Interaction of Tonic and Phasic Pain in Rabbit Ontogenesis

In the experiments on the 20–25-day-old and adult rabbits, effects of tonic pain focus (a subcutaneous injection of formalin into leg dorsal surface) on behavioral and electrophysiological characteristics of acute pain were studied. The effect of the 40–60-min-long tonic pain was seen as a decrease of defensive reaction threshold and an increase of inhibitory effect of brain rewarding zones on evoked potential recorded in thalamus parafascicular complex in response to a nociceptive electrocutaneous stimulation in narcotized rabbits. The changes observed were biphasic and coincided in time with an enhancement of the earlier described [26] specific behavioral responses to formalin injection. It is established that the effect of tonic pain is more expressed by its intensity and duration in the 20–25-day-old than in adult rabbits.     

Roles of different neurochemical systems in mechanisms underlying the antinociceptive effect of extrahigh-frequency electromagnetic radiation

We studied the effect of low-intensity extrahigh-frequency (EHF) electromagnetic radiation (EMR) on the duration of a pain behavioral reaction in rats under conditions of experimental induction of tonic pain (formalin test). The antinociceptive effect of EHF irradiation was modulated by suppression of the activity of a few neurochemical systems resulting from the blockade of receptors of opioid peptides, α-and β-adrenoreceptors, receptors of dopamine and melatonin, as well as from inhibition of serotonin synthesis. We demonstrated that all the respective neurochemical systems are to a certain extent involved in the mechanisms underlying the analgesic action of EHF EMR. Within an early phase of pain stress, functioning of the opioidergic and noradrenergic systems and the effects of melatonin play leading roles, while the activity of the serotonergic system plays such a role within the second (tonic) phase. Neirofiziologiya/Neurophysiology, Vol. 39, No. 2, pp. 165–173, March–April, 2007.     

ERK MAP Kinase Activation in Spinal Cord Regulates Phosphorylation of Cdk5 at Serine 159 and Contributes to Peripheral Inflammation Induced Pain/Hypersensitivity

Cyclin-dependent kinase 5 is a proline-directed serine/threonine kinase and its activity participates in the regulation of nociceptive signaling. Like binding with the activators (P35 or P25), the phosphorylation of Cdk5 plays a critical role in Cdk5 activation. However, it is still unclear whether Cdk5 phosphorylation (p-Cdk5) contributes to pain hyperalgesia. The aim of our current study was to identify the roles of p-Cdk5 and its upstream regulator in response to peripheral inflammation. Complete Freund''s adjuvant (CFA) injection induced acute peripheral inflammation and heat hyperalgesia, which was accompanied by sustained increases in phospho-ERK1/2 (p-ERK1/2) and phospho-Cdk5^S159 (p-Cdk5^S159) in the spinal cord dorsal horn (SCDH). CFA-induced p-ERK primarily colocalized with p-Cdk5^S159 in superficial dorsal horn neurons. Levels in p-ERK and p-Cdk5 were also increased in the 2^nd phase of hyperalgesia induced by formalin injection, which can produce acute and tonic inflammatory pain. MAP kinase kinase inhibitor U0126 intrathecal delivery significantly suppressed the elevation of p-Cdk5^S159, Cdk5 activity and pain response behavior (Heat hyperalgesia, Spontaneous flinches) induced by CFA or formalin injection. Cdk5 inhibitor roscovitine intrathecal administration also suppressed CFA-induced heat hyperalgesia and Cdk5 phosphorylation, but did not attenuate ERK activation. All these findings suggested that p-Cdk5^S159 regulated by ERK pathway activity may be a critical mechanism involved in the activation of Cdk5 in nociceptive spinal neurons contributes to peripheral inflammatory pain hypersensitivity.     

Microwave-induced and pharmacological suppression of somatic pain under conditions of the formalin test in mice

We examined pain-related behavioral reactions and non-pain behavioral manifestations in mice under conditions of the formalin test. Levels of analgesia induced by i.p. injections of analgin, microwave irradiation of an antinociceptive acupuncture point (AP), E-36, or combined application of the above factors were measured. The duration of the pain behavioral reaction (licking of the injured limb) decreased due to irradiation of the AP with microwaves and to injection of 8.3 mg/kg analgin by 24.3% and 53.8%, on average, respectively. Combination of injection of analgin in a smaller dose (4.2 mg/kg) and microwave irradiation of the AP suppressed manifestations of the pain behavioral reaction by 43.4%. Thus, combination of pharmacologically induced analgesia with the action of microwaves on the antinociceptive AP allows one to significantly decrease the doses of analgesic preparations necessary to provide a full-level analgesic effect; in such a way, side effects of the respective drugs can be weakened. Neirofiziologiya/Neurophysiology, Vol. 38, No. 1, pp. 46–51, January–February, 2006.     

