Neuronal correlates of behavior in freely moving rats.

Firing patterns of single neurons in the hypothalamus, preoptic area, midbrain reticular system, and hippocampus of awake, freely moving female rats were temporally correlated with exploratory sniffing and vibrissa twitching, feeding, lordosis, locomotion, and (or) arousal. These relationships were remarkably stable during continuous observations lasting many hours. During extended periods when certain of these movements were not performed, the correlated neurons showed no action potentials for minutes at a time. Electrical stimulation at certain recording sites elicited behavior patterns whose spontaneous occurrence was accompanied by neuronal activation. Self-stimulation was elicited from sites spontaneously activated during exploratory behavior.

Genital sensory field: enlargement by estrogen treatment in female rats.

Recordings of neuronal activity in the pudendal, genitofemoral, and pelvic nerves indicate that the sensory fields of these three nerves are the perineum, the caudal abdomen, and the vagino-cervical area and rectum, respectively. The sensory field of the pudendal nerve was significantly larger in estrogen-treated ovariectomized female rats than in uninjected controls. This effect of estrogen was not mediated by pudendal efferents.

Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia.

The endogenous neuropeptide cholecystokinin, when administered systemically or perispinally, potently antagonizes opiate analgesia produced by foot shock and morphine. Nonopiate foot-shock analgesia is not reduced by this neuropeptide. The spinal cord appears to be a critical site of cholecystokinin action. These experiments suggest a physiological role for cholecystokinin as a specific opiate antagonist in analgesia-mediating systems. A similar mode of action may explain other behavioral effects of cholecystokinin, such as suppression of food intake.

Morphine analgesia potentiated but tolerance not affected by active immunization against cholecystokinin.

Administration of cholecystokinin was recently found to attenuate opiate analgesia. In the present study, the role of endogenous cholecystokinin in opiate analgesia was examined. Endogenously released cholecystokinin was sequestered by antibodies to cholecystokinin developed in response to an active immunization procedure. Morphine analgesia was potentiated and prolonged in rats immunized against cholecystokinin. The rate of development of morphine tolerance, however, was not affected by the antibodies. Endogenous cholecystokinin appears to function as a short-term modulator of opiate action.

Antagonism of morphine analgesia by nonopioid cold-water swim analgesia: direct evidence for collateral inhibition.

The demonstrated existence of opioid and nonopioid forms of pain control has raised questions as to how they interact. Previous indirect evidence suggests that activation of one system inhibited the activation of the other. The present study assessed this directly using morphine as an opiate form of analgesia and continuous cold-water swims (CCWS, 4 degrees C, 2 min) as the nonopioid form. A significant reduction in morphine (8 mg/kg, SC) analgesia on the tail-flick test was observed if rats were acutely exposed to CCWS immediately prior to morphine administration. The inability of naloxone (10 mg/kg, SC) to reduce CCWS analgesia verified its nonopioid nature. The antagonism of morphine (3 mg/kg, SC) analgesia was greater following preexposure to 2 min of CCWS than 1 min of CCWS. CCWS was also more effective in antagonizing analgesia induced by the 3 mg/kg than the 8 mg/kg dose of morphine. The antagonism of morphine analgesia by CCWS was dependent upon the temporal patterning of stimulus presentation: exposure to CCWS 20 or 60 min prior to morphine failed to alter subsequent morphine analgesia. A significant reduction in analgesia induced by intraperitoneal administration of morphine (10 mg/kg) was also observed when CCWS was presented immediately prior to injection, suggesting that pharmacokinetic factors such as altered drug absorbance by CCWS-induced vasoconstriction do not appear to explain these effects. These data provide direct support for the existence of collateral inhibitory mechanisms activated by CCWS and morphine, and suggests that these opioid and nonopioid forms of analgesia do not function synergistically, but instead involve some form of hierarchical order.

'Complete' spinal cord injury does not block perceptual responses to genital self-stimulation in women.

