Changes In Nociceptive Responses Research Articles

Effects of repetitive pinprick stimulation on preterm offspring: Alterations in nociceptive responses and inflammatory hypersensitivity in adulthood

IntroductionThis study investigates the effects of repetitive pinprick stimulation on preterm offspring and its impact on nociceptive responses and inflammatory hypersensitivity in adulthood. ObjectivesThe objective is to shed light on the potential long-term consequences of neonatal pain and prematurity on sensory processing. MethodsTerm and preterm rats were subjected to repetitive pinprick (PP) stimulation or control (CC) during the neonatal period. Adult rats received CFA injection to induce inflammatory hypersensitivity, and mechanical hypersensitivity was measured. Gender differences in inflammatory hypersensitivity were also examined. Maternal behavior, litter weight, and offspring growth were monitored to assess any potential influences of the stimulation on these parameters. ResultsIn preterm rats, the PP stimulation did not affect baseline thresholds to mechanical stimuli, but increased mechanical hypersensitivity after CFA injection in adult rats. Females exhibited greater inflammatory hypersensitivity compared to males. Maternal behavior, litter weight, and offspring growth were not influenced by the stimulation. PP stimulation during the neonatal period led to changes in nociceptive responses in adulthood, potentially altering sensory processing. ConclusionPP stimulation in preterm rats during the neonatal period resulted in changes in nociceptive responses in adulthood, leading to increased inflammatory hypersensitivity. The study emphasizes how early development can significantly impact sensory processing and further highlights the potential long-term consequences of prematurity and neonatal pain on this processing.

Intrathecal urocortin I in the spinal cord as a murine model of stress hormone-induced musculoskeletal and tactile hyperalgesia.

Stress is antinociceptive in some models of pain, but enhances musculoskeletal nociceptive responses in mice and muscle pain in patients with fibromyalgia syndrome. To test the hypothesis that urocortins are stress hormones that are sufficient to enhance tactile and musculoskeletal hyperalgesia, von Frey fibre sensitivity and grip force after injection of corticotropin-releasing factor (CRF), urocortin I and urocortin II were measured in mice. Urocortin I (a CRF1 and CRF2 receptor ligand) produced hyperalgesia in both assays when injected intrathecally (i.t.) but not intracerebroventricularly, and only at a large dose when injected peripherally, suggesting a spinal action. Morphine inhibited urocortin I-induced changes in nociceptive responses in a dose-related fashion, confirming that changes in behaviour reflect hyperalgesia rather than weakness. No tolerance developed to the effect of urocortin I (i.t.) when injected repeatedly, consistent with a potential to enhance pain chronically. Tactile hyperalgesia was inhibited by NBI-35965, a CRF1 receptor antagonist, but not astressin 2B, a CRF2 receptor antagonist. However, while urocortin I-induced decreases in grip force were not observed when co-administered i.t. with either NBI-35965 or astressin 2B, they were even more sensitive to inhibition by astressin, a non-selective CRF receptor antagonist. Together these data indicate that urocortin I acts at CRF receptors in the mouse spinal cord to elicit a reproducible and persistent tactile (von Frey) and musculoskeletal (grip force) hyperalgesia. Urocortin I-induced hyperalgesia may serve as a screen for drugs that alleviate painful conditions that are exacerbated by stress.

Mice undergoing neuropathic pain induce anxiogenic-like effects and hypernociception in cagemates.

Rodents can recognize pain-related responses in conspecifics. Therefore, cohabitation with a conspecific animal with chronic pain can potentially promote a stressful situation, which can trigger behavioral changes such as anxiety and depression and alter nociceptive responses. In this study we investigated the effect of cohabitation with a mouse undergoing sciatic nerve constriction (neuropathic pain model). The cagemates were evaluated for nociception (writhing test), anxiety (elevated plus-maze and open field tests), depression (forced swim, tail suspension, and sucrose preference tests), and corticosterone levels. Male Swiss mice were housed in pairs for 14 days, and then divided into three groups: cagemate nerve constriction, in which one animal of each pair was subjected to constriction of the sciatic nerve; cagemate sham, in which one animal from each pair was subjected to the same surgery but without constriction; and control, in which animals were not subjected to any surgical procedure. After 14 days, the cagemates were evaluated using behavioral tests. Social interaction with a conspecific undergoing constriction of the sciatic nerve induced hypernociception and increased anxiety-related responses, whereas in depression tests inconclusive responses and no changes in corticosterone levels were found. In conclusion, cohabitation with suffering conspecifics induces changes in nociceptive responses, as well as in affective responses including anxiety.