Antinociceptive properties of the 5-HT3 receptor antagonist in the model of inflammatory pain in rats of different age with prenatal deficit of serotonine and under stress

The role of peripheral 5-HT3 receptors in the nociceptive behavioral response and the effect of the 5-HT3 antagonist ondansetron on indices of acute and tonic pain were investigated in the formalin test in 25- and 90-day-old Wistar male rats. The experimental rats were prenatally exposed to 5-HT depletion (a single injection ofparachlorophenilalanine 400 mg/kg/2 ml, i. p.; ICN, USA to the dams on day 9 of pregnancy) and to stress (dams immobilization during the last week of pregnancy). Antinociceptive effects of ondansetron in the rats with both prenatal 5-HT deficiency and stress (experimental rats) and prenatal injection of saline solution and stress (control rats) were more obvious in the younger animals. Prenatal 5-HT deficiency attenuated the antinociceptive effect of ondansetron in licking patterns in the younder age group in acute pain, and in adults--in tonic pain. Thus, the data obtained in the rats with prenatal 5-HT deficiency and stress indicate involvement of 5-HT3 receptors in mediation of prolonged pain in the formalin test, and antinociceptive effect of ondansetron which is attenuated in animals with prenatal 5-HT deficiency and specifically depends on rat's age.     

Effects of Decrease of Serotonin Synthesis and Subsequent Stress in Embryogenesis on Rat Pain Sensitivity during the Prepuberty Period of Development

In the 25-day old rats there were studied effects of prenatal serotonin (5-HT) depletions and stress on pain sensitivity evaluated using formalin test by indexes of the biphasic behavioral response (BBR)-the number of flexions and shakings as well as duration of licking of the formalin injected leg, duration of the first and second response phases and on morphofunctional characteristics of the brain structures involved in BBR. The 5-HT depletion (a single intraperitoneal injection of parachlorophenylalanine, an inhibitor of 5-HT synthesis, to pregnant females at the initial period of development of the serotoninergic system) produced morphological lesions in the neocortex areas and hippocampus and raphe nuclei, which were accompanied by an essential decrease of the pain sensitivity (until its complete inhibition) during the second, tonic, BBR phase. In the prenatally stressed rats (immobilization of pregnant females for the last pregnancy week) with prenatal 5-HT depletion the nerve cell death in the above brain structures was accompanied by an increase of the pain sensitivity revealed by all response indexes during the second, tonic phase, whereas in the prenatally stressed rats developed without the intervention into the serotoninergic system, only one index was found to increase. The obtained results indicate that 5-HT participates in formation of the tonic nociceptive system and in mediation of effects of the prenatal stress on the pain sensitivity to the long-term nociceptive stimulus.__________Translated from Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, Vol. 41, No. 2, 2005, pp. 168–175.Original Russian Text Copyright © 2005 by Butkevich, Mikhailenko, Khozhai, Otellin.     

Infantile stage of rat development in behavioral parameters of depression-like state and pain response

In the 7–8- and the 10–11-day old male rat pups born to dams exposed to an immobilization stress for the last week of pregnancy and to the dams exposed to no stress (control), behavioral parameters were studied: the level of depression in the test of forced swimming (the Porsolt’s test) and 24 h after a long pain response during inflammation (the formalin test—a subcutaneous injection of 2.5% formalin into the hind leg plantar pad). In control pups, significant age-related changes in the forced swimming were revealed: the immobility time was longer in animals of the older age group, whereas no age differences were found in parameters of the persistent inflammatory pain and in flexing + shaking behavior. The prenatal stress produced an increase in the immobility time and the flexing + shaking behavior in the 7–8-day old, but not in the 10–11-day old rat pups. This resulted in elimination of the age differences in the immobility time in the prenatally stressed animals. Thus, use of different methodic approaches has allowed revealing peculiarities in the parameters of the degree of depression and duration of the pain response at inflammation in the 7–8- and 10–11-day old rat pups, which indicates heterogeneity of the infantile development stage that, according to literature data, includes in rats the period from the 5th to the 10th postnatal days.     

