Disrupted stress-induced analgesia in a neuropathic pain state is rescued by the endocannabinoid degradation inhibitor JZL195.

Acute stress normally engages descending brain pathways to produce an antinociceptive response, known as stress-induced analgesia. Paradoxically, these descending pain modulatory pathways are also involved in the maintenance of the abnormal pain associated with chronic neuropathic pain. It remains unclear how stress-induced analgesia is affected by neuropathic pain states. We therefore examined the impact of a chronic constriction nerve-injury (CCI) model of neuropathic pain on restraint stress-induced analgesia in C57BL/6 mice. Thirty minutes of restraint stress produced analgesia in the hotplate thermal nociceptive assay that was less in CCI compared to control mice who underwent a sham-surgery. In sham but not CCI mice, stress-induced analgesia was reduced by the opioid receptor antagonist naltrexone. The cannabinoid CB1 receptor antagonist AM281 did not affect stress-induced analgesia in either sham or CCI mice. Low-dose pre-treatment with the dual fatty acid amide hydrolase and monoacylglycerol lipase inhibitor JZL195 increased stress-induced analgesia in CCI but not sham mice. The JZL195 enhancement of stress-induced analgesia in CCI mice was abolished by AM281 but was unaffected by naltrexone. These findings indicate that the acute opioid-mediated analgesic response to a psychological stressor is disrupted in a nerve-injury model of neuropathic pain. Importantly, this impairment of stress-induced analgesia was rescued by blockade of endocannabinoid breakdown via a cannabinoid CB1 receptor dependent mechanism. These findings suggest that subthreshold treatment with endocannabinoid degradation blockers could be used to alleviate the disruption of endogenous pain control systems in a neuropathic pain state.

Implementing Quality Improvement Initiatives to Improve the Use of Adolescent- and Youth-Friendly Health Services in Zou, Benin.

INTRODUCTION: In Benin, the unmet need for family planning services is especially high for adolescent girls and youth aged 15-24 years. The Challenge Initiative (TCI) supported the health system to assess and improve the quality of adolescent and youth sexual reproductive health services and enhance contraceptive uptake in 65 service delivery points (SDPs) of the Zou department. PROGRAM DESCRIPTION: Between June 2019 and March 2021, TCI supported the health districts in Zou to train an assessment team to complete 3 cycles of quality assessments (QAs) using a QA checklist adapted to the local context. Based on assessment scores, the SDPs were categorized into poor, moderate, or good to excellent quality. The SDP managers developed remedial action plans after each cycle and for each SDP and followed up with supportive supervision. RESULTS: The first QA cycle showed that 52% of assessed SDPs achieved a good to excellent classification; by the second QA cycle, this reached 74%. However, the quality of adolescent- and youth-friendly health services regressed during the third QA cycle (during COVID-19 pandemic disruptions), when only 40% of SDPs achieved the good to excellent category. Between the first and second QA cycles, contraceptive uptake for adolescents and youth improved in the SDPs that had good or excellent quality of services, compared to the ones that were of lower quality (established significance level of 5% with a P value of .031). CONCLUSION: Further assessments could deepen our understanding of the internal and external factors that can affect service quality. The findings reinforce the importance of investing in quality improvement strategies to maximize the use of sexual and reproductive health services among adolescents and youth. They also underscore the need for a contextual and nuanced approach to ensure enduring results.

Boosting Contraceptive Uptake in Urban Uganda: Older Women Benefit When Layering Adolescent and Youth Interventions Onto Existing Family Planning Programming.

