[Immunomodulation of pain]. / Immunomodulacja bólu.

Review of the interacting elements of nociceptive, neuroimmune and neuroendocrine systems with a stress on sympathetic innervation of the lymphoid organs. Special attention is given to dysfunctions within the nociceptive, neuroendocrine and immune systems due to: damage to the: 1) afferent fibers; 2) sympatho-adrenal system; 3) structure of the hypothalamo-pituitary-adrenal axis. The role of peripheral immunocytes in the generation of pain, including local cytokines, opioids and CRF is also discussed.

Recent advances in neonatal pain research.

Pain accompanies most of illnesses. Pain results in from activation of a specific sensory system and is not direct result of an illness. Pain system may be activated early in the fetal development before its projections will penetrate the frontal cortex. Therefore, painful experience may induce some physiological consequences even it has been not perceived as pain and may lead to the long-lasting and profound consequences. Noxious stimuli applied in the developmental period may exert dramatical effects upon growing children. Human infants and neonatal rats demonstrate hyperresponsivity to nociceptive input that may result in hyperalgesia. After birth, peripheral cutaneous innervation, neuroendocrine functions and mechanisms of inflammation still undergo developmental changes. The neurotransmitters of the inhibitory descending system (5HT, NE, DA) develop late or postnatally. Progress in research on the developmental aspects of nociceptive transmission is necessary basis for advances in pharmacology of pain and analgesia for fetuses in the last trimester, preterm and term neonates.

A method for improving the accuracy of stereotaxic procedures in monkeys using implanted fiducial markers in CT scans that also serve as anchor points in a stereotaxic frame.

We developed a relatively inexpensive method for stereotaxic placement of electrodes or needles in the brains of monkeys. Steel balls were affixed to the skulls of monkeys. These balls served as fiducial markers and were also used as points at which the monkey's skull was held in a modified stereotaxic apparatus. Computed tomography (CT) was used to establish the location of an injection target with respect to the fiducial markers. A computer program related the CT coordinates to stereotaxic coordinates. These were used to direct an electrode marker toward a target in the hypothalamus. With the marker left in place, the monkey was removed from the stereotaxic frame and a second CT scan was performed. Corrections for errors in marker placement were made and retrograde tracers were injected. This procedure was found to be more accurate and reliable than conventional stereotaxic procedures. The accuracy and repeatability of the technique were also established using a phantom model of a monkey's skull. Two important advantages of this method are that animals can be repeatedly placed into the stereotaxic frame in precisely the same position and that there are many opportunities during the procedure to check for and correct errors.

Spinohypothalamic tract neurons in the cervical enlargement of rats: locations of antidromically identified ascending axons and their collateral branches in the contralateral brain.

Antidromic activation was used to determine the locations of ascending spinohypothalamic tract (SHT) axons and their collateral projections within C1, medulla, pons, midbrain, and caudal thalamus. Sixty-four neurons in the cervical enlargement were antidromically activated initially by stimulation within the contralateral hypothalamus. All but one of the examined SHT neurons responded either preferentially or specifically to noxious mechanical stimuli. A total of 239 low-threshold points was classified as originating from 64 ascending (or parent) SHT axons. Within C1, 38 ascending SHT axons were antidromically activated. These were located primarily in the dorsal half of the lateral funiculus. Within the medulla, the 29 examined ascending SHT axons were located ventrolaterally, within or adjacent to the lateral reticular nucleus or nucleus ambiguus. Within the pons, the 25 examined ascending SHT axons were located primarily surrounding the facial nucleus and the superior olivary complex. Within the caudal midbrain, the 23 examined SHT ascending axons coursed dorsally in a position adjacent to the lateral lemniscus. Within the anterior midbrain, SHT axons traveled rostrally near the brachium of the inferior colliculus. Within the posterior thalamus, all 17 examined SHT axons coursed rostrally through the posterior nucleus of thalamus. A total of 114 low-threshold points was classified as collateral branch points. Sixteen collateral branches were seen in C1; these were located primarily int he deep dorsal horn. Forty-five collateral branches were located in the medulla. These were primarily in or near the medullary reticular nucleus, nucleus ambiguus, lateral reticular nucleus, parvocellular reticular nucleus, gigantocellular reticular nucleus, cuneate nucleus, and the nucleus of the solitary tract. Twentysix collateral branches from SHT axons were located in the pons. These were in the pontine reticular nucleus caudalis, gigantocellular reticular nucleus, parvocellular reticular nucleus, and superior olivary complex. Twenty-three collateral branches were located in the midbrain. These were in or near the mesencephalic reticular nucleus, brachium of the inferior colliculus, cuneiform nucleus, superior colliculus, central gray, and substantia nigra. Int he caudal thalamus, two branches were in the posterior thalamic nucleus and two were in the medial geniculate. These results indicate that SHT axons ascend toward the hypothalamus in a clearly circumscribed projection in the lateral brain stem and posterior thalamus. In addition, large numbers of collaterals from SHT axons appears to project to a variety of targets in C1, the medulla, pons, midbrain, and caudal thalamus. Through its widespread collateral projections, the SHT appears to be capable of providing nociceptive input to many areas that are involved in the production of multifaceted responses to noxious stimuli.

