Gene expression changes in dorsal root ganglia following peripheral nerve injury: roles in inflammation,cell death and nociception

Subsequent to a peripheral nerve injury, there are changes in gene expression within the dorsal root ganglia in response to the damage. This review selects factors which are well-known to be vital for inflammation, cell death and nociception, and highlights how alterations in their gene expression within the dorsal root ganglia can affect functional recovery. The majority of studies used polymerase chain reaction within animal models to analyse the dynamic changes following peripheral nerve injuries. This review aims to highlight the factors at the gene expression level that impede functional recovery and are hence are potential targets for therapeutic approaches. Where possible the experimental model, specific time-points and cellular location of expression levels are reported.

Ligustrazine inhibits high voltage-gated Ca^(2+) and TTX-resistant Na^+ channels of primary sensory neuron and thermal nociception in the rat:a study on peripheral mechanism

Objective Ligustrazine, also named as tetramethylpyrazine, is a compound purified from Ligusticum chuanxiong hort and has ever been testified to be a calcium antagonist. The present investigation was to determine the antinociceptive effect of ligustrazine and, if any, the peripheral ionic mechanism involved. Methods Paw withdrawal Latency （PWL） to noxious heating was measured in vivo and whole-cell patch recording was performed on small dorsal root ganglion （DRG） neurons. Results Intraplantar injection of ligustrazine （0.5 mg in 25 μl） significantly prolonged the withdrawal latency of ipsilateral hindpaw to noxious heating in the rat. Ligustrazine not only reversibly inhibited high-voltage gated calcium current of dorsal root ganglion （DRG） neuron in dose-dependent manner with IC50 of 1.89 mmol/L, but also decreased tetrodotoxin （TTX） -resistant sodium current in relatively selective and dose-dependent manner with IC50 of 2.49 mmol/L. Conclusion The results suggested that ligustrazine could elevate the threshold of thermal nociception through inhibiting the high-voltage gated calcium current and TTX-resistant sodium current of DRG neuron .in the rat.

Melanocortin-4 Receptor Expression in the Rostral Ventromedial Medulla Involved in Modulation of Nociception in Transgenic Mice

The rostral ventromedial medulla （RVM） is a prominent component of the descending modulatory system involved in the control of spinal nociceptive transmission. In the current study, we investigated melanocortin-4 receptor （MC4R） expression in the RVM, where the neurons involved in modulation of nociception reside. Using a line of mice expressing green fluorescent protein （GFP） under the control of the MC4R promoter, we found a large number of GFP-positive neurons in the RVM [nucleus raphe magnus （NRM） and nucleus gigantocellularis pars a （NGCa）]. Fluorescence immunohisto- chemistry revealed that approximately 10% of MC4R-GFP-positive neurons coexpressed tyrosine hydroxylase, indicating that they were catecholaminergic, whereas 50%-75% of those coexpressed tryp- tophan hydroxylase, indicating that they were serotonergic. Our findings support the hypothesis that MC4R signaling in RVM may modulate the activity of serotonergic sympathetic outflow sensitive to nociceptive signals, and that MC4R signaling in RVM may contribute to the descending modulation of nociceptive transmission.

3D-QSAR Studies on 3-Substituted N-Benzhydryl-nortropane Analogs as Nociception Receptor Agonists