P‐Cymene Complexed in β‐Cyclodextrin to Cancer Pain Control

p‐Cymene (PC) is an alkylbenzene commonly found in cumin oil which has shown antinociceptive activity in animal models. Now, we evaluated the effect of encapsulation of PC in β‐cyclodextrin (PC/β‐CD) on nociception induced by tumor cells (sarcoma 180) in rodents. PC/β‐CD complex was administered (12.5 ‐ 50 mg/kg, p.o.) in mice with tumor (106 cells/25 mL, s.c.) on the hind paw, which were evaluated regarding hyperalgesia (digital von Frey apparatus), spontaneous and palpation‐induced nociception. The experimental protocols were approved by UFS Ethic Committee (CEPA: 19/11). PC/β‐CD (12.5, 25 e 50 mg/kg) was able to reduce significantly hyperalgesia (p < 0.001 or 0.05), and this effect was maintained for 24 hours after treatment. Oral administration of PC/β‐CD complex (12.5‐50 mg/kg) on alternate days also reduced spontaneous and nociception induced by palpation (p<0.001 ‐ 0.05). Free PC (50 mg/kg, p.o.) and PC no complexed with β‐CD, were unable promote significant changes in nociceptive responses. Therefore, results obtained suggest the inclusion complex containing p‐cymene and β‐cyclodextrin may improve the pharmacological characteristics of terpenoids or related compounds with potential applicability in chronic pain, such as cancer.Financial support: FAPITEC‐SE and CNPq (Brazil).

Encapsulation of carvacrol, a monoterpene present in the essential oil of oregano, with β-cyclodextrin, improves the pharmacological response on cancer pain experimental protocols

Cancer pain is a major public health problem worldwide due to the strong impact on the quality of life of patients and side effects of the existing therapeutic options. Monoterpenes, as carvacrol (CARV), have been extensively studied about their therapeutic properties, especially their importance in the control of painful conditions and inflammation, which can be improved through the use of inclusion complexes of β-cyclodextrin (β-CD). We evaluated the effect of encapsulation of CARV in β-CD (CARV/β-CD) on the nociception induced by tumor cells (Sarcoma 180) in rodents. Inclusion complexes were prepared in two different procedures and characterized through thermal analysis and scanning electron microscopy. CARV/β-CD complex was administered (50mg/kg, p.o.) in mice with tumor on the hind paw and was able to reduce the hyperalgesia (von Frey) during 24h, unlike the free CARV (100mg/kg, p.o.), which promoted effects until 9h. Administration on alternate days of complex of CARV/β-CD (12.5–50mg/kg, p.o.) reduced hyperalgesia, as well as spontaneous and palpation-induced nociception. However, pure CARV (50mg/kg) did not cause significant changes in nociceptive responses. Together, these results produced evidence that the encapsulation of carvacrol in β-cyclodextrin can be useful for the development of new options for pain management.

Assessment of intraoral mucosal pain induced by the application of capsaicin

ObjectiveTo develop an objective method for assessing nociceptive behaviour in an animal model of capsaicin-induced intraoral pain. Changes in nociceptive responses were also examined after injury to the inferior alveolar nerve (IAN). DesignNociceptive responses evoked by the intraoral application of various doses of capsaicin were analyzed in lightly anaesthetized rats. The number of c-Fos protein-like immunoreactive (Fos-LI) neurons in the medullary dorsal horn (MDH) induced by the intraoral application of capsaicin was measured. Behavioural and c-Fos responses were also examined 14 days after injury to the IAN. ResultsLarger doses of intraoral capsaicin (1, 10 and 100μg) induced vigorous licking behaviour and c-Fos response in the MDH in a reproducible manner. The magnitudes of both behavioural activity and the c-Fos response from the 10 and 100μg doses of capsaicin were significantly greater than that by the 1μg dose. Injury to the IAN exaggerated the behavioural and c-Fos responses evoked by intraoral capsaicin. ConclusionsThe intraoral application of capsaicin is a valid and reliable method for studying intraoral pain and hyperalgesia following nerve injury.

Changes in thermal nociceptive responses in dairy cows following experimentally induced Escherichia coli mastitis.