Spinothalamic and spinohypothalamic tract neurons in the sacral spinal cord of rats. I. Locations of antidromically identified axons in the cervical cord and diencephalon.

1. A goal of this study was to determine the sites in the diencephalon to which neurons in sacral spinal segments of rats project. Therefore, 95 neurons were recorded extracellularly in spinal segments L6-S2 of rats that were anesthetized with urethan. These neurons were activated initially antidromically with currents < or = 30 microA from a monopolar stimulating electrode placed into the contralateral posterior diencephalon. The mean +/- SE current for antidromic activation from these sites was 16 +/- 0.8 microA. These neurons were recorded in the superficial dorsal horn (4%), deep dorsal horn (89%), and intermediate zone and ventral horn (4%). 2. Systematic antidromic mapping techniques were used to map the axonal projections of 41 of these neurons within the diencephalon. Thirty-three neurons (80%) could be activated antidromically with currents < or = 30 microA only from points in the contralateral thalamus and are referred to as spinothalamic tract (STT) neurons. Eight neurons (20%) were activated antidromically with low currents from points in both the contralateral thalamus and hypothalamus, and these neurons are referred to as spinothalamic tract/ spinohypothalamic tract (STT/SHT) neurons. Three additional neurons were activated antidromically with currents < or = 30 microA only from points within the contralateral hypothalamus and are referred to as spinohypothalamic tract (SHT) neurons. The diencephalic projections of another 51 neurons were mapped incompletely. These neurons are referred to as spinothalamic/unknown (STT/ U) neurons to indicate that it was not known whether their axons ascended beyond the site in the thalamus from which they initially were activated antidromically. 3. For 31 STT neurons, the most anterior point at which antidromic activation was achieved with currents < or = 30 microA was determined. Fourteen (45%) were activated antidromically only from sites posterior to the ventrobasal complex (VbC) of the thalamus. Sixteen STT neurons (52%) were activated antidromically with low currents from sites at the level of the VbC, but not from more anterior levels. One STT neuron (3%) was activated antidromically from the anteroventral nucleus of the thalamus. 4. STT/SHT neurons were antidromically activated with currents < or = 30 microA from the medial lemniscus (ML), anterior pretectal nucleus (APt), posterior nuclear group and medial geniculate nucleus (Po/MG), and zona incerta in the thalamus and from the optic tract (OT), supraoptic decussation, or lateral area of the hypothalamus. No differences in the sites in the thalamus from which STT and STT/SHT neurons were activated antidromically were apparent. Five STT/SHT neurons (62%) were activated antidromically from points in the thalamus in the posterior diencephalon and from points in the hypothalamus at more anterior levels. Three STT/SHT neurons (38%) were activated antidromically with currents < or = 30 microA from sites in both the thalamus and hypothalamus at the same anterior-posterior level of the diencephalon. All three of these STT/SHT neurons projected to the intralaminar nuclei (parafascicular or central lateral nuclei) of the thalamus. 5. Seven STT/SHT neurons were tested for additional projections to the ipsilateral brain. Two (29%) were activated antidromically with currents < or = 30 microA and at longer latencies from sites in the ipsilateral diencephalon. One could only be activated antidromically from the hypothalamus ipsilaterally. The other was activated antidromically at progressively increasing latencies from points in the ipsilateral brain that extended as far posteriorly as the posterior pole of the MG. 6. Fifty-eight STT, STT/SHT, and STT/U neurons were classified as low-threshold (LT), wide dynamic range (WDR), or highthreshold (HT) neurons based on their responsiveness to innocuous and noxious mechanical stimuli applied to their cutaneous receptive fields.(ABSTRACT TRUNCATED)