Analgesia induced by combined action of Tramadol and microwave irradiation in somatic pain in mice

In experiments on albino male mice weighing 24 to 32 g, we studied the suppression of the pain reaction induced by injection of formalin into the dorsal surface of the foot, using a combination of injection of tramadol hydrochloride (Tramal) in a dose of 0.42 mg/kg and irradiation of the acupuncture point (AP) E-36 with low-intensity microwaves (frequency 30 to 300 GHz and power rate density 3·10⁻⁹ W/cm²). The combined use of tramadol injection and the action of microwaves on the AP led to a decrease in the duration of the pain reaction (licking of the pain nidus), on average, by 58.2%, as compared with that in the control animal group. The analgesic effect was more strong in the case of such a combination than after isolated injection of tramadol in doses of 0.83 and 0.42 mg/kg (by 14.4 and by 10.0%, respectively) and isolated microwave irradiation of the AP TA E-36 (by 48.7%). The data obtained demonstrate the possibility of effective analgesia using a combination of microwave irradiation of the AP and the pharmacological influence with a significant decrease in the dose of the analgesic. Neirofiziologiya/Neurophysiology, Vol. 38, No. 4, pp. 314–319, July–August, 2006.     

Effects of maternal corticosterone and stress on behavioral and hormonal indices of formalin pain in male and female offspring of different ages

In previous studies, we showed for the first time that prenatal stress in rats produces long-term alterations of formalin-induced pain behavior that are dependent on age and sex, and we demonstrated an important role of the serotonergic system in mechanisms of prenatal stress (Butkevich, I.P. and Vershinina, E.A., 2001; Butkevich, I.P. and Vershinina, E.A., 2003; Butkevich, I.P., Mikhailenko, V.A., Vershinina, E.A., Khozhai, L.I., Grigorev, I.P., Otellin, V.A., 2005; Butkevich, I.P., Mikhailenko, V.A., Khozhai, L.I., Otellin, V.A., 2006). In the present study, we focus on the influence of the maternal corticosterone milieu and its role in the effects of stress during pregnancy on formalin-induced pain and the corticosterone response to it in male and female offspring of different ages. For this purpose, we used adrenalectomy (AD) in female rats 3-4 weeks before mating (as distinct from AD typically performed at the beginning of pregnancy). Since AD is considered a reliable method to treat hypercortisolism, researches on the effects of long-term AD in dams on the systems responsible for adaptive behavior in offspring are important (such studies are not described in the literature). The results demonstrate that the differences in the corticosterone response to injection of formalin and saline are obvious in 90-day-old (adult) female offspring but masked in 25-day-old ones. AD promoted the corticosterone response to formalin-induced pain but not to injection of saline in prenatally non-stressed female offspring of both ages. Prenatal stress canceled the differences in corticosterone response to injection of formalin and saline in 25-day-old offspring of AD dams and in adult offspring of sham-operated (SH) dams but caused similar differences in adult offspring of AD dams. Sex differences were found in basal corticosterone levels in AD prenatally stressed rats of both age groups, with a higher level in females, and in the corticosterone response to formalin-induced pain in the adult rats of all groups investigated, with higher corticosterone levels in females. In regard to pain behavior, AD induced significant changes in flexing + shaking in prenatally non-stressed adult offspring and canceled the differences in this behavior between non-stressed and stressed 25-day-old offspring. There were sex differences in pain behavior of the adult rats: greater flexing + shaking in AD non-stressed males but in SH non-stressed females; greater licking in prenatally-stressed AD and SH females. These results indicate that the long-term influences of maternal corticosterone on formalin-induced pain and the corticosterone response to it are determined by the sex and age of the offspring and suggest that other mechanisms, including serotonergic ones revealed in our previous studies, are involved in the effects of prenatal stress on inflammatory pain behavior.     

Sex Differences in Effects of Prenatal Stress on Specific Biphasic Behavioral Response in Nociceptive Formalin Test in Adult Rats

Remote effects of stress (immobilization) in pregnant females at critical stages of fetal development on pain sensitivity to a long-term nociceptive stimulus (formalin test) were studied in their female and male off-spring at the age of 90 days. Prenatal stress produced changes of the standardized specific biphasic behavior response (BBR), whose intensity was evaluated by the number of flexion and shakings and by duration of licking of thee extremity injected with formalin. Apart from intensity of the BBR, duration of its both phases and of interphase interval was determined. It was found that the response intensity by the licking pattern increased significantly at the first response phase reflecting acute pain in males, whereas at the second phase reflecting tonic pain, both in females and males; duration of the phases and interphase interval increased statistically significantly only in females. Thus, in the prenatally stressed adult rats, an increase of pain sensitivity to a long-term nociceptive stimulus producing inflammation has been revealed by the BBR patterns organized at the supraspinal, but not at the spinal CNS level. Sex differences were found in the acute phase intensity and in duration both of acute and of tonic response phase. The data obtained indicate different effects of prenatal stress on the nociceptive systems involved in realization of the BBR in the formalin test in adult females and males and are an essential argument in favor of the concept of different characteristics of the acute and tonic pain.     