BackgroundMastitis is a high incidence disease in dairy cows. The acute stage is considered painful and inflammation can lead to hyperalgesia and thereby contribute to decreased welfare. The aim of this study was to examine changes in nociceptive responses toward cutaneous nociceptive laser stimulation (NLS) in dairy cows with experimentally induced Escherichia coli mastitis, and correlate behavioral changes in nociceptive responses to clinical and paraclinical variables.MethodsSeven Danish Holstein-Friesian cows were kept in tie-stalls, where the E. coli associated mastitis was induced and laser stimulations were conducted. Measurements of rectal temperature, somatic cell counts, white blood cell counts and E. coli counts were conducted. Furthermore, scores were given for anorexia, local udder inflammation and milk appearance to quantify the local and systemic disease response. In order to quantify the nociceptive threshold, behavioral responses toward cutaneous NLS applied to six skin areas at the tarsus/metatarsus and udder hind quarters were registered at evening milking on day 0 (control) and days 1, 2, 3, 6 and 10 after experimental induction of mastitis.ResultsAll clinical and paraclinical variables were affected by the induced mastitis. All cows were clinically ill on days 1 and 2. The cows responded behaviorally toward the NLS. For hind leg stimulation, the proportion of cows responding by stepping was higher on day 0 than days 3 and 6, and the frequency of leg movements after laser stimulation tended to decrease on day 1 compared to the other days. After udder stimulation, the proportion of cows responding by stepping was higher on day 1 than on all other days of testing. Significant correlations between the clinical and paraclinical variables of disease and the behavioral responses toward nociceptive stimulation were found.ConclusionsChanges in behavioral responses coincide with peaks in local and systemic signs of E. coli mastitis. During the acute stage of E. coli mastitis nociceptive thermal stimulation on hind leg and mammary glands results in decreased behavioral responses toward nociceptive stimulation, which might be interpreted as hypoalgesia.

Contribution of peripheral endothelin ET A and ET B receptors in neuropathic pain induced by spinal nerve ligation in rats

Endothelins (ETs) contribute to the sensory changes seen in animals models of inflammatory, cancer and diabetic neuropathic pain, but little is known about their nociceptive role following peripheral nerve injury. The current study evaluated mechanisms by which ETs can drive changes in nociceptive responses to thermal stimulation of the hind paw of rats induced by unilateral lumbar L5/L6 spinal nerve ligation (SNL) injury. SNL sensitizes rats to acetone-evoked cooling of and radiant heat application (Hargreaves test) to the ipsilateral hind paw (throughout 3–40 and 9–40 days after surgery, respectively). At 12 days after SNL, intraplantar (i.pl.) injection of endothelin-1 (ET-1, 10 pmol) induces greater overt nociception that was reduced only by treatment with the selective ET A peptidic antagonist (BQ-123, 10 nmol, i.pl), but unchanged by the selective ET B peptidic antagonist (BQ-788). Cold allodynia evoked by cooling the ipsilateral hind paw with acetone was reduced by i.pl. injection of both antagonists BQ-123 or BQ-788 (3 or 10 nmol). In contrast, heat hyperalgesia evaluated by Hargreaves method was reduced only by BQ-123. SNL enhanced the [Ca +2] i increases induced by ET-1 (100 nM) in neurons from L5/L6 (injured) and L4 (intact) cultured dorsal root ganglion, but did not change the responses of non-neuronal cells. Furthermore, Western blot analysis revealed that SNL increased ET A and ET B receptor protein expression in spinal nerves. Thus, SNL induces marked hind paw hypersensitivity to thermal stimulation in part via up-regulation of peripheral sensory nerve pronociceptive ET A and ET B receptor-operated mechanisms.

Chronic psychological stress enhances nociceptive processing in the urinary bladder in high-anxiety rats

This study sought to determine whether acute and/or chronic psychological stress produce changes in urinary bladder nociception. Female Sprague–Dawley (SD; low/moderate anxiety) or Wistar–Kyoto (WK; high-anxiety) rats were exposed to either an acute (1 day) or a chronic (10 days) water avoidance stress paradigm or a sham stress paradigm. Paw withdrawal thresholds to mechanical and thermal stimuli and fecal pellet output, were quantified at baseline and after the final stress or sham stress exposure. Rats were then sedated, and visceromotor responses (VMRs) to urinary bladder distension (UBD) were recorded. While acute stress exposure did not significantly alter bladder nociceptive responses in either strain of rats, WK rats exposed to a chronic stress paradigm exhibited enhanced responses to UBD. These high-anxiety rats also exhibited somatic analgesia following acute, but not chronic, stress. Furthermore, WK rats had greater fecal pellet output than SD rats when stressed. Significant stress-induced changes in nociceptive responses to mechanical stimuli were observed in SD rats. That chronic psychological stress significantly enhanced bladder nociceptive responses only in high-anxiety rats provides further support for a critical role of genetics, stress and anxiety as exacerbating factors in painful urogenital disorders such as interstitial cystitis (IC).