The nociceptin receptor（NOP） has been involved in multiple biological functions, including pain, anxiety, cough, substance abuse, cardiovascular control, and immunity. Thus, selective NOP agonists might have clinical potential for the treatment of related diseases. In the present work, three-dimensional quantitative structure-activity relationship（3D-QSAR） studies were performed on a series of 3-substituted N-benzhydryl-nortropane analogs as NOP agonists using comparative molecular field analysis（Co MFA） and comparative molecular similarity indices analysis（CoM SIA） techniques. The statistically significant models were obtained with 54 compounds in training set by ligand-based atom-by-atom matching alignment. The CoM FA model gave cross-validated coefficient（q2） value of 0.530 using 6 components, non-cross-validated（r2） value of 0.921 with estimated F value of 93.668, and standard error of estimate（SEE） of 0.185. The best Co MSIA model resulted in q2 = 0.592, r2 = 0.945, N = 10, SEE = 0.162, and F = 75.654, based on steric, electrostatic, hydrophobic and hydrogen bond acceptor fields. The predictive ability of the Co MFA and CoM SIA models was further validated using a test set of 18 molecules that were not included in the training set, which resulted in predictive correlation coefficients（r2pred） of 0.551 and 0.637, respectively. Moreover, the CoM FA and CoM SIA contour maps identified the features important for exhibiting potent binding affinities on NOP, and can thus serve as a useful guide for the design of potential NOP agonists.

Pain-related mediators underlie incision-induced mechanical nociception in the dorsal root ganglia

Approximately 50-70% of patients experience incision-induced mechanical nociception after sur- gery. However, the mechanism underlying incision-induced mechanical nociception is still unclear. Interleukin-10 and brain-derived neurotrophic factor are important pain mediators, but whether in- terleukin-10 and brain-derived neurotrophic factor are involved in incision-induced mechanical no- ciception remains uncertain. In this study, forty rats were divided randomly into the incision surgery （n = 32） and sham surgery （n = 8） groups. Plantar incision on the central part of left hind paw was performed under anesthesia in rats from the surgery group. Rats in the sham surgery group re- ceived anesthesia, but not an incision. Yon Frey test results showed that, compared with the sham surgery group, incision surgery decreased the withdrawal threshold of rats at 0.5, 3, 6 and 24 hours after incision. Immunofluorescence staining in the dorsal root ganglia of the spinal cord （L3-5） showed that interleukin-10 and brain-derived neurotrophic factor were expressed mainly on small- and medium-sized neurons （diameter 〈 20 pm and 20-40 pm） and satellite cells in the dorsal root ganglia of the spinal cord （L3-5） in the sham surgery group. By contrast, in the surgery group, high expression of interleukin-10 and brain-derived neurotrophic factor appeared in large-sized neurons （diameter 〉 40 pm） at 6 and 24 hours after incision surgery, which corresponded to the decreased mechanical withdrawal threshold of rats in the surgery group. These experimental findings suggest that expression pattern shift of interleukin-10 and brain-derived neurotrophic factor induced by inci- sion surgery in dorsal root ganglia of rats was closely involved in lowering the threshold to me- chanical stimulus in the hind paw following incision surgery. Pain-related mediators induced by in- cision surgery in dorsal root ganglia of rats possibly underlie mechanical nociception in ipsilateral hind paws.

The Differing Effects of Nociception and Pain Memory on Pain Thresholds in Participants with and without a History of Injury: A Pretest-Posttest Quasi Experimental Study

Purpose: Memory has been identified as an important protective feature to prevent future injury, but its role has yet to be ascertained. The current study aimed to determine whether there was a difference in pressure pain threshold (PPT) responses between participants with a prior history of injury of lower extremity injury (PSI) and those without (NPSI) when exposed to 1) experimental mechanical pain, 2) short-term memory recall of a painful stimulus, or 3) long-term memory of the pain associated with a prior injury. Subjects and Methods: The study used a pretest-posttest quasi-experimental design. A convenience sample of 59 pain-free participants was recruited from an urban university. Twenty-nine PSI and 30 NPSI were stratified into two groups based on their injury history with PPT values measured at baseline and immediately following each of the three experimental conditions. A repeated measure ANCOVA analysis was conducted for each condition to determine whether there was a difference in PPT responses between the two groups. Results: There was a statistically significant difference in PPT values between the two groups when exposed to experimental pain, F(1,57) = 6.010, p = 0.017, partial η2 = 0.095 and with long-term pain memory, F(1,57) = 4.886, p = 0.031, partial η2 = 0.079. There was no statistically significant difference between groups with short-term pain memory, F(1,57) = 3.925, p = 0.052, partial η2 = 0.064. Conclusions: These findings suggest that pain processing may be altered by pain memory, highlighting the role of experience and memory in the rehabilitation process.