Nociceptive sensitivity to a long-term stimulus in the formalin test in female and male rats in postnatal ontogenesis

In Wistar rats, a comparative study of pain sensitivity to the long-term stimulus in the formalin test was carried out at different age periods—the prepubertal (25 days), pubertal (40 days), and sex maturity (90 days) periods. The pain sensitivity was evaluated by standard indexes of the biphasic behavioral response (BBR)—patterns of flexing, shaking, licking of the leg injected by formalin, and by duration of the first and second response phases and of the interphase interval. It is found that with development of the central nervous system the pain sensitivity changed, with differences in the first, acute and the second, tonic BBR phases: in the tonic phase of response the pain sensitivity increased in males by the indexes organized at the spinal, while in females, at the supraspinal level, whereas in the acute phase it decreased essentially at the supraspinal level in individuals of both sexes. The greater number of age differences in the pain sensitivity is revealed in females by the response patterns organized at the supraspinal level. At the same level, essential readjustments in hormonal and neurotransmitter systems are reflected in the high BBR indexes. In adult individuals the sex dimorphism is detected in duration of the interphase intervals. Activity of the bulbospinal descending inhibitory monoaminergic systems is shown to continue increasing for the first three months of life, with predominance of this process in females. The obtained data allow concluding that the BBR characteristics depend on age and sex of individuals and are determined by the organization level in CNS of the response patterns characterizing the pain sensitivity in the formalin test.Translated from Zhurnal Evolyutsionnoi Biokhimii i Fiziologii, Vol. 41, No. 1, 2005, pp. 76–81.Original Russian Text Copyright © 2005 by Butkevich, Vershinina.     

Hypokinetic stress-induced modifications of the pain sensitivity in rats

We examined the modifying effect of hypokinetic stress on the duration of behavioral phenomena in rats under conditions of experimentally induced tonic somatic, visceral, acute thermal, and electrostimulation-evoked pain. Stress of the above type (hypokinetic) was found to modify the pain sensitivity in rats related to all tested types of pain stresses of different etiology. Changes in the pain sensitivity of the animals under conditions of experimental pain tests depended on the duration of mobility restriction and could demonstrate opposite directions. Neirofiziologiya/Neurophysiology, Vol. 39, No. 2, pp. 174–183, March–April, 2007.     

The Effect of Nimodipine on Calcium Homeostasis and Pain Sensitivity in Diabetic Rats

Summary 1. The pathogenesis of diabetic neuropathy is a complex phenomenon, the mechanisms of which are not fully understood. Our previous studies have shown that the intracellular calcium signaling is impaired in primary and secondary nociceptive neurons in rats with streptozotocin (STZ)-induced diabetes. Here, we investigated the effect of prolonged treatment with the L-type calcium channel blocker nimodipine on diabetes-induced changes in neuronal calcium signaling and pain sensitivity.2. Diabetes was induced in young rats (21 p.d.) by a streptozotocin injection. After 3 weeks of diabetes development, the rats were treated with nimodipine for another 3 weeks. The effect of nimodipine treatment on calcium homeostasis in nociceptive dorsal root ganglion neurons (DRG) and substantia gelatinosa (SG) neurons of the spinal cord slices was examined with fluorescent imaging technique.3. Nimodipine treatment was not able to normalize elevated resting intracellular calcium ([Ca²⁺] _i ) levels in small DRG neurons. However, it was able to restore impaired Ca²⁺ release from the ER, induced by either activation of ryanodine receptors or by receptor-independent mechanism in both DRG and SG neurons.4. The beneficiary effects of nimodipine treatment on [Ca²⁺] _i signaling were paralleled with the reversal of diabetes-induced thermal hypoalgesia and normalization of the acute phase of the response to formalin injection. Nimodipine treatment was also able to shorten the duration of the tonic phase of formalin response to the control values.5. To separate vasodilating effect of nimodipine Biessels et al., (Brain Res. 1035:86–93) from its effect on neuronal Ca²⁺ channels, a group of STZ-diabetic rats was treated with vasodilator – enalapril. Enalapril treatment also have some beneficial effect on normalizing Ca²⁺ release from the ER, however, it was far less explicit than the normalizing effect of nimodipine. Effect of enalapril treatment on nociceptive behavioral responses was also much less pronounced. It partially reversed diabetes-induced thermal hypoalgesia, but did not change the characteristics of the response to formalin injection.6. The results of this study suggest that chronic nimodipine treatment may be effective in restoring diabetes-impaired neuronal calcium homeostasis as well as reduction of diabetes-induced thermal hypoalgesia and noxious stimuli responses. The nimodipine effect is mediated through a direct neuronal action combined with some vascular mechanism.     

