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Anterior external arcuate fibers (AEAF) are efferents of the arcuate nuclei, which are located on the ventral surface of pyramids. Several types of fibre bundles superficial to the pyramids have been described in early and mid 20th century. Recently, few of these have been studied in detail. Objective of present study was to observe the morphology of AEAF in the Indian population. Distinct AEAF were noted in 13 out of 50 brain specimens. Based on their relation to olive, AEAF were further classified as supraolivary, preolivary and supraolivary fibers and their prevalence noted as 25%, 15%, and 9% respectively. Supraolivary and preolivary fibers were present together in 9 brainstem sides, while co-presence of preolivary and circumolivary fibers was noted in only 1 side. All three types of fibres were observed together in 5 brainstem sides. When present bilaterally, supraolivary and preolivary fibers were seen in 92.30% and 66.66% of brainstem respectively, while circumolivary fibers were seen bilaterally in 28.57% of brainstem. Supraolivary and circumolivary fibers exhibited variable morphology as single, double and multiple fiber bundles. Morphometric analysis revealed presence of thicker supraolivary fiber bundle on right side, while thicker circumolivary fiber bundles were noted on left side. Present study will add to knowledge of this variable fiber bundle pattern, which has been reported to play an important role in regulation of crucial physiological functions such as breathing and cardiorespiratory mechanisms. These observations open avenues for further research into developmental factors involved in migration of neurons from the rhombic lip.

Background: The study purpose was to analyze the characteristics of patients presenting for evaluation of pediatric trigger thumb over a 20-year period and to determine what factors were associated with operative versus nonoperative management., Methods: All patients evaluated for a pediatric trigger thumb by 1 of 2 hand surgeons at our institution between January 1, 2000, and August 31, 2021, were retrospectively reviewed. Data were collected, including patient demographics, laterality, patient age and stage of triggering at presentation, treatment recommendations, age at surgery (if performed), and complications. Comparison was made based on age group (<2 years, 2-5 years, and >5 years). Subgroup analysis was performed for patients who had alternative treatments recommended prior to surgery., Results: A total of 381 patients (468 thumbs) were identified. The average age at presentation was 3.1 years, 76% were stage IV locked trigger thumbs, and 78% underwent surgery. Patients below 2 years were more likely to have bilateral involvement and have nonoperative management recommended prior to surgery. Those below 5 years were more likely to present with stage IV triggering. Patients who presented with a stage IV trigger thumb and had an initial alternative treatment were more likely to go on to have surgery. The total complication rate was 5.3%., Conclusions: These findings are helpful in counseling families and better understanding this patient population. We recommend early surgical intervention, rather than observation or splinting, for patients with stage IV trigger thumbs who can safely undergo anesthesia., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Opioids such as morphine are used for treating moderate to severe pain. However, they also produce adverse effects such as nausea, constipation, addiction, and respiratory depression. Thus, other suitable analgesics need to be identified. Somatostatin is an inhibitory neuropeptide that modulates the transmission of pain. However, the half-life of somatostatin is short. In the present study, the antinociceptive effect of octreotide (a stable long-acting analog of somatostatin) was evaluated in rats with acute inflammatory pain., Methods: Sprague Dawley rats ( n = 42) were divided into control ( n = 6) and carrageenan injected groups ( n = 36). The carrageena group was divided into three equal subgroups and treated with saline, morphine (10 mg/kg), and octreotide (3 µg). Rats belonging to each subgroup ( n = 12) were again randomly divided into two equal sets. They were subjected to (a) behavioral evaluation of pain (allodynia) and estimation of paw edema, followed by immunohistochemical analysis of the expression of somatostatin type 2 receptor (sst2r) in the spinal cord and (b) estimation of open-field activity. Allodynia and paw edema were measured by von Frey filaments and plethysmometer, respectively, at 3 and 4 h after carrageenan injection. Expression of sst2r was examined after 24 hours, whereas open-field activity was evaluated after 3 hours., Results: In comparison to the saline-treated group, allodynia was partially attenuated by octreotide, though this was almost completely reversed by morphine. Paw edema was unaffected by octreotide, though it was marginally increased by morphine. This was not related to increased activity of rats, following relief from pain. Immunohistochemistry revealed a significant increase in the expression of sst2r in saline-treated rats, but a decrease in other groups., Conclusion: Octreotide has an antinociceptive effect, which was less than morphine. Increased edema following morphine could result from venodilation. Variations in the sst2r expression suggest its involvement in pain modulation at the spinal level. This information may have clinical relevance., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© 2021 Indian Academy of Neurosciences (IAN).)

Contribution of emotional valence and arousal to attentional processing over time is not fully understood. We employed a rapid serial visual paradigm (RSVP) in three experiments to investigate the role of valence and arousal. In three experiments, participants had to identify the expression of the two targets (experiment 1 - happy and angry; experiment 2 - angry and surprise; experiment 3 - happy and surprise) presented among neutral upright face distracters. In the first and third experiments, the two targets differed both in valence and arousal ratings. In experiment 2, the surprise and angry expressions differed in terms of valence but were matched for arousal. There was a happy expression advantage (lesser attentional blink) when the first target was anger (experiment 1) or surprise (experiment 3) and a surprise expression advantage when the first target was anger (experiment 2). There was a backward blink with reduced detection of the first target primarily by the relatively more positive valence second target. These results indicate that the benefit for happy and surprise expressions in comparison to angry expression identification is probably due to valence (more positive) and not arousal. Our results demonstrate a novel dynamic interplay of emotional information on temporal attention.

A new generation of cardiac implantable devices, known as Closed Loop Stimulation pacemakers, are now utilized to reduce episodes of bradycardia, syncope, and tachycardia in pregnant women. The device functions differently than conventional pacemakers by responding to changes in the patient`s cardiac output and heart rate based on physiologic demands and acute mental stress. Increased metabolic demands, including physiologic stress often accompany pregnancy, labor, and delivery. The Certified Registered Nurse Anesthetist providing analgesia and anesthesia for the laboring patient with CLS pacemaker may encounter rapid changes in heart rates, initiation of pacing modes, and hypotension resulting from reduced cardiac outputs. The ability to differentiate and diagnose the causes of hemodynamic changes and provide appropriate interventions is essential to optimize maternal and fetal outcomes. This case report details the anesthetic management of a laboring twenty-five-year-old primigravida with an implantable CLS pacemaker secondary to a history of third degree heart block, cardiac ablation after supraventricular tachycardia, and seizures. The parturient experienced intermittent pacing after neuraxial analgesia. Anticipation of the CLS pacemaker's response to the parturient's physiological and emotional response during the labor process will be discussed including recommendations to optimize maternal and fetal outcomes., Competing Interests: The authors have declared no financial relationships with any commercial entity related to the content of this article. The authors did not discuss off-label use within the article. Disclosure statements are available for viewing upon request., (Copyright© by the American Association of Nurse Anesthetists.)