Spinothalamic and spinohypothalamic tract neurons in the sacral spinal cord of rats. II. Responses to cutaneous and visceral stimuli.

1. A goal of this study was to determine whether neurons in the sacral spinal cord that project to the diencephalon are involved in the processing and transmission of sensory information that arises in the perineum and pelvis. Therefore, 58 neurons in segments L6-S2 were activated antidromically with currents < or = 30 microA from points in the contralateral diencephalon in rats that were anesthetized with urethan. 2. Responses to mechanical stimuli applied to the cutaneous receptive fields of these neurons were used to classify them as low-threshold (LT), wide dynamic range (WDR) or high-threshold (HT) neurons. Twenty-two neurons (38%) responded preferentially to brushing (LT neurons). Eighteen neurons (31%) responded to brushing but responded with higher firing frequencies to noxious mechanical stimuli (WDR neurons). Eighteen neurons (31%) responded only to noxious intensities of mechanical stimulation (HT neurons). LT neurons were recorded predominantly in nucleus proprius of the dorsal horn. Nociceptive neurons (WDR and HT) were recorded throughout the dorsal horn. 3. Cutaneous receptive fields were mapped for 56 neurons. Forty-five (80%) had receptive fields that included at least two of the following regions ipsilaterally: the rump, perineum, or tail. Eleven neurons (20%) had receptive fields that were restricted to one of these areas or to the ipsilateral hind limb. Thirty-eight neurons (68%) had cutaneous receptive fields that also included regions of the contralateral tail or perineum. On the perineum, receptive fields usually encompassed perianal and perivaginal areas including the clitoral sheath. There were no statistically significant differences in the locations or sizes of receptive fields for LT neurons compared with nociceptive (WDR and HT) neurons. 4. Thirty-seven LT, WDR, and HT neurons were tested for their responsiveness to heat stimuli. Five (14%) responded to increasing intensities of heat with graded increases in their firing frequencies. Thirty-two LT, WDR, and HT neurons also were tested with cold stimuli. None responded with graded increases in their firing frequencies to increasingly colder stimuli. There were no statistically significant differences among the responses of LT, WDR, and HT neurons to either heat or cold stimuli. 5. Forty LT, WDR, and HT neurons were tested for their responsiveness to visceral stimuli by distending a balloon placed into the rectum and colon with a series of increasing pressures. Seventeen (43%) exhibited graded increases in their firing frequencies in response to increasing pressures of colorectal distention (CrD). None of the responsive neurons responded reproducibly to CrD at an intensity of 20 mmHg, and all responded at intensities of > or = 80 mmHg. More than 90% responded abruptly at stimulus onset, responded continuously throughout the stimulus period, and stopped responding immediately after termination of the stimulus. 6. Thirty-one neurons were tested for their responsiveness to distention of a balloon placed inside the vagina. Eleven (35%) exhibited graded increases in their firing frequencies in response to increasing pressures of vaginal distention (VaD). The thresholds and temporal profiles of the responses to VaD were similar to those for CrD. Twenty-nine neurons were tested with both CrD and VaD. Thirteen (45%) were excited by both stimuli, four (14%) responded to CrD but not VaD, and one (3%) was excited by VaD but not CrD. Neurons excited by CrD, VaD, or both were recorded throughout the dorsal horn. 7. As a population, WDR neurons, but not LT or HT neurons, encoded increasing pressures of CrD and VaD with graded increases in their firing frequencies. The responses of WDR neurons to CrD differed significantly from those of either LT or HT neurons. Regression analyses of the stimulus-response functions of responsive WDR neurons to CrD and VaD were described by power functions with exponents of 1.6 and 2.4, respectively.(ABSTRACT TRUNCATED)

