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Abnormal sensation and pain are major dose-limiting factors in cancer chemotherapy with vincristine. In this study, we have adapted a model of this condition by using repeated daily intraperitoneal injections of vincristine in rats. Mechanical allodynia and hyperalgesia without change in responses to thermal stimuli were first observed following 5-8 days of vincristine treatment (0.1mg/kg/day) and then persisted throughout the remainder of the treatment interval (2-3 weeks). Electrophysiological recording from wide dynamic range (WDR) neurons in the lumbar (L4-L5) spinal dorsal horn in hyperalgesic rats demonstrated significantly increased spontaneous activity and after-discharges to noxious mechanical stimuli (von Frey filaments with a bending force greater than 58.02mN, skin compression 1.3 and 3N, 1mm(2)), increased acute A- and C-fiber responses, after-discharges and abnormal 'wind-up' to electrical stimuli (5mA, 2ms) at 0.1Hz applied across the receptive field. These results suggest a state of central sensitization develops in spinal WDR neurons with repeated vincristine treatment that contributes to the spontaneous pain and hyperalgesia seen in patients and the hyperresponsiveness to sensory stimuli seen in animals treated with vincristine.

Treatment of pain in newborns is associated with problematic drug side effects. Previous studies demonstrate that an intraoral infusion of sucrose and other sweet components of mother's milk are effective in alleviating pain in infant rats and humans. These findings are of considerable significance, as sweet tastants are used in pain and stress management in a number of clinical procedures performed in human infants. The ability of sweet stimuli to induce analgesia is absent in adult rats, suggesting that this is a developmentally transient phenomenon. However, the age range over which intraoral sucrose is capable of producing analgesia is not known. We investigated the effects of intraoral sucrose (7.5%) on nocifensive withdrawal responses to thermal and mechanical stimuli in naive and inflamed rats at postnatal days (P) P0-21. In some rats, Complete Freund's adjuvant (CFA) was injected in a fore- or hindpaw to produce inflammation. In non-inflamed animals, for noxious thermal stimuli, sucrose-induced analgesia emerged at P3, peaked at P7-10, then progressively declined and was absent at P17. For mechanical forepaw stimuli, sucrose-induced analgesia emerged, and was maximal at approximately P10, then declined and was absent at P17. By contrast, maximal sucrose-induced analgesia for mechanical hindpaw stimuli was delayed (P13) compared to that for the forepaw, although it was also absent at P17. In inflamed animals, sucrose reduced hyperesthesia and hyperalgesia assessed with mechanical stimuli. Sucrose-induced analgesia in inflamed animals was initially present at P3 for the forepaw and P13 for the hindpaw, and was absent by P17 for both limbs. Intraoral sucrose produced significantly greater effects on responses in fore- and hindpaws in inflamed rats than in naive rats indicating that it reduces hyperalgesia and allodynia beyond its effects on responses in naive animals. These findings support the hypothesis that sucrose has a selective influence on analgesic mechanisms and that an enhanced sucrose effect takes place in hyperalgesic, inflamed animals as compared to naive animals. Taken together, these results indicate that intraoral sucrose alleviates transient pain in response to thermal and mechanical stimuli, and also effectively reduces inflammatory hyperalgesia and allodynia. Sucrose-induced analgesia is age-dependent and limited to the pre-weaning period in rats. The age-dependency of sucrose-induced analgesia and its differential maturation for the fore- and hindpaw may be due to developmental changes in endogenous analgesic mechanisms and developmental modulation of the interaction between gustatory and pain modulatory pathways.