Background: Brennan's rodent paw incision model has been extensively used for understanding mechanisms underlying postoperative pain in humans. However, alterations of physiological parameters like blood pressure and heart rate, or even feeding and drinking patterns after the incision have not been documented as yet. Moreover, though eicosanoids like prostaglandins and leukotrienes contribute to inflammation, tissue levels of these inflammatory mediators have never been studied. This work further investigates the antinociceptive effect of protein C after intra-wound administration., Methods: Separate groups of Sprague-Dawley rats were used for quantitation of cyclooxygenase (COX) activity and leukotriene B4 level by enzyme-linked immunosorbent assay, as well as estimation of cardiovascular parameters and feeding and drinking behavior after paw incision. In the next part, rats were subjected to incision and 10 µg of protein C was locally administered by a micropipette. Both evoked and non-evoked pain parameters were then estimated., Results: COX, particularly COX-2 activity and leukotriene B4 levels increased after incision. Hemodynamic parameters were normal. Feeding and drinking were affected on days 1 and 3, and on day 1, respectively. Protein C attenuated non-evoked pain behavior alone up to day 2., Conclusions: Based upon current observations, Brennan's rodent paw incision model appears to exhibit a prolonged period of nociception similar to that after surgery, with minimal interference of physiological parameters. Protein C, which is likely converted to activated protein C in the wound, attenuated the guarding score, which probably represents pain at rest after surgery in humans.

In the present study, we have evaluated the nephroprotective effect of hydroalcoholic extract of Terminalia chebula in cisplatin-induced nephrotoxicity model. Standardised extract was orally administered to Wistar rats for 10 days at different doses. On day 7, 8 mg/kg of cisplatin was administered intra-peritoneally to rats in all groups. T. chebula , in a dose-dependent manner significantly inhibited the elevation of serum creatinine, blood urea nitrogen and oxidant stress markers. The immunohistochemical analysis revealed the increased levels of apoptotic markers and cytokines in cisplatin group were significantly lowered by T. chebula extract. The cisplatin-treated rats kidney showed diffused tubular necrosis and infilteration of inflammatory cells which was reversed in the treatment group. Chemical characterisation of extract by HPLC revealed the presence of corilagin, chebulinic, chebulagic, chebulic, gallic and ellagic acid. The findings of this study discovered that T. chebula ameliorated oxidative and histological damage caused by cisplatin.

Background and Objectives: Infiltration of surgical wound with local anaesthetics attenuate postoperative pain. However, side effects can also occur. Somatostatin (SST) and its analogues like octreotide reportedly reduce peripheral sensitisation. The current study evaluates peripherally mediated antinociceptive effect of SST in a rat model of postoperative pain. This was compared with bupivacaine and morphine under identical experimental conditions., Design: Randomised vehicle-controlled blind study., Setting: Pain research laboratory, All India Institute of Medical Sciences, New Delhi from February 2014 to July 2017., Experimental Subject: Rodent hind paw incision model., Interventions: Sprague-Dawley rats were subjected to incision and one of the following drugs administered into the open wound once by a micropipette: SST (10, 30 or 100 μg), bupivacaine (3, 10, 30, 50 or 100 μg) or morphine (100 μg). Antinociceptive effect of SST was further evaluated for its reversibility, site of action, effect on spinal c-fos expression and blood glucose level. The site of action of morphine was also investigated., Main Outcome Measure: Nociception was estimated by nonevoked (guarding behaviour) and evoked (mechanical allodynia and thermal hyperalgesia) pain behaviours between 2 h and days 4 to 7., Results: Nociception was maximum 2 h after incision. SST (10 to 100 μg) significantly attenuated guarding behaviour between 2 h and day 2. A delayed inhibitory effect was observed on allodynia. Bupivacaine (10 to 100 μg doses) similarly decreased guarding score up to day 2 though evoked pain behaviours were relatively unaffected. In contrast, morphine produced a potent but transient inhibitory effect on guarding score at 2 h, which was mediated by both peripheral and central opioid receptors. The antinociceptive effect of SST was peripherally mediated by type 2 receptors and was associated with decreased c-fos staining. Blood glucose level was unaltered., Conclusion: Guarding behaviour, which likely represents pain-at-rest following surgery, was attenuated by both bupivacaine and SST to comparable extents. This novel peripherally mediated antinociceptive effect of SST needs further evaluation.

Background: Neuropeptide Y (NPY) is abundantly distributed in the mammalian nervous system. Its role in nociception arising from inflammatory and neuropathic pain conditions has been elucidated. However, its involvement in post-incisional nociception, particularly at the spinal cord level, is relatively unknown., Purpose: Management of postoperative pain is suboptimal. Evaluation of changes at the spinal level could facilitate better understanding of neural mechanisms underlying this type of pain., Methods: Rats were subjected to hind paw incision and spatiotemporal pattern of NPY expression in the dorsal horn was investigated by immunohistochemistry. Next, rats were implanted with intrathecal catheters using previously standardized procedure. NPY was injected into the intrathecal space by an indwelling catheter and behavioral assessment of nociception was performed., Results: Higher expression of NPY was observed in the superficial laminae of the dorsal horn. After incision, specific changes were observed like an abrupt decrease at 3 h after incision, which could be correlated with the intense nociception at this time. In contrast to morphine administration, which attenuated all 3 behavioral parameters of nociception, NPY decreased guarding behavior and thermal hyperalgesia during the acute phase., Conclusions: NPY is extensively expressed in the superficial laminae of the spinal cord and exhibit marked changes after incision. Nociception is also decreased after its administration. Hence, it is likely involved in post-incisional nociception. This information could have clinical relevance.