Spinohypothalamic tract neurons in the cervical enlargement of rats: descending axons in the ipsilateral brain.

Spinohypothalamic tract (SHT) cells are spinal cord neurons with axons that project directly to or through the contralateral hypothalamus. Frequently, SHT axons decussate in the posterior optic chiasm, turn posteriorly and descend to unknown locations in the ipsilateral brain. We attempted to determine the course and the termination of these descending axons. Sixty neurons in the cervical enlargement of rats were antidromically activated initially from the contralateral hypothalamus and then from multiple anterior-posterior levels in the ipsilateral brain. Fifty-three (88%) were backfired with low currents at increased latencies from the ipsilateral brain. The axons of 35 neurons were surrounded with electrode penetrations from which high currents could not activate the neuron antidromically, suggesting the examined axons terminated in the surrounded areas. Seven SHT axons that were surrounded (20%) appeared to terminate in the contralateral hypothalamus, 5 (14%) in the ipsilateral hypothalamus, and 9 (26%) in the ipsilateral thalamus. Fourteen SHT axons (40%) ended in the ipsilateral midbrain mainly in the superior colliculus, cuneiform nucleus or nucleus brachium inferior colliculus. An additional 11 axons were followed even further posteriorly into the ventral pons or rostral medulla. Each of the 26 neurons that could be physiologically classified responded either preferentially or specifically to noxious mechanical stimuli. These results indicate that SHT axons course through a surprisingly long and complex path. After decussating in the hypothalamus, the axons of many SHT neurons descend into the ipsilateral posterior thalamus, midbrain, pons, or even rostral medulla. These axons may provide nociceptive information to a variety of nuclei throughout the diencephalon and brainstem bilaterally.

Amphetamine effects on unconditional and conditional instrumental responses with alimentary and social rewards in dogs.

The effect of amphetamine dose (0.5 mg per 1 kg) on conditional and unconditional responses based on alimentary and social motivation was investigated in two groups of dogs. Amphetamine resulted in a significant decrease of conditional instrumental responses (CRs) in both groups but did not attenuate significantly the dogs' need for food or petting. On the contrary, the drug drastically increased the dogs' need for petting, and its anorectic effect was mild. The deteriorating effect of amphetamine on mnemonic processes and its facilitatory effect on behaviors directed to get more than the usual amount of pleasant tactile stimulation might underlie the behavioral changes described in this study.

Amphetamine increases intertrial but not conditional instrumental responding in the cortico-basomedial amygdalar dogs.

The effect of partial cortico-basomedial amygdaloid lesions on dogs' social behavior was investigated. The lesions did not affect the conditional instrumental responding (CRs) reinforced by petting or the dogs' need for petting (US). The lesions increased the number of intertrial responses (ITRs) in all dogs. Subsequently the effect of low amphetamine doses (0.5 mg/l kg) administered intramuscularly to the amygdalar animals on the same behavioral parameters of the social behavior was examined. Amphetamine did not affect CRs but dramatically increased the ITRs and dogs' need for petting. These findings suggest that the cortico-basomedial amygdaloid region may be involved in the cortical inhibitory mechanisms that are indispensable for promoting behavioral acts according to their usefulness and the situational context.

Studies of instrumental behavior with sexual reinforcement in male rats (Rattus norvegicus): I. Control by brief visual stimuli paired with a receptive female.