To clarify the mechanisms of allodynia we have examined whether 'wind-up' of nociceptive withdrawal reflexes (NWR), a phenomenon characteristic of nociceptive C fiber spinal processing, can be mimicked by stimulation of tactile A beta fibers in monoarthritic decerebrate spinal rats. Knee joint monoarthritis was induced by carrageenan/kaolin under halothane anaesthesia 5 h before recordings. In arthritic, but not in control rats, wind-up of NWR of the semitendinosus muscle could be evoked by repeated stimulation of A beta fibres. By contrast, peroneus longus reflexes did not exhibit marked wind-up. Bicuculline (0.03-0.3 mg/kg, i.v.) dose-dependently inhibited this wind-up. Hence, reflex wind-up can be elicited by tactile A beta fibers in arthritis rats through a GABAA dependent mechanism.

Time-dependent changes of nociceptive inhibition of hindlimb withdrawal reflex (WR) pathways were investigated in acute decerebrate spinal rats. Electromyographic recordings of WR of peroneus longus and extensor digitorum longus muscles were made. For each muscle, both short and long latency WR evoked by subcutaneous electrical stimulation and WR evoked by noxious pinch could be inhibited by noxious CO2 laser stimulation of a specific skin area of the ipsilateral hindlimb. The inhibitory effects and size of the inhibitory receptive fields increased spontaneously between two- and three-fold during the first 12 h after spinalization. The functional and possible clinical significance of the strengthened nociceptive inhibitory control and mechanisms underlying the changes of this control after spinal transection are discussed.

In the present study, partial lesions of the lower thoracic spinal cord in rats anaesthetized with halothane and nitrous oxide were made in order to elucidate which of the spinal funiculi mediate a nociceptive C fibre input to SI. Field potentials evoked by noxious CO2-laser stimulation were recorded in the left SI. Nociceptive C fibre input from the right hindpaw to SI was propagated by the dorsal funiculi (DF) and the left and right lateral funiculi (LLF and RLF, respectively). Nociceptive C fibre input from the left hindpaw was propagated by LLF and RLF, but not DF. Input from the hindpaws mediated by LLF and RLF caused widespread surface positive potentials throughout most of SI, although potentials in the hindlimb area tended to be larger than those in other areas of SI. Input from the right hindpaw mediated by DF caused surface positive potentials mainly in the hindlimb area of SI. Intracortically, the field potentials reversed polarity in the superficial laminae and had maximal negative amplitudes in laminae III-IV (input transferred by DF and LLF) and in laminae V-VI (input transferred by LLF and RLF). It is concluded that there are multiple spinal pathways which can transfer information from cutaneous nociceptive C fibres to SI in the rat. These ascending pathways seem to activate partly different thalamo-cortical systems.

In the present study, noxious thermal stimulation of the skin with short pulses of CO2-laser radiation was used to identify a cutaneous nociceptive C fibre input to SI and investigate the organization of this input in halothane-nitrous oxide anaesthetized rats. Noxious CO2-laser stimulation of the glabrous skin of the hindpaw consistently evoked late surface positive field potentials in SI (average onset latency 226 ms, peak latency 296 ms). It was demonstrated that these late potentials were evoked by an input from nociceptive C fibres, using a combination of latency measurements, anodal block of A fibre conduction and graded intensities of stimulation. Compared to the tactile evoked potentials in SI, the nociceptive C fibre evoked potentials were more widespread and exhibited a crude somatotopical organization. Intracortically, both tactile and nociceptive C fibre evoked potentials reversed polarity and exhibited a peak negativity in laminae III-IV. The nociceptive C fibre evoked potentials exhibited an additional peak negativity in laminae V-VI. The latter potential had a different time course as compared to the nociceptive C fibre potential evoked in laminae III-IV. In conclusion, an input from cutaneous nociceptive C fibres to SI was demonstrated for the first time in animal experiments. The input to SI from tactile receptors and cutaneous C nociceptors were differently organized.