Recent advances in the field of genomics have seen the successful implementation of whole exome sequencing as a rapid and efficient diagnostic strategy in several genodermatoses. The aim of this study was to explore the potential of molecular studies in dystrophic epidermolysis bullosa (DEB) in India. Whole exome sequencing was performed using genomic DNA from each case of epidermolysis bullosa, followed by massively parallel sequencing. Resulting reads were mapped to the human reference genome hg19. Sanger sequencing subsequently confirmed the potentially pathogenic mutations. Whole exome sequencing of 18 patients with DEB from 17 unrelated Indian families revealed 20 distinct sequence variants in the COL7A1 gene including 2 widely prevalent mutations. Dominant inheritance was seen in 7 patients, while 11 patients showed a highly variable recessive DEB. This preliminary study using exome sequencing is clearly encouraging and will serve as the basis for future large-scale molecular studies to actively identify and understand DEB in the Indian population.

Emotional databases are important tools to study emotion recognition and their effects on various cognitive processes. Since, well-standardized large-scale emotional expression database is not available in India, we evaluated Radboud faces database (RaFD)-a freely available database of emotional facial expressions of adult Caucasian models, for Indian sample. Using the pictures from RaFD, we investigated the similarity and differences in self-reported ratings on emotion recognition accuracy as well as parameters of valence, clarity, genuineness, intensity and arousal of emotional expression, by following the same rating procedure as used for the validation of RaFD. We also systematically evaluated the universality hypothesis of emotion perception by analyzing differences in accuracy and ratings for different emotional parameters across Indian and Dutch participants. As the original Radboud database lacked arousal rating, we added this as a emotional parameter along with all other parameters. The results show that the overall accuracy of emotional expression recognition by Indian participants was high and very similar to the ratings from Dutch participants. However, there were significant cross-cultural differences in classification of emotion categories and their corresponding parameters. Indians rated certain expressions comparatively more genuine, higher in valence, and less intense in comparison to original Radboud ratings. The misclassifications/ confusion for specific emotional categories differed across the two cultures indicating subtle but significant differences between the cultures. In addition to understanding the nature of facial emotion recognition, this study also evaluates and enables the use of RaFD within Indian population., Competing Interests: The authors have declared that no competing interests exist.

Background: Junctional epidermolysis bullosa (JEB) is a diverse group of genodermatoses associated with extreme skin fragility. Despite several well-characterized genetic studies, molecular diagnosis of this heterogeneous group is still challenging. Recent advances in the field of genomics have seen the successful implementation of whole exome sequencing (WES) as a fast and efficient diagnostic strategy in several genodermatoses., Objective: In view of the scarcity and need of molecular studies for JEB in India, we sought to explore the potential of WES in understanding the mutational spectrum of this rare, in certain subtypes lethal, sub-group of EB., Methods: WES was performed using genomic DNA from each case of EB, followed by massively parallel sequencing. Resulting reads were mapped to the human reference genome hg19. Sanger sequencing subsequently confirmed the potentially pathogenic mutations., Results: Overall, four unrelated families (6 patients) of JEB with a highly variable clinical presentation including a rare case of LOC syndrome were studied. WES revealed 4 variations in 3 genes (LAMA3, LAMB3 and COL17A1) that are implicated in JEB. None of the variations were recurrent. In addition we proposed the probable molecular consequence of a missense mutation on the structure-function relationship of lamininβ3 protein through computational modeling studies., Conclusions: Being the first report documenting the phenotype-genotype correlations of JEB patients from India, our preliminary experience with WES is clearly encouraging and serves as a nidus for future large-scale molecular studies to actively identify and understand JEB patients in Indian population., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Emotions play a significant role in guiding everyday actions and strongly interact with attention. The processing of emotional information over time and the influence of attention on such processing has been studied through the phenomenon of attentional blink using rapid serial visual presentations (RSVP) tasks. This chapter discusses the interaction between temporal attention and the type of emotional information (words, scenes, and facial expressions) presented during or before the RSVP stream. The findings show that the affective content and the arousal value of the emotional stimuli presented as first target, second target, or both affects the magnitude and the duration of the blink window. In addition, modulation of emotional context or presentation of emotions in the RSVP stream as task irrelevant distractors also influenced attentional blink. Further, this chapter discusses different models and theories of attentional blink and attempts to explain the emotional effects. The chapter concludes with possible scope for future studies., (© 2017 Elsevier B.V. All rights reserved.)

Background: Immunofluorescence (IFM) antigen mapping is the most commonly used technique to diagnose and differentiate epidermolysis bullosa (EB). In India, IFM is limited to few research laboratories and is not readily available, making the diagnosis largely clinical and often inaccurate. Ob jective of the Study: To examine the diagnostic usefulness of immunohistochemistry (IHC) as compared to IFM in resource-limited settings., Methods: Forty-four consecutive EB patients were included in this study. IHC and IFM were performed on 7-µm frozen tissue sections using standard laboratory protocols with a limited panel of antibodies. The kappa coefficient of agreement was calculated with genetic analysis as the gold standard., Results: IFM and IHC accurately identified the subtype of EB in 80.9% (p < 0.001) of the cases, when a clear blister cavity was evident on biopsy. The sensitivities and specificities of IHC and IFM for diagnosing EB simplex, junctional EB, and dystrophic EB were 100, 100, and 60% and 82.4, 100, and 100%, respectively. IHC was equally effective (p < 0.001) in establishing the type of EB as IFM., Conclusions: IHC staining and its interpretation were simple and comparable to IFM. IHC had an advantage of showing subtle changes in the epidermal architecture that could not be appreciated on IFM and hence can be considered useful in resource-limited settings., (© 2017 S. Karger AG, Basel.)

Objective: To observe the effect of L-type calcium channel blocker like nimodipine on morphine's withdrawal when it was administered continuously along with morphine versus a single bolus dose of nimodipine, which was administered at the end of the experiment before the precipitation of withdrawal reaction in morphine-dependent rats., Materials and Methods: Four groups of adult male Wistar rats were rendered morphine dependent by subcutaneous injections of morphine at a dose of 10 mg/kg for 10 days. Nimodipine 10 mg/kg intraperitoneally (ip) administered to one group once daily before morphine administration in the entire experimental period, and another group received nimodipine only once at the end of the experiment as a single bolus dose 2 mg/kg before the administration of naloxone. Naloxone 3 mg/kg was administered ip to all the groups to precipitate withdrawal reactions. The withdrawal reactions were evaluated and scored as per the Gellert and Holtzman global withdrawal rating scale., Results: Nimodipine when administered as a single bolus dose before naloxone administration in morphine-dependant rats reduced the features of withdrawal reactions more effectively than continuous administration of nimodipine along with morphine throughout the experimental period., Conclusion: We discovered that nimodipine helps in attenuating the severity of morphine withdrawal having potential role encountered during pharmacotherapy with morphine management of opioid dependence, well memory, impairement, cell signaling and phosphorylation of neuron., Competing Interests: There are no conflicts of interest.