Activation of the corticotropin-releasing factor receptor from the basolateral or central amygdala modulates nociception in guinea pigs

Corticotropin-releasing factor (CRF) is a peptide that is released from the hypothalamus into widespread areas of the brain. Evidence has suggested that CRF is involved as a neuromodulator outside of the hypothalamic-pituitary-adrenal axis, playing an important role in fear, anxiety, depression and pain modulation. Our previous report demonstrated that CRF receptor activation in basolateral (BLA) or central nuclei of the amygdala (CeA) produces innate fear in guinea pigs. Inhibition of these receptors via administration of α-helical CRF9-41 (a nonspecific antagonist) into the CeA or BLA decreased innate fear behavior [1]. Additionally, there is strong evidence that emotional behavior and nociception can be modulated simultaneously. The present study was conducted to investigate the involvement of the CRF receptors of the BLA or CeA in nociception in guinea pigs. Guinea pigs were treated with CRF and α-helical CRF>9-41> in three different doses or injected with α-helical CRF9-41 preceded by CRF into the BLA or CeA, and they were evaluated using the hot plate test. Our findings indicated that activation of CRF receptors in the BLA and in the CeA promoted antinociception, and this effect was reversed by preadministration of α-helical CRF9-41 in the same area. The treatment with α-helical CRF>9-41> per se into the BLA and CeA did not alter nociception. Thus, nociception modulation occurs in a phasic manner, whereas defensive behavior can occur tonically because the α-helical CRF9-41 did not cause any modification on the index of analgesia in the hot plate test but did reduce innate fear behavior [1].

Bidirectional regulation of the brain-gut-microbiota axis following traumatic brain injury

Traumatic brain injury is a prevalent disorder of the central nervous system.In addition to primary brain parenchymal damage,the enduring biological consequences of traumatic brain injury pose long-term risks for patients with traumatic brain injury;however,the underlying pathogenesis remains unclear,and effective intervention methods are lacking.Intestinal dysfunction is a significant consequence of traumatic brain injury.Being the most densely innervated peripheral tissue in the body,the gut possesses multiple pathways for the establishment of a bidirectional“brain-gut axis”with the central nervous system.The gut harbors a vast microbial community,and alterations of the gut niche contribute to the progression of traumatic brain injury and its unfavorable prognosis through neuronal,hormonal,and immune pathways.A comprehensive understanding of microbiota-mediated peripheral neuroimmunomodulation mechanisms is needed to enhance treatment strategies for traumatic brain injury and its associated complications.We comprehensively reviewed alterations in the gut microecological environment following traumatic brain injury,with a specific focus on the complex biological processes of peripheral nerves,immunity,and microbes triggered by traumatic brain injury,encompassing autonomic dysfunction,neuroendocrine disturbances,peripheral immunosuppression,increased intestinal barrier permeability,compromised responses of sensory nerves to microorganisms,and potential effector nuclei in the central nervous system influenced by gut microbiota.Additionally,we reviewed the mechanisms underlying secondary biological injury and the dynamic pathological responses that occur following injury to enhance our current understanding of how peripheral pathways impact the outcome of patients with traumatic brain injury.This review aimed to propose a conceptual model for future risk assessment of central nervous system-related diseases while elucidating novel insights into the bidirectional effects of the“brain-gut-microbiota axis.”