The spatial organization of the cutaneous input to hindlimb withdrawal reflexes was studied in spinalized, decerebrated, unanesthetized rats. Reflex activity in plantar flexors of the digits, pronators of the foot, dorsiflexors of the digits, and/or the ankle and flexors of the knee was recorded with electromyographic techniques for up to 12 h after spinalization. Graded mechanical (pinch) and thermal stimulation (CO2 laser) of the skin were used. Reflexes were absent ("spinal shock") during approximately 10-20 min after spinalization. The reflex thresholds for pinch and CO2 laser stimulation then decreased considerably during the following 5-8 h. After this time, even mild pressure (less than 0.1 N/mm2) on the skin was sufficient to evoke a reflex in most muscles. During the period from about 0.5-3 h after spinalization, the nociceptive receptive field of each muscle usually corresponded to the area of the skin withdrawn by the muscle. Maximal responses were evoked from the area of the receptive field maximally withdrawn. During this period, responses to innocuous pinch were evoked mainly from the most sensitive area of the receptive fields. Concomitant with the decrease in reflex thresholds, the nociceptive receptive fields expanded for all muscles, often to include areas of the skin not withdrawn by the muscles. For most muscles, reflexes on tactile stimuli were eventually elicited from the entire receptive fields. The receptive fields for thermonociceptive and mechanonociceptive inputs were similar in most muscles. The interossei muscles were exceptional in that they responded very weakly to thermal stimulation. It is concluded that there are neuronal networks in the spinal cord that translate cutaneous nociceptive and tactile input into a withdrawal. However, the control exerted by descending pathways is necessary to maintain a functionally adequate excitability in these reflex pathways and an appropriate size for their receptive fields.

Yu Chen Xu,1,&ast; Qiu Qin Wang,1,&ast; Meng Yuan Chen,1 Yu Jie Gao,1 Jia Yi Wang,1 Hao Tian Ge,1 Heng Weng,1 Ju Ping Chen,2 Gui Hua Xu1 1School of Nursing, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China; 2Department of Neurology, Changshu Hospital of Traditional Chinese Medicine, Suzhou, 215500, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gui Hua Xu, School of Nursing, Nanjing University of Chinese Medicine, Nanjing, 210023, People’s Republic of China, Email 7115@njucm.edu.cn Ju Ping Chen, Department of Neurology, Changshu Hospital of Traditional Chinese Medicine, Suzhou, 215500, People’s Republic of China, Email 1523515573@qq.comPurpose: Pain is a common yet undertreated symptom of Parkinson’s disease (PD). This study investigated the effect of Gua Sha therapy on pain in patients with PD.Patients and Methods: A total of 56 PD patients with pain were randomized into either the experimental group (n=28), receiving 12 sessions of Gua Sha therapy, or the control group (n=28) without additional treatment. Participants underwent assessment at baseline, after the twelfth invention, and at the 2-month follow-up timepoints. The primary outcome was KPPS and VAS. Secondary outcomes included UPDRS I–III, PDSS-2, HADS, PDQ-39, and blood biomarkers (5-HT, IL-8, IL-10).Results: The experimental group reported a significant improvement in pain severity, motor functions, affective disorder, and sleep quality (P < 0.05). Furthermore, increasing trends in both 5-HT and IL-10, as well as decreasing trends in IL-8 were observed. No serious adverse events occurred.Conclusion: The preliminary findings suggest that Gua Sha therapy may be effective and safe for alleviating pain and improving other disease-related symptoms in PD patients.Keywords: Parkinson’s disease, pain, Gua Sha therapy, randomized controlled trial

A recent article in Anaesthesia examined the association between pre-operative depression and postoperative pain outcomes. The study found that pre-operative depression was associated with worse pain severity in both the early postoperative period and later follow-up. However, the degree of improvement in pain scores from before surgery to 1-2 years after surgery was similar between depressed and non-depressed patients. The article also highlighted some methodological limitations in the study, including potential bias due to overestimation of sample size. The authors suggest that further evidence is needed before routine screening for depression and comprehensive psychological interventions are implemented in clinical practice. [Extracted from the article]