Visual attention modulates the firing rate of neurons in many primate cortical areas. In V4, a cortical area in the ventral visual pathway, spatial attention has also been shown to reduce the tendency of neurons to fire closely separated spikes (burstiness). A recent model proposes that a single mechanism accounts for both the firing rate enhancement and the burstiness reduction in V4, but this has not been empirically tested. It is also unclear if the burstiness reduction by spatial attention is found in other visual areas and for other attentional types. We therefore recorded from single neurons in the medial superior temporal area (MST), a key motion-processing area along the dorsal visual pathway, of two rhesus monkeys while they performed a task engaging both spatial and feature-based attention. We show that in MST, spatial attention is associated with a clear reduction in burstiness that is independent of the concurrent enhancement of firing rate. In contrast, feature-based attention enhances firing rate but is not associated with a significant reduction in burstiness. These results establish burstiness reduction as a widespread effect of spatial attention. They also suggest that in contrast to the recently proposed model, the effects of spatial attention on burstiness and firing rate emerge from different mechanisms., (© The Author 2016. Published by Oxford University Press.)

Background & Objectives: Treatment of inflammatory pain with opioids is accompanied by unpleasant and, at times, life-threatening side effects.Cannabis produces antinociception as well as psychotropic effects. It was hypothesized that peripheral cannabinoid receptors outside the central nervous system could be selectively activated for relief of pain. This study was undertaken to measure the antinociceptive effect of type 1 cannabinoid receptor (CB1r) agonist arachidonylcyclopropylamide (ACPA) in a rat model of inflammatory pain after intrawound administration and the effects were compared with lignocaine., Methods: Wounds were produced under controlled conditions by an incision in the right hind paw in rats. ACPA (10, 30 or 100 μg/10 μl) was administered directly into the wound. Antinociception was evaluated by guarding, allodynia and thermal hyperalgesia. This was compared to lignocaine (30 μg/10 μl). Reversal of ACPA (30 μg)-mediated antinociceptive effect was attempted by intrawound AM251 (100 μg), a CB1r antagonist. Antinociception was also evaluated after contralateral administration of ACPA (30 μg). Primary afferent nociceptive input to the spinal cord was investigated by c-Fos expression after ACPA treatment (100 μg)., Results: ACPA, but not lignocaine, inhibited guarding behaviour, which was locally mediated. Conversely, lignocaine, but not ACPA, inhibited thermal hyperalgesia and mechanical allodynia. ACPA-mediated inhibitory effect was reversible and dose dependent. It was associated with a decreased c-Fos expression. Locomotor activity was unaffected following ACPA (100 μg) treatment., Interpretation & Conclusions: Lignocaine attenuated evoked pain behaviour whereas ACPA decreased guarding score. This difference was likely due to blockade of sodium ion channels and the activation of peripheral CB1r, respectively. Central side effects were absent after ACPA treatment. Further studies need to be done to assess the effect of ACPA treatment in clinical conditions.

Objectives: Opioids such as morphine form the cornerstone in the treatment of moderate to severe pain. However, opioids also produce serious side effects such as tolerance. Fosaprepitant is a substance P (SP) receptor antagonist, which is used for treating chemotherapy-induced nausea and vomiting. SP is an important neuropeptide mediating transmission of pain at the spinal level. Thus, it was hypothesized that combining morphine with fosaprepitant would increase the antinociceptive effect of morphine. The objectives were to evaluate the effect of fosaprepitant on morphine-induced antinociception in rats and to investigate its mechanism of action., Methods: Sprague-Dawley rats were injected with morphine (10 mg/kg twice daily) and/or fosaprepitant (30 mg/kg once daily) for 7 days. Pain threshold was assessed by the hot plate test. Expression of SP and calcitonin gene-related peptide (CGRP) in the spinal cords of these rats was evaluated by immunohistochemistry., Results: Morphine administration resulted in an antinociceptive effect compared to the control group (day 1 and to a lesser extent on day 4). The decreased antinociception despite continued morphine treatment indicated development of tolerance. Co-administration of fosaprepitant attenuated tolerance to morphine (days 1 and 3) and increased the antinociceptive effect compared to control group (days 1-4). Expression of SP was increased in the morphine + fosaprepitant group., Conclusions: The results show that fosaprepitant attenuates the development of tolerance to morphine and thereby, increases the antinociceptive effect. This is likely linked to decreased release of SP from presynaptic terminals.

Wounds associated with injuries such as burns can produce moderate to severe pain. Besides causing distress to the patient, unrelieved pain could delay healing owing to stress-related problems. Thus, pain needs to be treated as early as possible after injury. It was hypothesised that local treatment of wounds with appropriate analgesic drugs could attenuate pain. HOE 140, a bradykinin receptor antagonist, reduced acute inflammatory pain in rats after intrawound administration. In this study, the analgesic effect of dimethylsulphoxide (DMSO) was investigated in a similar hind-paw incision model in rats. An extremely small quantity (10 µl) of 100% DMSO was administered into the incision site just before closure of the wound. It persistently attenuated guarding behaviour in rats over a period of 3 days without affecting thermal hyperalgesia or allodynia. Accumulated evidence indicates that guarding is equivalent to pain at rest in humans. The possible mechanisms of the analgesic effect could be inhibition of C group of peripheral nerve fibres or even free radical scavenging. Healing of the wound was found to be normal at the end of the study period. In conclusion, DMSO could be useful in the treatment of acute pain resulting from tissue injuries such as burns., (© 2014 The Authors. International Wound Journal © 2014 Medicalhelplines.com Inc and John Wiley & Sons Ltd.)