We describe a novel procedure for measuring instrumental sexual behavior in the male rat by using a second-order schedule of presentation of sexual reinforcement, an estrous female. Experimental assessment and validation of the paradigm have been achieved by examining (a) the importance of the conditioned stimulus in maintaining instrumental responding by measuring the effects of its omission during a test session, (b) the effects and motivational specificity on instrumental behavior of the postejaculatory refractory period (a period of sexual unarousability) and of satiety for food by measuring the impact of each manipulation on animals working for food and for a female, (c) the effects of replacing an estrous female with an anestrous one as the earned reward, and (d) the correlations between conditioned and unconditioned measures of sexual behavior. We conclude that the second-order paradigm provides a means of distinguishing between the effects of neuroendocrine manipulations on incentive motivational and performance variables underlying the expression of sexual behavior.

Autonomic correlates of alimentary conditioned and unconditioned reactions in the dog.

Analysis of changes in cardiac action and the secretion of saliva during unconditioned alimentary activity in 6 dogs revealed that the beginning of food consumption was accompanied by acceleration of the heart rate (HR) without an increase in salivation. In the course of eating, the heart rate decelerated and salivation increased. Alimentary conditioned stimuli of excitatory (CS+) and inhibitory (CS-) character always produced cardiac acceleration, which in the case of CS+ was accompanied by secretion of saliva. The findings indicate that during food consumption activation of the autonomic system depends upon the contents of motivational processes. In the course of an alimentary act the parasympathetic withdrawal (heart rate acceleration and decrease in salivation) seems to reflect the drive component of the act, while the following parasympathetic activation (heart rate deceleration and increase in salivation) is probably associated with an hedonic component of the consummatory reaction. In our study alimentary conditioned stimuli evoked both drive and hedonic components of alimentary motivation.

The amygdala and male reproductive functions: I. Anatomical and endocrine bases.

The present review is mainly concerned with the role of the amygdala (AMY) in male sexual behaviour and presents the characteristics of neuroanatomical and neuroendocrine organization of the cortico-medial amygdala as compared to the medial preoptic area (MPOA), in relation to sexual behaviour and gonadotropin secretion. It stresses the part played by AMY in processing sensory information which afterwards reaches the hypothalamus (HYP). Some data on the different function of steroids and luteinizing hormone releasing hormone (LHRH) systems within AMY and MPOA are provided. The role of AMY in the positive feedback effect on luteinizing hormone (LH) secretion and the involvement of steroid and opiate interaction as its mechanism are suggested. AMY is proposed to integrate external and internal sensory information granting the optimal conditions for sexual performance and possibly for regulation of LH release according to the behavioural context. The steroid content of AMY may influence these processes.

Changes in socio-emotional behavior under imipramine treatment in normal and amygdalo-hypothalamic dogs.

The effects of imipramine on learned social responses were examined in ten dogs with dorsomedial amygdalar lesions and/or lateral hypothalamic lesions. Six of the ten dogs were also tested preoperatively. The social responses were instrumentally conditioned using social interaction with the experimenter as reinforcement (petting and verbal reassurance). In the non-lesioned dogs imipramine treatment produced a dose-dependent deterioration of performance during drug administration followed by a long-term amelioration of performance. In the lesioned dogs imipramine produced various changes in performance depending on the pretreatment level of responding. When the pretreatment level of performance was high drug administration resulted in a long-term deterioration, and when performance was poor imipramine produced a continuous and long-term increase. It is suggested that imipramine facilitates the recovery of performance, but suppresses well-performed responses.

Food-motivated behavior in rats with cortico-basomedial amygdala damage.