BACKGROUND: A priori hypothesis: vaginal and/or cervical self-stimulation will not produce perceptual responses in women with "complete" spinal cord injury (SCI) at or above the highest level of entry of the hypogastric nerves (T10-12) but will produce perceptual responses if SCI is below T-10. DESIGN: Women with complete SCI were assigned to a group with "upper" (T-10 and/or above) (n = 6) or "lower" (below T-10) (n = 10) SCI; uninjured women (n = 5) constituted a control group. Perceptual response to vaginal and/or cervical self-stimulation was quantified as magnitude of analgesia to calibrated finger compressive force. SETTING: Rutgers, The State University of New Jersey, Human Physiology Laboratory, College of Nursing, Newark. PARTICIPANTS: Consecutive samples of first 16 of 34 women with SCI who responded to nationwide advertisements, met inclusion criteria, and volunteered; control group was the first 5 respondents. INTERVENTION: Vaginal or cervical (cervix uteri) self-stimulation applied for 12 minutes, interspersed with non-stimulation periods, while measuring analgesia. MAIN OUTCOME MEASURE: Quantify analgesia magnitude to vaginal or cervical self-stimulation. RESULTS: Significant analgesia was produced in the uninjured group and the group with lower SCI, supporting the hypothesis. Unexpectedly, significant analgesia was also produced in the group with upper SCI. Women in the group with upper SCI also experienced menstrual discomfort, awareness of vaginal and/or cervical stimulation per se, and orgasms. CONCLUSIONS: (1) Genitospinal visceral afferent pathways function in the women in the group with upper SCI, although unrecognized by the American Spinal Injury Association criteria, and/or (2) there exists a functional genital afferent pathway that bypasses the spinal cord and projects directly to the brain, which we propose to be via the vagus nerves.

Neural substrates of two different rhythmical vibrissal movements in the rat.

Normal rats show two types of rhythmical vibrissal movement, one synchronized precisely with alpha waves (about 9 Hz) of the thalamocortical system, and the other often synchronized with theta waves (about 7 Hz) of the septohippocampal system. The alpha-synchronized vibrissal movements appear while the rat stands still with a slow respiratory pattern, and are of small amplitude (a fine tremor). The theta-synchronized vibrissal movements appear during exploratory sniffing behavior, and are of large amplitude. Thus, a group of facial motoneurons which constitute the final common pathway for vibrissal movement apparently receive input convergently from these two neural systems. In the present study, we observed the following: (1) the two types of movement rarely, if ever, appeared simultaneously and the same was true of the two brain wave patterns. Topographically, the predominant appearance of the alpha waves was in the frontal (sensorimotor) cortex, whereas that of the theta waves was in the occipital cortex and hippocampus. (2) Bilateral ablation of either the entire neocortex or just its anterior (but not posterior) half eliminated the vibrissal alpha-tremor movement while leaving vibrissal theta-sniffing movement normal. In anterior decorticate rats, the tremor movements started to recover by 1-4 months, and were abolished again by the removal of the remaining posterior cortex. (3) Lesions of the medial septum or the fornix eliminated hippocampal theta waves, but had no effect on vibrissal sniffing movement or alpha wave-vibrissal tremor. (4) Cerebellectomy and, to a lesser extent, pharmacological lesions of the inferior olive slowed, but did not block, alpha waves. In addition, vibrissal tremor movement became intermittent and less vigorous. The same manipulations, however, did not affect theta wave-vibrissal sniffing movement. (5) Harmaline (30 mg/kg, i.p.) did not induce alpha-tremor, which, in combination with the results with cerebellectomy and inferior olive lesions, indicates that alpha-tremor is generated by a neural mechanism that is different from that for harmaline-induced generalized tremor of 10 Hz. These findings confirmed that there exist two patterns of synchrony between vibrissal movement and rhythmical brain activity in the rat, i.e. alpha wave-vibrissal tremor movement and theta wave-vibrissal sniffing movement, and suggest that the two patterns reflect a rhythmical mode of functioning of two different neural systems, probably the thalamocortical and the septohippocampal system, respectively.

Love as sensory stimulation: physiological consequences of its deprivation and expression.

For the present purpose, love is defined as one's having stimulation that one desires. The nature of the stimulation can range on a continuum from the most abstract cognitive, to the most direct sensory, forms. Thus, this definition of love encompasses having an emotional bond with a person for whom one yearns, as well as having sensory stimulation that one desires. We address some of the physiological and perceptual consequences both of having, and of not having, love. We propose a neural mechanism by which deprivation of love may generate endogenous, compensatory sensory stimulation that manifests itself as psychosomatic illness. In addition, we propose a neuroendocrine mechanism underlying sexual response and orgasm. The latter includes vaginocervical sensory pathways to the brain that can produce analgesia, release oxytocin, and/or bypass the spinal cord via the vagus nerve. We present evidence of the existence of non-genital orgasms, which suggests that genital orgasm is a special case of a more pervasive orgasmic process. Through recent studies, the mechanisms and manifestations of love and its deprivation are becoming better understood. The better is our understanding of love, the greater is our respect for the significance and potency of its role in mental and physical health.