Objectives: Noxious stimuli activate small to medium-sized dorsal root ganglion (DRG) neurons. Intense noxious stimuli result in the release of substance P (SP) from the central terminals of these neurons. It binds to the neurokinin type 1 receptor (NK1r) and sensitises the dorsal horn neurons. SP is also released from the peripheral terminals leading to neurogenic inflammation. However, their individual contribution at spinal and peripheral levels to postincisional nociception has not been delineated as yet., Methods: Sprague-Dawley rats were administered different doses (3-100 μg) of an NK1r antagonist (L760735) by intrathecal (i.t.) route before hind paw incision. On the basis of its antinociceptive effect on guarding behaviour, the 30 μg dose was selected for further study. In different sets of animals, this was administered i.t. (postemptive) and intrawound (i.w.). Finally, in another group, drug (30 μg) was administered through both i.t and i.w. routes. The antinociceptive effect was assessed and compared. Expression of SP was examined in the spinal cord. Intrawound concentration of SP and inflammatory mediators was also evaluated., Results: Postemptive i.t. administration significantly attenuated guarding and allodynia. Guarding was alone decreased after i.w. drug treatment. Combined drug administration further attenuated all nociceptive parameters, more so after postemptive treatment. Expression of SP in the spinal cord decreased post incision but increased in the paw tissue. Inflammatory mediators like the nerve growth factor also increased after incision., Conclusion: In conclusion, SP acting through the NK1r appears to be an important mediator of nociception, more so at the spinal level. These findings could have clinical relevance.

Acute tissue damage is accompanied by synthesis of nitric oxide (NO) in the inflamed tissue as well as in the spinal cord. NO release at the spinal level is likely involved in the neuroplastic changes contributing to pain. Also, previous studies indicate that this could be due to the inducible isoform of the nitric oxide synthase (iNOS) enzyme. Though, the role of NO has been investigated in several animal models of nociception, the precise contribution of NO to nociception arising from hind paw incision is unknown, which is a rodent model of postoperative pain. In the present work, we have estimated the formation of NO in Sprague-Dawley rats, both at the site of incision and the corresponding spinal cord levels by Griess assay. Subsequently, naive rats were implanted with chronic indwelling intrathecal (i.t.) catheters. Fixed quantity (30 μg) of 1400 W, an iNOS inhibitor, was either administered locally into the wound at the time of incision or into the i.t. space, 15 min before hind paw incision. In a different set, i.t. 1400 W was administered, 20 h after incision. Control group received i.t. saline. Nociception was evaluated by guarding score, mechanical allodynia and thermal hyperalgesia. NO level was significantly increased between 4 h - day 1 locally and at 4 h at the spinal level after incision. Local inhibition of iNOS produced transient decrease of guarding (4-12 h) whereas pronounced decrease of guarding and allodynia was evident after spinal inhibition of iNOS. Also, spinal NO level decreased after i.t. drug administration. Post-incision drug treatment resulted in greater antinociceptive effect at day 1 though not on day 2. These results indicate involvement of NO in postincisional nociception in rats., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Somatostatin (SST) and the somatostatin receptor type 2 (sstr2) are expressed in the superficial part (Laminae I-III) of the dorsal horn of the spinal cord. Since the neurons in these laminae also receive nociceptive sensation from the periphery, it was hypothesized that both SST and sstr2 could be involved in the modulation of nociceptive transmission. To the best of knowledge, there are no studies on the involvement of SST and sstr2 in hind paw incision model in rats, which mimics postoperative pain in humans. Sprague-Dawley rats were subjected to hind paw incision under isoflurane anaesthesia and the resulting mechanical allodynia and thermal hyperalgesia were evaluated for 5 days. In another set of animals, the spinal cord was isolated at specified time intervals after incision and examined for SST and sstr2 expression using immunohistochemistry and immunoblotting procedures. Finally, nociceptive parameters were again evaluated in incised rats, which had received SST (400 µg/kg i.p. three times per day). Blood glucose level and locomotor activity were determined after SST treatment. Both allodynia and hyperalgesia were highest immediately after incision. Spinal SST expression increased at 2 h. A further increase was noted on day 3. Expression of sstr2 increased initially but decreased at day 1. These changes could be due to exocytosis of SST and internalization of the ligand-receptor complex. SST injection significantly attenuated mechanical allodynia but not thermal hyperalgesia. Significant change in blood glucose level or locomotor activity was absent. SST appears to contribute to postincisional pain. This finding could be of clinical relevance., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Opioids like morphine form the mainstay of treatment for moderate to severe burn pain. However, lack of dedicated burn care service and potentially serious side effects of opioids often compromise effective treatment. Newer drugs as well as newer routes of administration of analgesic drugs are long-felt needs in the management of burn pain. Bradykinin is a potent inflammatory mediator present at sites of tissue damage. The present study investigated the analgesic effect of bradykinin type 2 receptor antagonist HOE 140 after direct intrawound administration in rats. Also, whether the analgesic effect was locally mediated was further evaluated. Tissue damage was produced by a surgical incision involving skin, fascia, and muscle. It has been reported that there are minor differences in inflammatory mediators underlying incision-related and burn injury-related pain. HOE 140 (1, 3, or 10 μg/10 μl physiological saline) was administered into the wound by a sterile micropipette. After an interval of 30 seconds, the wound was closed. HOE 140-induced analgesic effect was compared to other experimental groups of rats which did not receive any drug or those which were treated with either saline (vehicle) or water. Postincisional pain was determined by monitoring behavior, allodynia, and thermal hyperalgesia. Analgesic effect was also determined after drug administration in contralateral paw. HOE 140 (1, 3, 10 μg) significantly relieved mechanical allodynia and guarding in comparison with vehicle-treated group. The analgesic effect of HOE 140 was locally mediated. Healing of the wound was normal. In conclusion, the results suggest that bradykinin type 2 receptor antagonists such as HOE 140 could be useful in the treatment of acute inflammatory pain.

Plantar incision in rat generates spontaneous pain behaviour. The opioid drug, morphine used to treat postsurgical pain produces tolerance after long-term administration. Loperamide, a potent mu-opioid agonist, has documented analgesic action in various pain conditions. However, loperamide analgesia and associated tolerance following continuous spinal administration in postsurgical pain has not been reported. Chronic spinal infusion of drugs was achieved using intrathecal catheters connected to osmotic minipump. Coinciding with the onset of spinal infusion of loperamide or morphine, rats were subjected to plantar incision. Pain-related behaviour was assessed by Hargreaves apparatus (thermal hyperalgesia) and von Frey filaments (mechanical allodynia). Morphine and loperamide (0.5, 1 and 2 microL/h) induced analgesia was observed until 7th day post-plantar incision in Sprague-Dawley rats. Morphine and loperamide produced dose-dependent analgesia. Loperamide, in the highest dose, produced analgesia till 7th day. However, the highest dose of morphine produced inhibition of thermal hyperalgesia till 5th day and mechanical allodynia only till 3rd day post-plantar incision. Morphine and loperamide produced analgesia in postsurgical pain, which may be mediated through different mechanisms. Longer duration of analgesia with loperamide could probably be due sustained blockade of calcium channels.