Effect of quantitative consciousness index on seizure parameters during electroconvulsive therapy in patients with major depressive disorder

BACKGROUND Electroconvulsive therapy(ECT)is both an effective treatment for patients with major depressive disorder(MDD)and a noxious stimulus.Although some studies have explored the effect of sedation depth on seizure parameters in ECT,there is little research on the noxious stimulation response to ECT.In this study,we used two electroencephalography(EEG)-derived indices,the quantitative consci-ousness(qCON)index and quantitative nociceptive(qNOX)index,to monitor sedation,hypnosis,and noxious stimulation response in patients with MDD undergoing acute ECT.METHODS Patients with MDD(n=24)underwent acute bilateral temporal ECT under propofol anesthesia.Before ECT,the patients were randomly divided into three groups according to qCON scores(qCON60-70,qCON50-60,and qCON40-50).Continuous qCON monitoring was performed 3 minutes before and during ECT,and the qCON,qNOX,vital signs,EEG seizure parameters,and complications during the recovery period were recorded.The 24-item Hamilton Rating Scale for Depression,Zung’s Self-rating Depression Scale,and Montreal Cognitive Asse-ssment scores were evaluated before the first ECT session,after the fourth ECT session,and after the full course of ECT.RESULTS A total of 193 ECT sessions were performed on 24 participants.The qCON index significantly affected the EEG seizure duration,peak mid-ictal amplitude,and maximum heart rate during ECT(P<0.05).The qNOX index significantly affected the post-ictal suppression index(P<0.05).Age,number of ECT sessions,and anesthetic-ECT time intervals also had a significant effect on EEG seizure parameters(P<0.05).However,there were no significant differences in complications,24-item Hamilton Rating Scale for Depression scores,Zung’s Self-rating Depression Scale scores,or Montreal Cognitive Assessment scores among the three groups(P>0.05).CONCLUSION Electrical stimulation at a qCON index of 60-70 resulted in better EEG seizure parameters without increasing complications in patients with MDD undergoing bilateral temporal ECT under propofol anesthesia.

KCNQ Channels in the Mesolimbic Reward Circuit Regulate Nociception in Chronic Pain in Mice

Mesocorticolimbic dopaminergic(DA) neurons have been implicated in regulating nociception in chronic pain, yet the mechanisms are barely understood. Here, we found that chronic constructive injury(CCI) in mice increased the firing activity and decreased the KCNQ channel-mediated M-currents in ventral tegmental area(VTA) DA neurons projecting to the nucleus accumbens(NAc). Chemogenetic inhibition of the VTA-to-NAc DA neurons alleviated CCI-induced thermal nociception.Opposite changes in the firing activity and M-currents were recorded in VTA DA neurons projecting to the medial prefrontal cortex(mPFC) but did not affect nociception. In addition, intra-VTA injection of retigabine, a KCNQ opener, while reversing the changes of the VTA-to-NAc DA neurons, alleviated CCI-induced nociception, and this was abolished by injecting exogenous BDNF into the NAc.Taken together, these findings highlight a vital role of KCNQ channel-mediated modulation of mesolimbic DA activity in regulating thermal nociception in the chronic pain state.

Effects of a non-selective TRPC channel blocker, SKF-96365, on melittin-induced spontaneous persistent nociception and inflammatory pain hypersensitivity

Objective Melittin is the main peptide in bee venom and causes both persistent spontaneous nociception and pain hypersensitivity. Our recent studies indicated that both transient receptor potential （TRP） vanilloid receptor 1 （TRPV 1） and canonical TRPs （TRPCs） are involved in mediating the melittin-induced activation of different subpopulations of pri- mary nociceptive cells. Here, we further determined whether TRPC channels are involved in melittin-induced inflamma- tory nociceptive responses in behavioral assays. Methods The anti-nociceptive and anti-hyperalgesic effects of localized peripheral administration of three doses of the non-selective TRPC antagonist, SKF-96365 （1-{[3-[3-（4-methoxyphenyl） propoxy]-4-methoxyphenyl}-lH-imidazole hydrochloride）, were evaluated in melittin tests. Pain-related behaviors were rated by counting the number of paw flinches, and measuring paw withdrawal thermal latency （s） and paw withdrawl me- chanical threshold （g）, over a l-h time-course. Results Localized peripheral SKF-96365 given before melittin prevented, and given after melittin significantly suppressed, the melittin-evoked persistent spontaneous nociception. Pre-blockade and post-suppression of activation of primary nociceptive activity resulted in decreased hypersensitivity to both thermal and mechanical stimuli applied to the primary injury site of the ipsilateral hindpaw, despite dose-effect differences between thermal and mechanical hyperalgesia. However, local administration of SKF-96365 into the contralateral hindpaw had no significant effect on any pain-associated behaviors. In addition, SKF-96365 had no effect on baseline threshold for either thermal or mechanical sensitivity under normal conditions. Conclusion Besides TRPV1, SKF-96365-sensitive TRPC channels might also be involved in the pathophysiological processing of melittin-induced inflammatory pain and hyper- sensitivity. Therapeutically, SKF-96365 is equally effective in preventing primary thermal and mechanical hyperalgesia as well as persistent spontaneous nociception. However, this drug is likely to be more effective in the relief of thermal hyper- algesia than mechanical hyperalgesia when applied 5 min after establishment of primary afferent activation.