Analgesia induced by vaginal stimulation in rats is apparently independent of a morphine-sensitive process.

Previous studies have suggested that in rats probing against the vaginal cervix with a glass of is analgesic, for this stimulus elevates the threshold for eliciting vocalization in response to tail shock. In the present studies pretreatment with naloxone HCl (1 or 10 mg/kg), a potent narcotic antagonist did not antagonize this vaginal stimulation-induced analgesia. Furthermore, vaginal stimulation was found to exert its analgesic effect even in rats made tolerant to, and dependent upon, morphine sulfate. These results suggest that the analgesic effect of vaginal stimulation is not necessarily mediated by an opiate-sensitive neural system. However, we hypothesize that even though vaginal stimulation and other analgesic manipulations may act via different neural substrates, they may nevertheless converge onto a final common mechanism for pain suppression.

Antinociceptive effects of vaginal stimulation in rats: neurophysiological and behavioral studies.

The present studies extend previous findings that probing the vaginal cervix of rats blocks withdrawal reflexes and induces immobilization44. In the present studies, we report that this effect is apparently not due to an action on the final motor pathway, for limb or facial movement induced by electrical stimulation of the pyramidal tract was not suppressed by the probing. In contrast, the sensory response of neurons in the ventrobasal complex of the thalamus to noxious pinch stimulation was markedly attenuated by probing the vaginal cervix. However, the response of these neurons to gentle tactile stimulation was not attenuated, indicating a selective antinociceptive effect of the probing. The antinociceptive effect was not necessarily related to changes in arousal. These findings were supported by behavioral studies in which probing the vaginal cervix blocked vocalization in response to tail shock, and elevated the current threshold for eliciting vocalization in response to tail shock. Furthermore, during the probing, the rats were found to be capable of vocalizing in response to presumably non-noxious (lifting) stimulation, even though their vocalization response to noxious tail shock was suppresed. These studies suggest that probing the vaginal cervix rats exerts an analgesic action.

Analgesia is produced by uterocervical mechanostimulation in rats: roles of afferent nerves and implications for analgesia of pregnancy and parturition.

Afferent activity from the reproductive tract activates intrinsic pain attenuating processes. For example, analgesia results from vaginocervical mechano-stimulation in nonpregnant rats and occurs during pregnancy and parturition. In the present study, the effect of uterocervical mechanostimulation on pain thresholds was investigated in order to determine whether direct stimulation of the uterine cervix could play a role in the analgesia of pregnancy. Uterocervical mechanostimulation was applied to nonpregnant rats via a silastic disc implanted in the uterus. The disc abutted against the cervix and was attached to a thread externalized through the vaginal orifice. Application of a force of 150 g, but not 100 g, produced a significant increase in tail flick latency (110.4 +/- 40.6%, P less than 0.03). This effect was abolished by pelvic neurectomy, but was not altered by hypogastric neurectomy. Stimulation of the uterine cervix in combined pelvic and hypogastric neurectomy rats produced a decrease in tail flick latency. These results indicate that the analgesia that occurs during pregnancy and/or parturition may result, at least in part, from the uterocervical mechanostimulation that occurs during this condition.

Evidence that oxytocin is an endogenous stimulator of autonomic sympathetic preganglionics: the pupillary dilatation response to vaginocervical stimulation in the rat.

Vaginocervical mechanostimulation (VS) was shown previously to release oxytocin within the spinal cord and to induce pupillary dilatation. In the present study, (a) injection of oxytocin directly to the spinal cord (10 or 25 microg intrathecally [i.t.] in 5 microl saline) induced pupillary dilatation when observed 1 min after the end of the injection and (b) injection of an oxytocin receptor antagonist ([d(CH2)5-Tyr (Me)2-Orn8]-Vasotocin [OTA]; 25 microg i.t. in 5 microl saline) significantly attenuated the pupillary dilatation response to VS, when VS was applied 3 min after the end of the injection. Since activation of autonomic sympathetic preganglionic neurons in the thoracic spinal cord produces pupillary dilatation, we propose that oxytocin is a central nervous system neurotransmitter that stimulates these neurons directly, or perhaps indirectly, and thus is a mediator of VS-produced pupillary dilatation.

Synchrony among rhythmical facial tremor, neocortical 'alpha' waves, and thalamic non-sensory neuronal bursts in intact awake rats.