INTRODUCTION: Uganda has a large young population with a high unmet need for family planning (FP). Although there have been many efforts to improve access to and uptake of contraception, improvements have been slow. The Ministry of Health Uganda partnered with The Challenge Initiative (TCI) to implement a novel multipronged approach layering adolescent and youth sexual reproductive health (AYSRH) onto a functioning general FP program for women of reproductive age in 3 local governments of Buikwe, Mukono, and Iganga. We describe the approach and aim to determine whether layering AYSRH interventions onto an existing program resulted in increased contraceptive uptake among adolescents and youth aged 10-24 years and among women aged 25-49 years. METHODS: We analyzed service statistics from the Uganda Health Management Information System to assess contraceptive uptake for adolescents and youth (aged 10-24 years) and older women (aged 25-49 years) before and after the implementation of the AYSRH approach in 3 areas (Buikwe, Iganga, and Mukono) compared to 11 areas where only the general FP program was implemented and the Uganda country total. RESULTS: This analysis showed that before the start of TCI's support, levels of contraceptive uptake were similar in all local governments. However, after implementation, there was an increase in uptake for general FP program only areas (1.7-point advantage over country total) and an even greater increase in general FP+AYSRH areas (2.4-point advantage over FP only programming). This was observed in both adolescents and youth aged 10-24 years and among women aged 25-49 years. CONCLUSION: The layering of TCI's AYSRH interventions onto a well-functioning FP platform not only increased contraceptive uptake among adolescents and youth aged 10-24 years but also boosted uptake among women older than age 25 years.

Student learning of head and neck anatomy using cone beam computed tomography and immersive virtual reality.

OBJECTIVES: The purpose of this study was to evaluate the efficacy of student learning of anatomy and 3D imaging concepts using cone beam computed tomography (CBCT) and immersive virtual reality (VR) technology. METHODOLOGY: Ninety (n = 90) first year dental students with no previous experience in 3D imaging were recruited. All participants completed a 10-item, multiple-choice questionnaire (MCQ) and a pre-survey prior to the educational intervention. Following a brief video orientation on CBCT and anatomy, each participant underwent a one-on-one educational intervention using immersive VR with calibrated instructors to identify head and neck anatomic structures using a VR/CBCT educational tool. Immediately following the intervention, all participants completed a postsurvey, a second MCQ, NASA task load index and presence questionnaires. Participants completed a third MCQ 2 weeks following the intervention. Analysis of objective measures of performance on MCQ's (p < 0.05) and subjective data from the questionnaires was completed. RESULTS: The students doubled their mean test scores 2.45 ± 1.274 to 5.99 ± 1.576 on MCQ's immediately following the educational intervention (p < 0.05). The significant increase in the MCQ test scores was maintained after 2 weeks, 5.73 ± 1.721 (p < 0.05). There were no gender differences in student test performance. Students rated the immersive VR/CBCT educational intervention experience highly for control, sensory, and realism factors with minimal distraction and frustration factors. CONCLUSION: Results from this study show that immersive VR/CBCT educational intervention improved test performance and contributed to information recall in students. Further benefits reported by participants include the sense of presence and increased engagement using immersive VR.

Intrathecal Actions of the Cannabis Constituents Δ(9)-Tetrahydrocannabinol and Cannabidiol in a Mouse Neuropathic Pain Model.

(1) Background: The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), synergistically reduce allodynia in various animal models of neuropathic pain. Unfortunately, THC-containing drugs also produce substantial side-effects when administered systemically. We examined the effectiveness of targeted spinal delivery of these cannabis constituents, alone and in combination. (2) Methods: The effect of acute intrathecal drug delivery on allodynia and common cannabinoid-like side-effects was examined in a mouse chronic constriction injury (CCI) model of neuropathic pain. (3) Results: intrathecal THC and CBD produced dose-dependent reductions in mechanical and cold allodynia. In a 1:1 combination, they synergistically reduced mechanical and cold allodynia, with a two-fold increase in potency compared to their predicted additive effect. Neither THC, CBD nor combination THC:CBD produced any cannabis-like side-effects at equivalent doses. The anti-allodynic effects of THC were abolished and partly reduced by cannabinoid CB1 and CB2 receptor antagonists AM281 and AM630, respectively. The anti-allodynic effects of CBD were partly reduced by AM630. (4) Conclusions: these findings indicate that intrathecal THC and CBD, individually and in combination, could provide a safe and effective treatment for nerve injury induced neuropathic pain.