Peripheral Leptin Signaling Mediates Formalin-Induced Nociception

Accumulating evidence suggests that obesity is associated with chronic pain. However, whether obesity is associated with acute inflammatory pain is unknown. Using a well-established obese mouse model induced by a highfat diet, we found that:(1) the acute thermal pain sensory threshold did not change in obese mice;(2) the model obese mice had fewer nociceptive responses in formalininduced inflammatory pain tests; restoring the obese mice to a chow diet for three weeks partly recovered their pain sensation;(3) leptin injection induced significant phosphorylation of STAT3 in control mice but not in obese mice,indicating the dysmodulation of topical leptin–leptin receptor signaling in these mice; and(4) leptin–leptin receptor signaling-deficient mice(ob/ob and db/db) or leptin–leptin receptor pathway blockade with a leptin receptor antagonist and the JAK2 inhibitor AG 490 in wildtype mice reduced their nociceptive responses in formalin tests. These results indicate that leptin plays a role in nociception induced by acute inflammation and that interference in the leptin–leptin receptor pathway could be a peripheral target against acute inflammatory pain.

Lifting the veil on the keratinocyte contribution to cutaneous nociception

Cutaneous nociception is essential to prevent individuals from sustaining injuries.According to the conventional point of view,the responses to noxious stimuli are thought to be exclusively initiated by sensory neurons,whose activity would be at most modulated by keratinocytes.However recent studies have demonstrated that epidermal keratinocytes can also act as primary nociceptive transducers as a supplement to sensory neurons.To enlighten our understanding of cutaneous nociception,this review highlights recent and relevant findings on the cellular and molecular elements that underlie the contribution of epidermal keratinocytes as nociceptive modulators and noxious sensors,both under healthy and pathological conditions.

Emerging roles of GPR109A in regulation of neuroinflammation in neurological diseases and pain

Neuroinflammation plays a critical role in the pathological process of multiple neurological disorders and pathological pain conditions.GPR109A,a Gi protein-coupled receptor,has emerged as an important therapeutic target for controlling inflammation in various tissues and organs.In this review,we summarized current data about the role of GPR109A in neuroinflammation.Specifically,we focused on the pharmacological features of GPR109A and signaling pathways used by GPR109A to ameliorate neuroinflammation and symptoms in Alzheimer’s disease,Parkinson’s disease,multiple sclerosis,stroke,and pathological pain conditions.

Stem cells and pain

ain can be defined as an unpleasant sensory and emotional experience caused by either actual or potential tissue damage or even resemble that unpleasant experience.For years,science has sought to find treatment alternatives,with minimal side effects,to relieve pain.However,the currently available pharmacological options on the market show significant adverse events.Therefore,the search for a safer and highly efficient analgesic treatment has become a priority.Stem cells(SCs)are non-specialized cells with a high capacity for replication,self-renewal,and a wide range of differentiation possibilities.In this review,we provide evidence that the immune and neuromodulatory properties of SCs can be a valuable tool in the search for ideal treatment strategies for different types of pain.With the advantage of multiple administration routes and dosages,therapies based on SCs for pain relief have demonstrated meaningful results with few downsides.Nonetheless,there are still more questions than answers when it comes to the mechanisms and pathways of pain targeted by SCs.Thus,this is an evolving field that merits further investigation towards the development of SCbased analgesic therapies,and this review will approach all of these aspects.