A fine (approx. 9 c/sec) tremor of the jaw and/or vibrissae was observed in normal rats while they were standing still and not showing gross bodily movement. The tremor was distinctly different in frequency, intensity, and behavioral context, from movements involved in gnawing, tooth chattering, or exploratory sniffing. Individual tremor movements (recorded as EMG) occurred in synchrony with individual bursts of multiunit activity (MUA) recorded in the ventrobasal complex of the thalamus and with individual 'spikes' in the cortical (frontal-occipital) EEG. Single trains of this rhythmical activity often lasted more than a minute. The phase relationships between EMG and MUA differed among individuals, but tended to remain consistent within each individual. Movement artifacts were ruled out since (1) the moments of occurrence of individual tremor movements and MUA bursts were interdigitated rather than simultaneous, and (2) during high amplitude EMG bursts accompanying sni ffing (associated with EEG theta rhythm), tooth chattering, eating or licking, no corresponding activity in the MUA was observed. We also ruled out the possibility that the neural activity was generated by reafference, for (1) during vigorous non-tremor sniffing movements of the vibrissae, or chattering or chewing movements of the jaws, the rhythmical MUA was absent (although the units did discharge if the vibrissae contacted an obstacle or were brushed by the experimenter), (2) rhythmical MUA often continued both during brief pauses in the motor tremor, and in its absence, and (3) injection of Xylocaine s.c. into the face abolished sensory responses of the thalamic units, but the rhythmical MUA persisted. We discuss evidence which suggests that (1) the rhythmical cortical EEG waves are the equivalent in the rat of the alpha (mu) rhythm, and (2) the existence of parallels between alpha-tremor and Parkinsonian tremor in terms of their mechanisms and functions.

Sensory innervation of the external and internal genitalia of the female rat.

Using a whole-nerve recording method, the genitalia of the female rat were found to receive afferent innervation as follows. Pelvic nerve: vagina, cervix, and perineal skin; hypogastric nerve: cervix and proximal three fifths of the uterus; pudendal nerve: skin of perineum, inner thigh, and clitoral sheath. It is probable that the pudendal and pelvic nerves are activated during copulation, and that all 3 nerves are activated during parturition.

Release of amino acids into regional superfusates of the spinal cord by mechano-stimulation of the reproductive tract.

Based on pharmacological evidence that inhibitory amino acids mediate vaginocervical mechano-stimulation produced analgesia (VSPA), we hypothesized that inhibitory amino acids would be released endogenously in the spinal cord in response to vaginocervical mechano-stimulation (VS). This hypothesis was tested by HPLC analysis of the amino acid content of 5-min superfusates of the spinal cord before, during and after VS (400 g force applied against the cervix) in urethane-anesthetized rats. Utilizing an in vivo push-pull superfusion method, artificial cerebrospinal fluid was continuously superfused over the spinal cord through the intrathecal space surrounding the sacral-lower thoracic region. In addition, concentrations of amino acids in the superfusate were measured in response to KCl stimulation (increasing the superfusion medium from 3.4 to 40.0 mM KCl to produce non-specific depolarization), and noxious hind paw mechano-stimulation (pinching the hind paw to produce a sustained flexor response in ipsilateral hind leg). There was a significant increase in the concentration of Gly, Tau, Asp, Glu and Lys in the superfusate in response to VS (n = 8) and to KCl (n = 8), but not to hind paw stimulation (n = 5). Also, GABA concentrations increased in response to KCl, and the concentration of Ala, Ser, Gln, Thr, Arg and Phe increased in response to VS, however, GABA levels were sometimes below the limits of detection. In contrast, there was no significant change in any amino acid concentration in response to hind paw pinch stimulation, and VS did not significantly affect the concentrations of Tyr, His, Ile, Leu, Met, Trp or Val. The present findings support our hypothesis that VS releases inhibitory amino acids in the spinal cord. Moreover, other amino acids, including 'excitatory' amino acids, are released into the superfusate. The profile of amino acid release in response to VS differs from that in response to paw pinch or KCl administration.

Momentary analgesia produced by copulation in female rats.