Abstract: Glutamatergic synaptic transmission is a dynamic process determined by the amount of glutamate released by presynaptic sites, the clearance of glutamate in the synaptic cleft, and the properties of postsynaptic glutamate receptors. Clearance of glutamate in the synaptic cleft depends on passive diffusion and active uptake by glutamate transporters. In this study, we examined the role of glial glutamate transporter 1 (GLT-1) in spinal sensory processing. Excitatory postsynaptic currents (EPSCs) of substantia gelatinosa neurons recorded from spinal slices of young adult rats were analyzed before and after GLT-1 was pharmacologically blocked by dihydrokainic acid. Inhibition of GLT-1 prolonged the EPSC duration and the EPSC decay phase. The EPSC amplitudes were increased in neurons with weak synaptic input but decreased in neurons with strong synaptic input upon inhibition of GLT-1. We suggest that presynaptic inhibition, desensitization of postsynaptic AMPA receptors, and glutamate “spillover” contributed to the kinetic change of EPSCs induced by the blockade of GLT-1. Thus, GLT-1 is a key component in maintaining the spatial and temporal coding in signal transmission at the glutamatergic synapse in substantia gelatinosa neurons. [Copyright &y& Elsevier]

Abstract: C fiber dorsal root reflexes (DRR) contribute to neurogenic inflammation and possibly also to touch-evoked pain (allodynia) induced by intradermal capsaicin. The responses of C fibers in the sural nerve to graded mechanical stimuli before and following intradermal capsaicin were studied in 39 adult male rats. Two-thirds of 111 fibers were without spontaneous activity, while the remaining fibers averaged 1.41±0.25 spontaneous antidromic spikes per second. Among the quiescent C fibers only two had excitatory receptive fields, whereas the active C fibers showed three patterns of activity, an excitatory response, an inhibitory response, or no response to mechanical stimulation. The excitatory responses were to high intensity mechanical stimuli alone, while inhibitory responses were evoked in a graded fashion by both noxious and innocuous mechanical stimuli. Intradermal injection of capsaicin increased spontaneous and evoked DRRs in all C fibers with excitatory responses to mechanical stimuli, but none acquired responses to innocuous stimuli. Capsaicin initially produced inhibition of spontaneous activity in C fibers with inhibitory or no receptive fields, but this later resumed and achieved a rate higher than baseline. Mechanical stimuli re-applied following the resumption of spontaneous discharges failed to produce any response. Spontaneous DRRs were increased by topical application of 1 mM β-alanine (a competitive antagonist for GABA transporters) and abolished by ipsilateral spinal nerve L5 lesion, verifying antidromic origin. The role of C fiber DRRs in normal sensory transmission and during hyperalgesia is discussed. [Copyright &y& Elsevier]

In this study ibuprofen (50.0 mg/kg, i.p.), rofecoxib (10.0 mg/kg, i.p.) and thalidomide (50.0 mg/kg, oral) were shown to prevent vincristine-induced mechanical hyperalgesia. Sprague-Dawley rats were injected every other day with vincristine (0.1 mg/kg) over 13 days. The animals were cotreated daily with vehicle (saline), ibuprofen, rofecoxib or thalidomide throughout the period of vincristine treatment. Mechanical withdrawal threshold to punctuate and radiant heat stimuli were determined prior to and then on alternate days throughout the treatment period. Vincristine vehicle-treated animals developed marked mechanical hyperalgesia from day 5 of chemotherapy and this lasted until the end of the experiment. Thermal thresholds were not altered by the administration of vincristine vehicle. Animals in the vincristine vehicle group neither gained nor lost weight during the treatment period. All three active drugs showed an antihyperalgesic effect on the responses to mechanical stimulation of the hind paw that was significant from day 5 for ibuprofen and thalidomide and from day 7 for rofecoxib. Thermal thresholds increased after the administration of both the NSAIDs and thalidomide. Rofecoxib was the only drug to show any beneficial effect in protecting the animals from failure to gain body weight. [ABSTRACT FROM AUTHOR]