‐like stroking also resulted in increased oxytocin‐like immunoreactivity (oxytocin‐LI) levels in plasma and periaquaductal grey matter (PAG). Furthermore, increases in HWLs were also present after injections of oxytocin into the PAG (0.1, 0.5 and 1.0 nmol). Intra‐PAG oxytocin injection of 1 nmol followed by 1 or 20 nmol of naloxone attenuated the increments in HWL. Also, there was a dose‐dependent attenuation of the oxytocin‐induced antinociceptive effects following intra‐PAG injection of the µ‐opioid antagonist β‐funaltrexamine (β‐FNA) and the κ‐opioid antagonist nor‐binaltorphimine (nor‐BNI) but not the δ‐antagonist naltrindole. The long‐term antinociceptive effects of massage‐like stroking may be attributed, at least partly, to the oxytocinergic system and its interaction with the opioid system, especially the µ‐ and the κ‐receptors in the PAG.

Anti-nociceptive effects of oxytocin in rats and mice

The existence of neural opioid-mediated networks that are specific for the modulation of nociception is well established. Parallel non-opioid pathways exist, but their underlying physiology is little known. We now report that oxytocin administered intraperitoneally to rats, and intraperitoneally or intracisternally to mice has an anti-nociceptive effect, which is related to the activation of descending anti-nociceptive pathways. This anti-nociceptive effect can be reversed by an oxytocin antagonist but not by the opioid antagonist naloxone. The anti-nociceptive effect of oxytocin is not directly dependent on the activation of serotonergic pathways or to changes in temperature. Our data indicate that the oxytocinergic system has a modulatory function on nociception.

The oxytocin antagonist 1-deamino-2-D-Tyr-(Oet)-4-Thr-8-Orn-oxytocin reverses the increase in the withdrawal response latency to thermal, but not mechanical nociceptive stimuli following oxytocin administration or massage-like stroking in rats

In this study the effect of exogenous oxytocin and of massage-like stroking on the withdrawal latency responses to heat and mechanical nociceptive stimulation were investigated in rats. A hot-plate test and the Randall-Selitto test were used to assess the withdrawal responses. Exogenous oxytocin (0.1-1 mg/kg) and stroking (a low frequency mechanical stimulation) significantly increased the withdrawal latencies in response to mechanical and to thermal nociceptive stimuli. The effect of oxytocin and of stroking in the hot-plate test was reversed by the oxytocin antagonist (1-deamino-2-D-Tyr-(Oet)-4-Thr-8-Orn-oxytocin) directed against the uterine receptor. In contrast, the antagonist did not affect the prolonged response latency in the mechanical nociceptive stimulation test following either exogenous oxytocin or stroking. These results support the view that (1) oxytocin administration affects directly or indirectly nociceptive related behaviour in response to heat stimulation, and (2) massage-like stroking may have an anti-nociceptive effect via activation of oxytocinergic mechanisms. Since the response to mechanical stimulation was not blocked by the antagonist the mechanisms mediating the withdrawal latency to heat and mechanical stimulation could be different.

High‐dose anabolic androgenic steroids modulate concentrations of nerve growth factor and expression of its low affinity receptor (p75‐NGFr) in male rat brain

The effects of treatment with a high dose of nandrolone or testosterone on nerve growth factor (NGF) levels and NGF low‐affinity receptor (p75‐NGFr) distribution in the brain were analyzed. Nandrolone, subcutaneously injected in rats for several weeks, caused an increase of NGF levels in the hippocampus and septum and a decrease in the hypothalamus. The number of p75‐NGFr‐immunoreactive neurons and the p75‐NGFr expression levels were reduced in the septum and vertical and horizontal Brocas bands. Testosterone injections caused an increase of NGF levels in the hippocampus, septum, and occipital cortex and induced an upregulation of p75‐NGFr in the forebrain NGF target regions. This testosterone effect suggests that nandrolone and testosterone affect brain NGF target cells by a different mechanism(s). Nandrolone may interfere with NGF transport and/or utilization by forebrain neurons, causing an altered p75‐NGFr expression and NGF accumulation as a consequence. Since NGF is known to maintain forebrain neurons and to regulate neurobehavioral functions, including memory, learning, and defensive behavior, it is possible to hypothesize that this neurotrophin may play a role in the mechanism of action of anabolic androgenic steroids (AAS) in the brain and be associated with endocrine and behavioral dysfunctions occurring due to AAS abuse. J. Neurosci. Res. 47:198–207, 1997.

Massage-like stroking of the abdomen lowers blood pressure in anesthetized rats: influence of oxytocin

The aim of this study was to determine how massage-like stroking of the abdomen in rats influences arterial blood pressure. The participation of oxytocinergic mechanisms in this effect was also investigated. The ventral and/or lateral sides of the abdomen were stroked at a speed of 20 cm/s with a frequency of 0.017-0.67 Hz in pentobarbital anesthetized, artificially ventilated rats. Arterial blood pressure was recorded with a pressure transducer via a catheter in the carotid artery. Stroking of the ventral, or both ventral and lateral sides of the abdomen for 1 min with a frequency of 0.67 Hz caused a marked decrease in arterial blood pressure (approx. 50 mmHg). After cessation of the stimulation blood pressure returned to the control level within 1 min. The maximum decrease in blood pressure was achieved at frequencies of 0.083 Hz or more. Stroking only the lateral sides of the abdomen elicited a significantly smaller decrease in blood pressure (approx. 30 mmHg decrease) than stroking the ventral side. The decrease in blood pressure caused by stroking was not altered by s.c. administration of an oxytocin antagonist (1-deamino-2-D-Tyr-(Oet)-4-Thr-8-Orn-oxytocin, 1 mg/kg) directed against the uterine receptor. In contrast, the administration of 0.1 mg/kg of oxytocin diminished the effect, which was antagonized by a simultaneous injection of the oxytocin antagonist. These results indicate that the massage-like stroking of the abdomen decreases blood pressure in anesthetized rats. This effect does not involve intrinsic oxytocinergic transmission. However, since exogenously applied oxytocin was found to diminish the effect of stroking, oxytocin may exert an inhibitory modulatory effect on this reflex arc.