Acupuncture inhibition on neuronal activity of spinal dorsal horn induced by noxious colorectal distention in rat

AIM: To observe how acupuncture stimulation influences the visceral nociception in rat and to clarify the interactions between acupuncture or somatic input and visceral nociceptive inputs in the spinal dorsal horn. These will provide scientific base for illustrating the mechanism of acupuncture on visceral pain.METHODS: Experiments were performed on SpragueDawley rats and the visceral nociceptive stimulus was generated by colorectal distention (CRD). Unit discharges from individual single neuron were recorded extracellularly with glass-microelectrode in L1-3 spinal dorsal horn.Acupuncture stimulation was applied at contralateral heterotopic acupoint and ipsilateral homotopic acupoint,both of which were innervated by the same segments that innervate also the colorectal-gut.RESULTS: The visceral nociception could be inhibited at the spinal level by the heterotopic somatic mechanical stimulation and acupuncture. The maximal inhibition was induced by acupuncture or the somatic noxious stimulation at spinal dorsal horn level with inhibiting rate of 68.61%and 60.79%, respectively (P＜0.01 and ＜0.001). In reversible spinalized rats (cervical-thoracic cold block)both spontaneous activity and responses to CRD increased significantly in 16/20 units examined, indicating the existence of tonic descending inhibition. The inhibition of acupuncture on the noxious CRD disappeared totally in the reversible spinalized rats (P＜0.001).CONCLUSION: The inputs of noxious CRD and acupuncture may interact at the spinal level. The nociceptive visceral inputs could be inhibited by acupuncture applied to hetero-topic acupoint. The effect indicates that the spinal dorsal horn plays a significant role in mediating the inhibition of acupuncture and somatic stimulation on the neuronal response to the noxious visceral stimulation and the inhibition is modulated by upper cervical cord and/or supra-spinal center.

Evidence and explanation for the involvement of the nucleus accumbens in pain processing

The nucleus accumbens(NAc)is a subcortical brain structure known primarily for its roles in pleasure,reward,and addiction.Despite less focus on the NAc in pain research,it also plays a large role in the mediation of pain and is effective as a source of analgesia.Evidence for this involvement lies in the NAc’s cortical connections,functions,pharmacology,and therapeutic targeting.The NAc projects to and receives information from notable pain structures,such as the prefrontal cortex,anterior cingulate cortex,periaqueductal gray,habenula,thalamus,etc.Additionally,the NAc and other pain-modulating structures share functions involving opioid regulation and motivational and emotional processing,which each work beyond simply the rewarding experience of pain offset.Pharmacologically speaking,the NAc responds heavily to painful stimuli,due to its high density ofμopioid receptors and the activation of several different neurotransmitter systems in the NAc,such as opioids,dopamine,calcitonin gene-related peptide,γ-aminobutyric acid,glutamate,and substance P,each of which have been shown to elicit analgesic effects.In both preclinical and clinical models,deep brain stimulation of the NAc has elicited successful analgesia.The multi-functional NAc is important in motivational behavior,and the motivation for avoiding pain is just as important to survival as the motivation for seeking pleasure.It is possible,then,that the NAc must be involved in both pleasure and pain in order to help determine the motivational salience of positive and negative events.