Neonatal immune challenge alters nociception in the adult rat

Intense pain or intense peripheral inflammation experienced during development can have pronounced effects upon adult pain sensation. However, little is known about the more commonly encountered mild systemic inflammation, such as that experienced with mild illness. Neonatal exposure to lipopolysaccharide (LPS), an established model of immune system activation, has been shown to affect febrile and cyclooxygenase-2 (COX-2) responses to a similar exposure in adulthood. Adult LPS also elicits a range of sickness behaviours, including enhanced responses to painful stimuli. We, therefore, hypothesized that adult sensation and pain responses could be affected by a neonatal LPS challenge. Male and female Sprague–Dawley rats were administered LPS at postnatal day 14 and were tested in adulthood for nociceptive responses to thermal and mechanical stimuli using, respectively, a plantar test apparatus and von Frey filaments, before and after adult LPS. Expression of dorsal root ganglion and lumbar spinal cord COX-2 was also examined. Animals treated as neonates with saline showed the expected hypersensitivity to painful stimuli after adult LPS as well as enhanced spinal cord COX-2. Neonatally LPS-treated rats, however, showed a significantly different profile. They displayed enhanced baseline nociception and elevated basal spinal cord COX-2 compared with neonatally saline-treated rats. Also, rather than the expected hyperalgesia after adult LPS, no changes in nociceptive responses and a reduction in spinal cord COX-2 expression were observed. These findings have important implications for the understanding of pain and its management and highlight the importance of the neonatal period in the development of pain pathways.

Effects of ACEA-1328, a NMDA receptor/glycine site antagonist, on U50,488H-induced antinociception and tolerance

Previously, we have shown that inhibition of the glycine site associated with the N-methyl- d-aspartate (NMDA) receptor is another viable approach to blocking morphine tolerance. In the present study, we sought to investigate the involvement of the NMDA receptor/glycine site in κ-opioid receptor-mediated antinociception and tolerance in CD-1 mice. In antinociception studies, mice were injected with 5-nitro-6,7-dimethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1328), a systemically bioavailable NMDA receptor/glycine site antagonist, or the vehicle (Bis-Tris, 0.2 M) and then immediately with trans-(±)-3,4-dichloro- N-methyl- N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzeneacetamide methanesulfonate (U50,488H), a κ-opioid receptor agonist. Thirty minutes later, mice were tested for changes in nociceptive responses in the tail flick assay. ACEA-1328, per se, prolonged tail flick latencies with an ED 50 of approximately 50 mg/kg. Concurrent administration of ACEA-1328, at doses that did not produce antinociception, with U50,488H increased the potency of U50,488H in a dose-dependent manner. In tolerance studies, mice were treated, either once a day for 9 days or twice daily for 4 days, with the vehicle or ACEA-1328. Immediately after the initial injection, mice then received an injection of saline or U50,488H. On the test day, mice were injected with U50,488H alone and tested for antinociception 30 min later. Chronic treatment with U50,488H by either method produced tolerance. Unlike the acute effect of the drug, chronic treatment with ACEA-1328 decreased the antinociceptive potency of U50,488H. Taken together, the data suggest that acute and chronic administration of ACEA-1328 differentially affected the antinociceptive effect of U50,488H. Furthermore, the decreased in the potency of U50,488H induced by chronic treatment with ACEA-1328 also confounded the interpretation of the tolerance data.