To assess possible changes in nociception during copulation in estrous rats, electric shocks that were 20% suprathreshold for eliciting vocalization in response to tail shock (STS), were applied to the tail before the initiation of copulation and, thereafter, coincident with the onset of mounting bouts by the male (Experiment 1). Females vocalized significantly less during non-intromittive mounts (M; P < 0.001), intromissions (I; P < 0.001), and ejaculation (E; P < 0.01) than before the initiation of copulation. In order to assess the importance of vaginal stimulation (VS) by penile insertion during mating, in Experiment 2 30% STS were applied 300-400 ms after the initiation of mounting to ensure that the stimuli fell within the period of penile insertion occurring during I and E. M failed to significantly inhibit vocalizations to 30% STS. By contrast, both I and E markedly inhibited vocalizations in response to STS. This effect was transitory since subjects (Ss) vocalized to nearly all 30% STS when delivered 15 s after I or E. Copulatory analgesia (CA) was abolished by the bilateral transection of the pelvic and hypogastric nerves but not by the transection of the pudendal nerve (Experiment 3). The magnitude of CA was calibrated by determining the doses of morphine sulfate (MS) required to produce similar decrements in vocalization to STS. The analgesic effects of I and E were equivalent to more than 10 mg/kg and 15 mg/kg, respectively, of MS (Experiment 4). Pelvic-hypogastric neurectomy, but not pudendal neurectomy, also significantly reduced the effect of VS on facilitating lordosis, inducing immobilization and hind leg extension, and blocking the withdrawal reflex to foot pinch (Experiment 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Vaginocervical stimulation attenuates hindpaw shock-induced substance P release into spinal cord superfusates in rats.

The present study was designed to elucidate the mechanism in the spinal cord by which vaginocervical stimulation (VS) attenuates responses to noxious stimulation. This was accomplished by testing the hypothesis that VS reduces noxious stimulation-induced release of substance P at the level of the spinal cord. Noxious foot shock significantly increased the release of substance P (measured using radioimmunoassay) into superfusates of the lumbosacral spinal cord region in urethane-anesthetized rats. VS applied concurrently with foot shock significantly attenuated the release of substance P compared to the foot shock-only condition. In addition, substance P levels were significantly lower after the VS-only condition than after the no stimulation or foot shock-only conditions. These findings indicate that VS may produce analgesia, at least in part, by suppressing the release of substance P within the spinal cord.

Attenuation of pregnancy-induced analgesia by hypogastric neurectomy in rats.

This study confirms previous observations of an increase in pain threshold prepartum followed by a decrease postpartum. Moreover hypogastric nerve transection significantly attenuated the analgesia of pregnancy by a factor of 5 but did not abolish it. Thus, the hypogastric nerve plays a major, but not exclusive, role in the analgesia of pregnancy.

Dibutyryl cAMP stimulates analgesia in rats bearing a ventricular adrenal medulla transplant.

In the present study, a significant increase in pain threshold (current to elicit vocalization to tail shock) was found 15 and 60 min after injection of dibutyryl cyclic AMP (db cAMP) (30 micrograms) into the lateral ventricle in rats bearing a transplant of fetal adrenal medulla (AM). By contrast, no effect on pain threshold was observed in rats bearing an AM transplant but receiving no db cAMP, or in rats receiving db cAMP but not bearing an AM transplant. In primary cultures of rat fetal chromaffin cells, db cAMP increased the number of neuron-like cells that showed both vasoactive intestinal polypeptide (VIP)- and tyrosine hydroxylase (TH)-like immunoreactivity. These findings indicate that db cAMP exerts a pharmacological modulation of the functional activity (i.e. elevation in pain thresholds) of fetal adrenal AM transplants, and induces phenotypic changes in cultured chromaffin cells with expression of a peptide that elevates pain threshold.

Dorsolateral funiculus and intraspinal pathways mediate vaginal stimulation-induced suppression of nociceptive responding in rats.

In rats, stimulation of the vaginal cervix with a glass rod reliably produces analgesia, as measured by the tail-flick test. The present studies sought to identify the neural substrates underlying this potent pain inhibition by examining the effects of decerebration, spinalization and bilateral dorsolateral funiculus (DLF) lesions on vaginal stimulation-produced analgesia (VSPA). These studies indicate that the neural circuitry mediating VSPA is contained within the caudal brainstem and spinal cord, since decerebration did not reduce VSPA when compared with sham-operated controls. A significant though markedly reduced level of analgesia was induced in spinalized rats, indicating that VSPA involves both intraspinal and descending pathways. This descending pathway, originating within supraspinal nuclei of the caudal brainstem, projects to the spinal cord via the DLF, since DLF lesions and spinalization produced equivalent reductions in VSPA compared to sham-operated controls. These results, considered in the light of previous electrophysiological and anatomical findings, indicate that the ventral medullary region may be the source of the descending DLF projection mediating VSPA.