Suppression of nociceptive reactions in mice under low-intensity microwave irradiation of acupuncture points

We studied nociceptive responses to subcutaneous injections of formalin and electrical stimulation of the limbs in control mice and in mice whose acupuncture points (AP) were subjected to low-intensity microwave irradiation. In the latter animals, nociceptive reactions were significantly weaker than those in the control mice. The analgesic effect depended on what AP was selected and irradiated and on the duration and timing of microwave irradiation. In different experimental series, the duration of a formalin injection-induced nociceptive behavioral reaction decreased by 23.3–59.6%. The threshold of vocalization responses to stimulation on an electrified floor increased by 25.8±28.0%. The results demonstrate that a technique of analgesia by influencing the AP with microwave irradiation of a nonthermal intensity is rather effective.     

Fluorocitrate,an Inhibitor of Glial Metabolism,Inhibits the Up-Regulation of NOS Expression,Activity and NO Production in the Spinal Cord Induced by Formalin Test in Rats

Previous experiments have suggested that nitric oxide plays an important role in nociceptive transmission in the spinal cord. In order to explore the involvement of glia in the NO-mediated nociceptive transmission, the present study was undertaken to investigate the effect of fluorocitrate (FC), an inhibitor of glial metabolism, on NOS expression and activity and NO production in the spinal cord during the process of peripheral inflammatory pain and hyperalgesia induced by formalin test in rats. Sixty adult male Sprague–Dawley rats were randomly assigned into sham, formalin, formalin + normal saline (NS), and formalin + FC groups. The NOS expression, NOS activity and NO production was detected by NADPH-d histochemistry staining, NOS and NO assay kit, respectively. It was found that formalin test significantly up-regulated NOS expression and activity and NO production in the laminae I–II of the dorsal horn and the grey matter around the central canal in the lumbar spinal cord at 1 h after the formalin test. Selective inhibition of glia metabolism with intrathecal administration of FC (1 nmol) significantly inhibited the up-regulation in NOS expression and activity and NO production normally induced by the formalin test, which was represented with decreases in the number and density of the NADPH-d positive cells in the dorsal horn and grey matter around the central canal, and decrease in density of NADPH-d positive neuropil in the dorsal horn in formalin + FC group compared with formalin group. The results suggested that glia may be involved in the NO-mediated nociceptive transmission in the spinal cord. X.-C. Sun, W.-N. Chen and S.-Q. Li contributed equally to this work.     

Long-term effects of stress in critical periods of development on reactivity of adult female rats

Effects of stress during different periods of ontogeny, namely, the prenatal, prepubertal, or their combination (prenatal+prepubertal), on the indices of psychoemotional and tonic pain-related behaviors, as well as corticosterone reactivity after pain behavior were investigated in adult 90-day-old female Wistar rats. Our data show for the first time, the similarity of effects of prenatal (immobilization stress of a rat dam during the last week of pregnancy) and prepubertal (forced swimming, pain-related response in the formalin test) stresses on the indices under study, an increase in the time of immobility and in licking duration, but the difference between effects of combined stress on these indices. Pain-related response increased corticosterone in prepubertally stressed rats while in prenatally stressed rats, decreased it. In rats experienced combined stress, formalin-induced pain increased corticosterone as compared with that in prenatally, but not in prepubertally stressed rats. A positive correlation between pain-related reaction and stressed hormonal response was revealed in prepubertally stressed animals. So, long-term effects of stress during critical periods of ontogeny determine stress reactivity of behavioral and hormonal responses in adult female rats.     