The central nucleus of amygdala is involved in tolerance to the antinociceptive effect of NSAIDs

Aim: Repeated microinjections of non-opioid an-algesics into the midbrain periaqueductal gray matter and rostral ventro-medial medulla induce antinociception with development of tolerance. Antinociception following systemic administra-tion of non-steroidal anti-inflammatory drugs (N SAIDs) also exhibit tolerance. Presently our aim was to investigate the development of tolerance to the antinociceptive effects of NSAIDs analgine, ketorolac, and xefocam microinjected into cen-tral nucleus of amygdala (Ce) in rats. Methods: Under anesthesia with thiopental a stainless steel guide cannula was stereotaxically implanted uni- laterally or bilaterally into the Ce using stereo-taxic atlas coordinates, and anchored to the cra- nium by dental cement. Five days after surgery, 3 μl of these NSAIDs were injected via the injec-tion cannula while the rat was gently restrained. Twenty min post microinjection, i.e. 10-min be-fore the peak of the drugs’ effect is normally rea- ched, animals were tested with tail flick (TF) and hot plate (HP) tests. On the 5th experimental day all animals received a Ce microinjection of mor-phine. Results: Daily microinjection of NSAIDs into the Ce uni- or bilaterally, produced antino-ciception with development of complete toler-ance over a 5-day period. Following the treat-ment period, morphine microinjection into the Ce failed to elicit antinociception, indicating cro- ss-tolerance to the antinociceptive effect of N SAIDs. In other words, the “non-opioid tolerant” rats showed cross-tolerance to morphine. Con-clusions: Our data confirmed the suggestion that NSAIDs interact with endogenous opioid systems, which likely play a key role in the development of tolerance to the antinociceptive effects of NSA IDs.

Pain in chronic pancreatitis: Managing beyond the pancreatic duct

Chronic pancreatitis(CP)continues to be a clinical challenge.Persistent or recurrent abdominal pain is the most compelling symptom that drives patients to seek medical care.Unfortunately,in spite of using several treatment approaches in the clinical setting,there is no single specific treatment modality that can be earmarked as a cure for this disease.Traditionally,ductal hypertension has been associated with causation of pain in CP;and patients are often subjected to endotherapy and surgery with a goal to decompress the pancreatic duct.Recent studies on humans(clinical and laboratory based)and experimental models have put forward several mechanisms,including neuroimmune alterations,which could be responsible for pain.This might explain the partial or no response to single modality treatment in a significant proportion of patients.The current review discusses the recent concepts of pain generation in CP and evidence based therapeutic approaches(other than ductal decompression)to handle persistent or recurrent pain.We focus primarily on parenchymal and neural components;and discuss the role of antioxidants and the existing controversies,drugs that interfere with neural transmission,pancreatic enzyme supplementation,celiac neurolysis,and pancreatic resection procedures.The review concludes with the treatment approach that we follow at our institute.

Anti-inflammatory,analgesic and antipyretic activity of methanolic Tecomaria capensis leaves extract

Objective:To evaluate the analgesic,anti-inflammatory and antipyretic activity of methanolic Tecomaria capensis(T.capensis) leaves extract using different models in rats.Methods: Methanolic T.capenssis leaves extract(100,300,1000 and 2000 mg/kg body weight) was given to rats orally to observe acute toxicity,and observed for 14 days.Analgesic activity was evaluated using tail immersion and formalin induced paw licking models in rats.Anti-inflammatory activity was evaluated using carrageenan induced paw edema model in rats.Antipyretic activity was evaluated using brewer's yeast induced pyrexia model in rats.Methanolic T.capensis leaves extract were given at dose of 100,200 and 500 mg/kg p.o.Results:Results demonstrated that the no mortality was reported even after 14 days.This indicated that the methanol extract was safe up to a single dose of 2000 mg/kg body weight Methanolic 71 capensis leaves extract(100,200 and 500 mg/kg p.o.) significantly increased the latency period in the tail immersion test,reduced the licking time in both the neurogenic and inflammatory phases in the formalin test.Methanolic T.capensis leaves extract(100,200 and 500 mg/kg p.o.) significantly prevented increase in volume of paw edema. Methanolic 7.capensis leaves extract at the doses of(100,200 and 500 mg/kg p.o.) significantly decreased the rectal temperature of the rats.Conclusions:This study exhibites that methanolic T. capensis leaves extract possesses analgesic,anti-inflammatory and antipyretic activity which may be mediated by the central and peripheral mechanisms.