Twelve rats with amygdala damage (CBM) and 20 sham-operated controls were tested in several food-related situations. The CBM rats showed a longer latency to eat than controls in a novel environment due to more pronounced exploration. In the competition for food, CBM rats lost 85% of encounters with controls. Immediately after the contest, when allowed to eat singly, CBM rats displayed a higher persistence of alimentary responses to an emptied cup than did controls, presumably because they experienced more losses in the food competition. Both groups were equally able to overcome obstacles on the way to food, which suggests similar alimentary motivation. The only direct indication of a lowered responsiveness to hunger in CBM rats was 24-hr-fasting-induced hypophagia. The results of this study indicate the involvement of the cortico-basomedial amygdaloid region in the control of relations between alimentary and other motivations. The contribution of eventual changes of food motivation in the postoperative alteration of this balance is discussed.

Heart rate mechanisms in instrumental conditioning reinforced by petting in dogs.

The aim of this experiment was to determine heart rate (HR) responses during conditioned stimuli (CS) and the petting reward (US) delivered by the experimenter to the dogs after performance of the instrumental conditioned response (CR). It was found that in five dogs for which petting served as a positive reinforcement the delivery of petting was accompanied by cardiac deceleration followed by sudden acceleration at the moment of petting withdrawal. Presentation of CS evoked heart rate deceleration until performance of the first CR. At the start of performance of CRs, heart rate accelerated. It was suggested that heart-rate deceleration is an important component of cardiac response to petting reward and, that probably, it is associated with the hedonic aspect of the reinforcement.

Autonomic responses accompanying conditioned and unconditioned alimentary reactions in amygdalo-hypothalamically lesioned dogs.

Lesions in the amygdalo-hypothalamic system decreased conditioned and unconditioned alimentary responses in five dogs. During three postoperative months no improvement was observed. The introduction of the new food reward (chosen for each dog as the most preferred) produced a sudden or progressive increase of conditioned and unconditioned alimentary performance. In the cardiac responses accompanying postoperative conditioned and unconditioned alimentary reactions, the lack or diminution of the decelerative response during food .consumption and a less pronounced postoperative acceleration of heart rate during conditioned stimuli were observed. Conditioned and unconditioned salivary responses decreased postoperatively and the pattern of the salivary responses varied individually. The results support the hypothesis that damage of amygdalo-hypothalamic system produces a decrease of the hedonic values of the usually used food rewards. Decrease or lack of the decelerative cardiac response during eating may reflect this ahedonic state.

Training of instrumental responses in dogs socially reinforced by humans.

The motivational bases of the social reinforcement in human-dog relations were examined. In experiment I, performed on seven dogs, it was found that dogs were able to learn and sustain the natural responses of sitting, paw extension, and lying prostrate to conditional stimuli in the form of vocal commands reinforced only by social rewards given by the experimenter, such as petting and vocal encouragement. Overtraining did not produce deterioration of performance but, on the contrary, the continual decrease of latencies. It was evidenced that tactile stimulation plays an important role in social reward. In experiment II, instrumental responses to the auditory conditional stimuli were elaborated in two groups of dogs. The first group (nine dogs) was reinforced by food, and the second group (eight dogs) was reinforced exclusively by petting. A similar course of learning and level of performance during overtraining sessions in both groups indicated that petting serves as a good reinforcement, with rewarding value comparable to that of food reinforcement. It is suggested that a strong rewarding effect of pleasurable sensory stimuli occurs in the formation of the bond between dog and human and in the learning of different tasks.

Motivational role of social reinforcement in dog-man relations.

Lesions of dorsomedial amygdala (DMA) or lateral hypothalamus (LH) produced prominent impairment of the alimentary behavior in dogs. Besides, various behavioral responses, including social, were depressed. To evaluate whether these changes were either specific for alimentary disturbances or dependent on changes in the general reward system, another type of reward, i.e. social contact with experimenter as a reinforcement for several motor responses was introduced. Damage of amygdalo-hypothalamic system, which produced a syndrome of depression, also impaired socially reinforced responses. This impairment lasted much longer then decrease of food intake. Therefore it was assumed that DMA and LH damage produced impairment not limited to alimentary mechanisms, but involving various aspects of positive motivational system and in particular including the social behavior during man-dog relations. Taking into account various theories of reinforcement in instrumental learning the authors are inclined towards a hedonistic theory of reward.