Sex-dependent differences in parameters of a long-term pain caused by inflammatory focus in prenatally stressed newborn rats

In experiments on the 7-day-old female and male Long-Evans rat pups, for the first time, there was studied effect of prenatal (immobilization) stress on dynamics of nociceptive behavioral response caused by an inflammatory focus. The nociceptive sensitivity was evaluated for 1 h by the number of 7-day-old organized at the spinal level in response to injection of formalin (10%, 10 microl) to the posterior leg sole. Control rat pups were not submitted to any prenatal stress; in these animals the response in the formalin test was found to be represented by one phase. It the prenatally stressed rat pups the studied patterns were organized into two phases characteristic of the definitive type of response. At the period between them (during interphase), the nociceptive behavior was absent. At the second, tonic phase the number of flexes+shakes in the prenatally stressed males was statistically significantly higher than in the prenatally stressed females, which indicates a sensitization of the neurons involved in the tonic pain chains in male individuals. Thus, the data obtained on prenatally stressed animals confirm the previous data about immaturity of the mechanisms mediating the second phase of response in the formalin test in the 7-day-old rat pups. An important fact is revealed which indicates that in the prenatally stressed rat pups of the same age the second phase of response is already obvious. Mechanisms underlying the behavioral response caused by the inflammatory focus in the formalin test in the number flexes + shakes old stressed rat pups are characterized by sexual dimorphism: the pain sensitivity in males at the second phase of response is statistically significantly higher than in females.     

Regulation of the phonotactic threshold of the female cricket, Acheta domesticus : juvenile hormone III, allatectomy, L1 auditory neuron thresholds and environmental factors

Juvenile hormone III (JHIII), when applied to the abdomen of 1-day-old female Acheta domesticus (in quantities that would create JHIII titers in the hemolymph that were within the range measured in females of this species) caused a significant decrease in phonotactic thresholds (Fig. 1). Removal of the corpora allata from 5-day-old females with low phonotactic thresholds caused significantly increased phonotactic thresholds 2–5 days later. After a temporary increase (24 h) of, on average, about 25 dB, the phonotactic thresholds drop to about 10 dB above preallatectomy levels (Fig. 2), but remain significantly higher than controls. Application of JHIII to allatectomized females, with a mean increase in thresholds of 20 dB, results in significantly decreased thresholds (mean of about 20 dB) over the next 6 h (Fig. 3). Exposure to males 1 week before the imaginal molt causes the phonotactic thresholds of postimaginal females to drop 1–2 days significantly earlier than controls (Fig. 4). One- and 3-day-old females, phonotactically tested only once, exhibit lower thresholds in the early morning than they do in the late afternoon (Fig. 5). Five-day-old females do not exhibit such a diurnal rhythm. Phonotactically testing females more than once a day significantly influences their phonotactic thresholds (Figs. 6, 7). In 1-day-old females, with high (above 70 dB) phonotactic thresholds, the threshold of their L1 auditory interneurons can be 30 dB or more below their phonotactic threshold (Fig. 8). In females with phonotactic thresholds of 70 dB or lower, the L1 threshold is within 10 dB of their phonotactic threshold. Both JHIII and allatectomy influence phonotactic and L1 thresholds in a similar manner. Accepted: 29 September 1997     

Consequences of the prenatal depletion of serotonin and stress on nociceptive sensitivity in rats

The long-term effects of serotonin (5-HT) synthesis alteration and of restraint stress experienced by pregnant Wistar rats on pain sensitivity (evaluated by the indices of the biphasic behavioral response in the formalin test) were studied in their 90-day-old offspring. Prenatal 5-HT depletion decreased pain sensitivity in one third of the rats and failed to change it in the rest of the rast. In these later, however, an obvious tendency for an increase of interphase duration in females and its decrease in males were revealed that indicates changing of the activity of the descending serotoninergic system modulating nociceptive signals at the level of the spinal dorsal horns. Prenatal stress decreased pain sensitivity in 50% of the rats with prenatal deficiency of 5-HT but increased it in the rest of the animals. Increase of pain sensitivity also occurred in the control rats but to a lesser extent (significantly in flexing + shaking behavior during the second phase) compared to the animals with prenatal 5-HT depletion. In the latter, sex differences were found in effects of prenatal stress on pain sensitivity. The present data point an important role of 5-HT in: 1) embryonic development of tonic nociceptive system which is modulated in the CNS by mechanisms differing from those of acute pain; 2) mediation of the prenatal stress influence on pain sensitivity in the formalin test in adult rats.