Morphine is a gold standard analgesic commonly used to alleviate pain. However, its use is associated with unavoidable side effects including the risk for addiction. Peripherally administered loperamide lacks effect on the central nervous system as it is a substrate for the permeability glycoprotein (P-gp) efflux pump which blocks its entry into brain. However, when administered intrathecally, loperamide has been reported to produce analgesia. The present study investigates the mechanism of the central analgesic effect of loperamide. Adult male Sprague-Dawley rats were subjected to surgery for catheter placement. Following baseline testing, different groups of rats were administered fixed intrathecal doses (1 μg, 3 μg, 10 μg and 30 μg) of loperamide and morphine. Analgesia was compared employing Hargreaves paw withdrawal apparatus at 15 min, 30 min, 60 min, 90 min and 120 min. Additionally, CTOP, a specific mu-opioid receptor antagonist was co-administered with loperamide to examine the mu-opioid receptor mediated loperamide analgesia. Furthermore, nefiracetam, a calcium channel opener, was co-administered with loperamide or morphine to evaluate the involvement of Ca(2+) channels in Loperamide showed an analgesic effect which was comparable to morphine. However, loperamide produced longer analgesia and the analgesic effect was significantly better at 42 h and 49 h compared to morphine. CTOP completely reversed loperamide analgesia. Though nefiracetam significantly reversed loperamide analgesia, it did not have any effect on morphine induced analgesia. Our findings suggest that loperamide administered intrathecally produces analgesia which is mediated through mu-opioid receptor and subsequent blockade of downstream calcium channels., (Copyright © 2012 Elsevier B.V. All rights reserved.)

L-type calcium channel blockers like verapamil are used in the prophylaxis of migraine. However, their effect on the expression of CGRP in the trigeminal nucleus caudalis (TNC) is unknown. It is important because an earlier study had shown that olcegepant, a CGRP receptor antagonist, acts at the level of the trigeminal spinal nucleus rather than the trigeminal ganglia. Nimodipine was used in the present study as it crosses the blood-brain barrier. The objective of the study was to determine the pattern of expression of calcitonin gene-related peptide (CGRP) in the TNC after administration of nimodipine and/or morphine. Wistar rats were injected with saline, morphine, nimodipine or morphine + nimodipine for 14 days. Subsequently, the lowest part of the medulla oblongata containing the spinal nucleus was removed and processed for immunohistochemical localization of CGRP. The density of expression was quantified using Image J software. The results were statistically analyzed. CGRP expression was noted over the superficial part of the TNC, which decreased significantly after nimodipine administration. Conversely, morphine produced an up-regulation. The expression was unchanged with reference to saline in the morphine + nimodipine treated group. Decreased expression of CGRP in the trigeminal nucleus caudalis after nimodipine is being reported for the first time. Also, whether CGRP expression can be used as a marker for predicting the therapeutic efficacy of an anti-migraine drug is currently being investigated.

The cell bodies of pseudounipolar neurons of the trigeminal ganglia have been presumed to play a supportive role to neurites, which transmit various sensations like pain from the periphery to the brain stem. However, several studies have recently shown that these neuronal cell bodies could modulate the afferent stimuli by up-regulating various ion channels and also by increasing the synthesis of neuropeptides like calcitonin gene-related peptide (CGRP). Since voltage-sensitive calcium ion channels (VSCCs) determine neuropeptides/neurotransmitters released by neurons, the aim of the present study was to localize the various VSCCs (N-, P/Q-, L-, T- and R-types) in the trigeminal ganglia neurons by immunohistochemistry. The results showed that all the VSCCs are expressed by the cell bodies of neurons though the small-sized neurons showed higher expression of these channels. The small-sized neurons were identified by immunohistochemical localization of CGRP, the most common neuropeptide for pain transmission in the trigeminal ganglia neurons. Some of these channels (N, P/Q and T types) were also expressed on the cell surface though previous electrophysiological studies have shown the expression of all the channels on the cell surface. It is suggested that the cell bodies could play a more active role than hereto ascribed to these, in the modulation of sensory stimuli.

Earlier, we had reported that co-administration of opioids and L-type calcium channel blockers (L-CCBs) like diltiazem could prove useful in the treatment of cancer pain. Much of this report was based upon earlier published work involving animal models of pain exposed to brief periods of noxious radiant heat without any tissue injury. However, pain in clinical situations usually result from tissue injury. Thus, the aim of the current investigation was to study the analgesic effect of this combination of drugs in the rat formalin test which is associated with actual tissue injury. Wistar rats (n=60) received either L-CCB (nifedipine/nimodipine/verapamil/diltiazem i.p.) or morphine (s.c.) or both drugs. The formalin test was done 30 min after morphine or placebo injection. The naloxone reversal test was also done. Administration of L-CCBs alone, particularly diltiazem, increased pain in the formalin test. In contrast, co-administration of these L-CCBs with morphine led to decreased pain response, though statistically significant decrease was noted only with nimodipine + morphine. Naloxone reversed this analgesic effect, indicating that it was primarily an opioid-mediated effect. The results show that administration of L-CCBs alone may prove counterproductive in the therapeutic management of pain (anti-analgesic effect). However, co-administration of both drugs (morphine and nimodipine) in quick succession could lead to adequate pain relief.

We have earlier reported that nifedipine and nimodipine, both L-type voltage-sensitive calcium channel (L-VSCC) antagonists, attenuate the development of tolerance to chronic administration of morphine in the rat. In the present study, we have investigated the expression of L- and N-type VSCC using immunohisto-chemistry, in the cervical region of the spinal cords from animals treated chronically with morphine alone or in combination with nimodipine. The highest expression of both VSCCs within the spinal cord was detected within the superficial laminae of the dorsal horn, which indicates that these channels play an important role in the spinal processing of pain. After morphine tolerance, the expression of both the channels in the superficial laminae was significantly higher than control animals. However, morphine+nimodipine administration produced a differential effect, that is, the expression of L-VSCC decreased while that of N-VSCC increased. The study shows that the expression of these channels is plastic and subject to change depending upon the drug administered. This in turn can determine overall responsiveness to morphine.