Persistent behavioral and autonomic supersensitivity to stress following prenatal stress exposure in rats

Prenatal restraint stress (PS) has been suggested as an attractive chronic model of anxiety. Here, we characterized the behavioral and autonomic responsivity to acute stress exposure in adult PS subjects. In Wistar rats, locomotor activity, as well as spontaneous behavior in an established animal model of anxiety, the elevated plus-maze, was unaffected by PS. However, the anxiogenic-like response normally seen on the plus-maze following a restraint stress was markedly potentiated in adult PS subjects, despite indistinguishable corticosterone responses. In addition, we assessed the tail skin temperature response to a mild social stressor, transient social mixing. The diazepam-sensitive, late phase of the temperature response was markedly potentiated in adult PS subjects. In summary, PS induces a persistent phenotype of increased behavioral and autonomic sensitivity to stress. This paradigm might serve as an attractive screening model for anti-anxiety compounds.

Olfactory cues from an oxytocin-injected male rat can induce anti-nociception in its cagemates.

WE recently demonstrated an olfactorily induced tail skin temperature drop in saline-injected rats exposed to an oxytocin-injected cagemate, an effect abolished by olfactory impairment. Treatment with oxytocin may induce both nociceptive and anti-nociceptive effects. The contrasting effects likely depend on the model and dosage used. Here we report an increased hindpaw withdrawal latency in response to nociceptive heat following the subcutaneous administration of oxytocin (1 mg/kg). An increased withdrawal response latency was also found in the untreated cagemates of an oxytocin-treated rat. The anti-nociceptive effect was abolished in oxytocin-antagonist-injected cagemates. Our results suggests that an olfactorily induced oxytocinergic mechanism is activated in the cagemates of an oxytocin-injected rat promoting anti-nociception.

Cardiac hypertrophy in deceased users of anabolic androgenic steroids: an investigation of autopsy findings

BACKGROUND The use of anabolic androgenic steroids (AASs) has been associated with hypertrophy of the left cardiac ventricle (LVH) as diagnosed by echocardiography. Case reports suggest that AAS-related LVH may lead to sudden death. We performed an investigation of the gross cardiac pathological findings in deceased male AAS users in order to further elucidate the proposed role of AAS in cardiac hypertrophy. METHODS Eighty-seven deceased males who tested positive for AAS at autopsy and 173 age-adjusted control deceased males without suspected AAS use were studied for cardiac hypertrophy. The AAS-positive subjects had been examined at any of the six departments of forensic medicine in Sweden during the period from 1989 to 2009. Data were assessed employing multivariate analyses controlling for body weight, height, age, bleeding after trauma, and the impact of weight training. RESULTS The analysis of the logarithm of heart mass by multivariate statistics implied that strong correlations existed between body mass and heart mass (P<.00001), height and heart mass (P<.02), age and heart mass (P<.00001), and trauma (bleeding) and heart mass (P=.00001). After controlling for these factors, a significantly higher heart mass (P=.0001) was found among the AAS-positive males. CONCLUSION Our findings suggest that use of AAS may lead to cardiac hypertrophy with a direct cardiotropic effect.

Behavioural Anxiolytic Effects of Low-Dose Anabolic Androgenic Steroid Treatment in Rats

The use of anabolic androgenic steroids (AAS) in supratherapeutic doses has been associated with aggressive behaviour as well as with severe affective and psychotic symptoms. These symptoms usually follow a chronic exposure for several months. However, AAS also may have milder effects with hypomania-like features such as an increase in confidence, energy and self-esteem. We have studied the short-term effects on male rat behaviour in a modified open-field test of the AAS Metenolon administered three times at a low dose (0.01 mg/kg/week x 3). The control rats showed indications of increased timidity and aversive learning following retesting, a reaction that was absent in the AAS-treated rats. The AAS-treated rats showed less fear or anticipatory anxiety compared to control animals. Furthermore, the suppressed marking behaviour and altered morphological allometric relationships were compatible with a modified social and sexual competence in the AAS treated rats.

Olfactory cues from an oxytocin-injected male rat can reduce energy loss in its cagemates.

RATS can recognize the odor of a stressed conspecific and react with stress themselves. Stress mobilizes energy, causing increased core temperatures and energy loss by radiation from the naked tail. Oxytocin administered in high doses (1 mg/kg, s.c.) reduces a rats tail skin temperature and thereby the radiated energy loss. While administration of this high dose of oxytocin induces sedation low doses induce anxiolysis. This study demonstrates that the cagemates of an oxytocin-treated (1 mg/kg s.c.) rat, which themselves have not received any oxytocin-treatment, show energy conservation, apparent as reduced tail skin temperature. This effect was blocked by olfactory impairment. The temperature reduction in the cagemates probably reflects an oxytocin-mediated olfactorily activated stress inhibitory mechanism.