Development of mustard oil-induced hyperalgesia in rats

Age-dependent changes in nociceptive responses were investigated using either the electromyogram (EMG) recorded from the hamstring muscle in response to electrical stimulation of the hind foot in spinal transected rats or measurement of the tail-flick (TF) reflex latency in intact rats. The development of hyperalgesia produced by topical application of mustard oil was subsequently studied. In experiments involving EMG recordings, rats were tested from day 2 to day 34 after birth (4-day interval) and as adults. In experiments involving measurement of the TF reflex, rats were tested from day 5 to day 30 after birth (5-day interval) and as adults. It was found that the latency and the duration of an early component of the EMG decreased with an increase in animal age, and was similar to adult animals at approximately 18 days after birth. The thermal tail withdraw threshold was lower in pups in comparison with older rats, and took more than 30 postnatal days to become similar to that of adult rats. Although nociceptive behaviors such as biting, body movement, and vocalization could be produced in intact rats by mustard oil in rats as young as 5 days old, the intensities of these responses were subjectively less than those of adult rats. Mustard oil application enhanced significantly the EMG response to electrical stimulation and the effect increased with increasing age. Similarly, mustard oil applied to a hind leg facilitated the TF reflex (decreased response latency). In both experiments, it took approximately 34–40 postnatal days for mustard oil-produced hyperalgesia to become similar to that of adult rats. These data confirm that nociceptive processing is not mature in the young animal and that a developmental period after birth is required for hyperalgesia-related mechanisms to mature.

NOCICEPTIVE RESPONSES IN INTERLEUKIN-6-DEFICIENT MICE TO PERIPHERAL INFLAMMATION AND PERIPHERAL NERVE SECTION

The cutaneous nociceptive response threshold to mechanical and thermal stimulation, the development of hyperalgesia and plasma extravasation after subcutaneous injection of carrageenan and the development of autotomy behaviour after nerve section were assessed in interleukin-6-deficient (IL-6 −/−) and age-matched wild-type (IL-6 +/+) mice. IL-6 −/−mice had significantly lower response threshold to both mechanical and thermal stimulation in comparison to IL-6 +/+controls. Both IL-6 −/−and IL-6 +/+mice developed hyperalgesia to mechanical and thermal stimulation after localized carrageenan injection, but the magnitude of the hyperalgesia was less in the IL-6 −/−than in the IL-6 +/+controls. IL-6 −/−mice also exhibited less plasma extravasation after carrageenan injection. No difference was noted between males and females in basal nociception and inflammatory hyperalgesia. However, female IL-6 −/−mice exhibited autotomy behaviour, a sign of neuropathic pain, significantly more frequently and after a shorter interval following peripheral nerve injury than male IL-6 −/−or male and female IL-6 +/+mice. It is suggested that IL-6 −/−mice exhibited numerous changes in nociceptive responses compared to controls, some of which are sex related. The mechanisms of these changes in relation to null-mutation of the IL-6 gene and the influence of genetic background are discussed.

Characterization of the foot withdrawal response to noxious radiant heat in the rat

The rat foot withdrawal response to noxious radiant heat has been used as a model of nociception that is particularly useful for measurements of unilateral changes in nociceptive responses. The purpose of these studies was to characterize the foot withdrawal response to graded rates of noxious skin heating. Response latencies and both surface and subsurface temperatures produced by 6 different intensities of radiant heat were measured to determine whether response latency is an appropriate measure of nociceptive threshold. With constant intensity heating, the temperature of the skin surface increased as logarithmic function of time, while subsurface temperature increased linearly with time. In contrast, a heating function that linearly increased the temperature at the skin surface increased the subsurface temperature as an exponential function of time. These results and published reports of nociceptive afferent recordings which used similar skin heating parameters, indicate that nociceptive foot withdrawal responses occur at about the same skin temperature as the activation of nociceptors. These results also indicate that since constant intensity heating produces linear increases in the subsurface temperature, then response latency can be used as an accurate measure of changes in nociceptive threshold produced by drug treatments. These observations lead to the conclusion that the foot withdrawal response latency is a valid and useful measure of nociceptive threshold in rodents.

Analgesic actions of local anesthetics and cobalt chloride in the rat brain stem

A low-intensity thermally evoked tail avoidance reflex (LITETAR) was used to study changes in nociceptive response produced by local anesthetics and cobalt chloride microinjected into the dorsal posterior mesencephalic tegmentum (DPMT) of conscious rats. Dose-related prolongation of the LITETAR (e.g., analgesia) was observed when lidocaine, cocaine, and bupivacaine were administered into the DPMT. Analgesic actions were also demonstrated when cobalt chloride was microinjected into the DPMT. The analgesic actions of these different neuronal suppressants provide support for the hypothesis that there exists tonic activity of hyperalgesic processes in the rat brain stem.