Opioids like morphine produce antinociception after intrathecal administration. Being hydrophilic in nature, morphine also spreads rostrally which leads to respiratory depression. Loperamide has been reported to produce antinociception after both intracisternal and intrathecal administration. It is also hydrophobic, which could restrict its diffusion in the spinal canal. However, the mechanism of its antinociceptive action after intrathecal administration is not definitely known. In the present study, the antinociceptive effect of loperamide was evaluated by the formalin test. It significantly inhibited Phase II flinching behavior. This antinociceptive effect was reversed by pre-administration of naloxone indicating that it was predominantly due to activation of opioid receptors.

Opioids, when co-administered with L-type calcium channel blockers (L-CCBs) show morphine like higher antinociceptive effect. This antinociceptive effect has been further investigated using a different experimental paradigm. The effect of two different L-CCBs (nifedipine and nimodipine) on morphine-induced antinociception was studied by the tail-flick test (40 min after morphine administration) in adult Wistar rats. A fixed-dose of nimodipine or nifedipine (2 mg/kg, once daily) was combined with a fixed dose of morphine (10 mg/kg, twice daily) for 10 days. Co-administration of L-CCBs significantly increased the antinociceptive effect of morphine, even 12 hr after administration. Also, nimodipine was more effective than nifedipine. Nimodipine was further studied using a higher and escalating doses of morphine (20-30 mg/kg twice daily for 14 days). Nimodipine increased the antinociceptive effect of morphine in the latter part of the study (days nine to fourteen) though significant difference was observed on 11th evening and 12th morning. No obvious adverse effects were observed in the present study. The results show for the first time that nimodipine is more effective than nifedipine and that these L-CCBs continue to be effective, even 12 hr after administration in the tail-flick test.

Background & Objective: Slime is a major determinant of Staphylococcus epidermidis adherence. The established methods of laboratory detection of slime production by this organism i.e., Christensen's tube method and congo red agar plate method, can both yield inconclusive and/or intermediate results. We, therefore tried to find out electronmicroscopically the localization of slime in relation to the bacterial cell wall and look for the effect, if any of the slime location on the staphylococcal adherence as well as on the quantum of slime production., Methods: A total of 132 coagulase negative staphylococci from cases of infectious keratitis were identified as S. epidermidis following the recommended protocol. Slime was detected both by Christensen's tube method and congo red agar plate method. Antibiotic sensitivity testing was performed by standardized disc diffusion method. Adherence of the organisms to artificial surfaces was determined by a quantitative method and transmission electron microscopy was carried out by the conventional techniques., Results: Of the total 132 isolates, 57 (43.2%) were slime positive and 75 (56.8%) were slime negative. Twenty seven (47.4%) of the 57 slime producing organisms were multi drug resistant as compared to only 12 (16%) of 75 nonslime-producing organisms (P<0.001). A majority i.e., 45 (78.9%) of 57 adherent organisms were slime producers as against 12 (16%) of 75 nonadherent organisms. Electron microscopic study revealed a thick viscid layer of slime anchoring to the bacterial cell wall, especially in adherent organisms and those yielding positive slime test. Some of the organisms showed loose nonadherent slime and those were mostly nonadherent to artificial surfaces., Interpretation & Conclusion: Slime and multi drug resistance were the important virulence factors of S. epidermidis in bacterial keratitis. It was the adherent slime (i.e., slime in intimate association with the bacterial cell wall as shown by electron microscopy) only, which was responsible for resistance to multiple antibiotics and for the adhesion phenomenon observed in the quantitative slime test.

Earlier, we reported that morphine-nimodipine combination produces significantly higher antinociception after intrathecal but not after systemic administration in mice. Different doses of morphine and nimodipine (5 microg of morphine, 5 microg of nimodipine, 5 microg each of morphine and nimodipine, 10 microg of morphine, 10 microg of nimodipine, 10 microg morphine with 5 microg nimodipine and 5 microg of morphine with 10 microg of nimodipine) were now injected intrathecally in Wistar rats to further characterise this antinociceptive effect. The acute antinociceptive effect was measured by the tail-flick test between 15 min to 7 h. The onset of maximum antinociception (100% MPE) was earlier (by 15 min) in nimodipine (5 microg) than in morphine (5 microg) treated group (by 30 min). Though earlier in onset, 5 microg nimodipine produced transient antinociception, which was significantly higher than saline treated controls for the initial 30 min only. Morphine (5 microg) produced significantly higher antinociception between 15 min to 3:30 h in comparison to control animals. However, co-administration of both morphine and nimodipine led to significantly higher antinociception than morphine alone at 4:00 h and also between 5:00 to 6:30 h. Interestingly, the combined antinociceptive action of morphine and nimodipine was not significantly different from 10 microg of morphine, which indicated synergistic interaction. Naloxone (5 mg/kg) could reverse this antinociceptive effect of morphine-nimodipine combination though it failed to reverse nimodipine (5 microg)-mediated antinociception at 15 min. Increasing the dose of either morphine or nimodipine to 10 mug did not increase antinociception except between 6:30-7:00 h. No obvious side effect was noted after administration of either morphine or nimodipine or both.

Calcium plays an important role in the pathophysiology of pain. A number of studies have investigated the effect of L-type calcium channel blockers on the analgesic response of morphine. However, the results are conflicting. In the present study, the antinociceptive effect of morphine (2.5 microg) and nimodipine (1 microg) co-administered intraspinally in mice was observed using the tail flick test. It was compared to the analgesic effect of these drugs (morphine - 250 microg subcutaneously; nimodipine - 100 microg intraperitoneally) after systemic administration. Nimodipine is highly lipophilic and readily crosses the blood brain barrier. Addition of nimodipine to morphine potentiated the analgesic response of the latter when administered through the intraspinal route but not when administered through systemic route. It may be due to direct inhibitory effect of morphine and nimodipine on neurons of superficial laminae of the spinal cord after binding to mu -opioid receptors and L-type calcium channels respectively.

Loperamide, a mu opioid receptor agonist, which is commonly used as an antidiarrhoeal agent has been reported to possess analgesic activity after intrathecal administration. However, the exact analgesic profile, i.e., onset, duration and intensity of analgesia in relation to morphine is not fully known. In the present study, the acute analgesic effect of loperamide (5 microg) was compared with that of morphine (5 microg) and morphine + loperamide (5 microg of each) using the tail flick method after intrathecal administration. Naloxone (5 mg/kg) reversibility of the analgesic effect was also studied. The analgesic response of loperamide was significantly higher than morphine. Even after 22 hr, maximum possible effect was greater than 49%. Naloxone partially antagonized the analgesic effect of loperamide. This suggested that loperamide may be acting through blockade of Ca2+ channels besides activating mu opioid receptors. Loperamide may prove to be a better substitute for morphine as spinal analgesic.

Background & Objective: The mechanism underlying the development of tolerance to morphine is not clearly understood though a number of factors have been implicated. One of the likely factors may be increased activity of anti-opioid peptides like nociceptin (also known as orphanin FQ or N/OFQ). N/OFQ and morphine bind to opioid receptor-like 1 (ORL1) receptor and muopioid receptor respectively. The present work was undertaken to investigate the density of ORL1 and mu (mu) receptor expression in the spinal cord of mice after inducing morphine tolerance., Methods: Swiss albino mice were injected with either morphine (experimental group, n=15) or saline (control, n=15), twice a day for 9 days. The development of tolerance was noted by the hotplate test. Cryostat sections of the cervical region of spinal cord were labeled with specific ligands to localize ORL1 and mu receptors. The density of receptor expression over laminae I-II of spinal cord was evaluated using image analysis system., Results: The morphine treated mice developed tolerance by day 9 as evident by the hot plate test. Both receptors were selectively expressed at a higher concentration over the superficial laminae (I-II) of the dorsal horn, indicating a role in pain processing. An increased expression of ORL1 receptors was also noted over the gray matter around the central canal. Quantitative analysis showed an increased expression of ORL1 and mu receptors though the increase was not statistically significant., Interpretation & Conclusion: The present study showed that both, ORL1 and mu-opioid receptors were expressed in areas of the spinal cord, concerned with transmission of pain signals. The density of these receptors increased in the superficial laminae (I-II) though not significantly from control after morphine tolerance. The increase in ORL1 receptors could oppose the analgesic action of morphine, contributing to tolerance. Further studies need to be done to elucidate the mechanism of morphine tolerance.

The expression of mu-opioid receptors in the developing rat spinal cord (Postnatal days 7, 14, 30) was studied by autoradiography using [3H]DAMGO. When compared to camera lucida drawings, the receptor was noted over the entire gray matter and dorsal root ganglia at postnatal days 7 and 14. At postnatal day 30, the receptor expression decreased over the gray matter except the superficial laminae (laminae I and II). At all age groups studied, a higher expression of the receptor was noted over the superficial laminae. The study shows that micro-opioid receptors appears early in postnatal development and attains mature receptor distribution relatively late in ontogeny, suggesting a possible role in the normal development of nervous system. This is affirmed by an impairment of psychomotor development in babies born to mothers, addicted to opiates.

Though morphine remains the most powerful drug for treating pain, its effectiveness is limited by the development of tolerance and dependence. The mechanism underlying development of tolerance to morphine is still poorly understood. One of the factors could be an alteration in the number of micro-receptors within specific parts of the nervous system. However, reports on changes in the micro-opioid receptor density in the spinal cord after chronic morphine administration are conflicting. Most of the studies have used subcutaneously implanted morphine pellets to produce tolerance. However, it does not simulate clinical conditions, where it is more common to administer morphine at intervals, either by injections or orally. In the present study, rats were made tolerant to morphine by injecting increasing doses of morphine (10-50 mg/kg, subcutaneously) for five days. In vitro tissue autoradiography for localization of micro-receptor in the spinal cord was done using [3H]-DAMGO. As compared to the spinal cord of control rats, the spinal cord of tolerant rats showed an 18.8% increase or up-regulation in the density of micro-receptors in the superficial layers of the dorsal horn. This up-regulation of micro-receptors after morphine tolerance suggests that a fraction of the receptors have been rendered desensitized, which in turn could lead to tolerance

Purpose: The plasma level of nitric oxide (NO), that has been reported to possess various antineoplastic properties, was found to be diminished due to the impairment of insulin-activated nitric oxide synthase (IANOS) as a result of the appearance of a novel antibody (free light chain of IgG, M(r) 44 kD) against the enzyme in the circulation in various cancers compared to normal control., Methods: We report here two NO-generating agents, antineoplastin I (a protein, M(r) 5000) and antineoplastin II (an inorganic compound), which when applied to the skin of cancer patients were capable of neutralizing the antibody in vivo through the production of NO in the skin cells due to the stimulation of membrane IANOS of these cells and, subsequently, in erythrocytes in the circulation., Results: Neither antineoplastin I nor antineoplastin II itself enters into the circulation but due to the application of these agents on the skin, the NO synthesis in erythrocytes was normalized in these patients through "feedback" activation and amplification of IANOS activity by NO itself., Conclusion: It was found that the resumption of NO synthesis through the neutralization of antibody resulted in favorable modifications of various cancer-associated pathophysiologic consequences.

The distribution of mu opioid receptors was studied in human fetal spinal cords between 12-13 and 24-25 wk gestational ages. Autoradiographic localisation using [3H] DAMGO revealed the presence of mu receptors in the dorsal horn at all age groups with a higher density in the superficial laminae (I-II). A biphasic expression was noted. Receptor density increased in the dorsal horn, including the superficial laminae, between 12-13 and 16-17 wk. This could be associated with a spurt in neurogenesis. The density increased again at 24-25 wk in laminae I-II which resembled the adult pattern of distribution. A dramatic proliferation of cells was noted from the region of the ventricular zone between 16-17 and 24-25 wk. These were considered to be glial cells from their histological features. Mu receptor expression was noted over a large area of the spinal cord including the lateral funiculus at 24-25 wk. This may be due to receptor expression by glial cells. The study presents evidence of mu receptor expression by both neurons and glia during early development of human spinal cord.

The kinetics and mechanism of clearance of pancreatic cationic and anionic trypsinogens from the circulation have been investigated in a rat model. 125I-labeled rat cationic trypsinogen is cleared from the bloodstream with a half-life of approximately 4 min. In contrast, 125I-labeled rat anionic trypsinogen has a half-life in the circulation of approximately 55-60 min. The major site of clearance for both enzymes is the kidney. Neither zymogen binds to plasma proteins to a significant extent over a period of three half-lives. The relative rates of clearance of these zymogens from the circulation appears to correlate with their respective isoelectric points.