Scaling Access to Contraception for Youth in Urban Slums: The Challenge Initiative's Systems-Based Multi-Pronged Strategy for Youth-Friendly Cities.

INTRODUCTION: More than half of all adolescents globally live in Asia, with India having the largest adolescent population in the world at 253 million. In sub-Saharan Africa, adolescents make up the greatest proportion of the population, with 23% of the population aged 10-19. And these numbers are predicted to grow rapidly-particularly in urban areas as rural youth migrate to cities for economic opportunities. While adolescents and youth are subject to high sexual and reproductive health risks, few efforts have been documented for addressing these in urban settings, especially in poor settlements. METHODS: The Challenge Initiative (TCI) is a demand-driven, family planning platform for sustainable scale and impact that lets city governments-in particular urban slums-lead implementation. It is currently active in 11 countries in Africa and Asia. In June 2018, TCI heightened its focus on adolescent and youth sexual and reproductive health (AYSRH) for youth living in urban slums. It now supports 39 city governments. TCI dedicates technical and program support to married (including first-time parents) and unmarried youth ages 15-24 years. Using an innovative coaching model and an online learning platform (TCI University), TCI supports city governments as they implement AYSRH interventions to accelerate the impact of TCI's model for rapid scale. RESULTS: TCI has been assessing the performance of cities implementing its AYSRH approaches using its RAISE tool and has found considerable improvement over two rounds of assessments through TCI coaching and support for adaptation of its high-impact interventions between the first and second round. CONCLUSIONS: TCI's AYSRH approach scaled rapidly to 39 cities and multiple urban slums since 2018, using its evidence-based interventions and coaching model. In the context of universal health coverage, TCI has supported segmented demand generation and improved access to quality and affordable contraceptive as well as youth-friendly health services. It provides a menu of interventions for cities to implement for youth-including such approaches as public-private partnerships with pharmacies and quality assurance using quick checklists-along with an innovative coaching model. This approach has facilitated greater access to contraceptive methods of choice for youth.

Oral efficacy of Δ(9)-tetrahydrocannabinol and cannabidiol in a mouse neuropathic pain model.

The psychoactive and non-psychoactive constituents of cannabis, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have synergistic analgesic efficacy in animal models of neuropathic pain when injected systemically. However, the relevance of this preclinical synergy to clinical neuropathic pain studies is unclear because many of the latter use oral administration. We therefore examined the oral effectiveness of these phytocannabinoids and their interactions in a mouse chronic constriction injury (CCI) model of neuropathic pain. THC produced a dose-dependent reduction in mechanical and cold allodynia, but also induced side-effects with similar potency. CBD also reduced allodynia, albeit with lower potency than THC, but did not produce cannabinoid-like side-effects at any dose tested. Combination THC:CBD produced a dose-dependent reduction in allodynia, however, it displayed little to no synergy. Combination THC:CBD produced substantial, synergistic side-effects which increased with the proportion of CBD. These findings demonstrate that oral THC and CBD, alone and in combination, have analgesic efficacy in an animal neuropathic pain model. Unlike prior systemic injection studies, combination THC:CBD lacks analgesic synergy when delivered orally. Furthermore, both THC and combination THC:CBD display a relatively poor therapeutic window when delivered orally. This suggests that CBD provides a safer, albeit lower efficacy, oral treatment for nerve injury induced neuropathic pain than THC-containing preparations. This article is part of the special issue on 'Cannabinoids'.

THC and gabapentin interactions in a mouse neuropathic pain model.

Clinical studies have shown that the major psychoactive ingredient of Cannabis sativa Δ9-tetrahydrocannabinol (THC) has some analgesic efficacy in neuropathic pain states. However, THC has a significant side effect profile. We examined whether the profile of THC could be improved by co-administering it with the first-line neuropathic pain medication gabapentin. This was done using the chronic constriction injury (CCI) model of neuropathic pain in C57BL6 mice. At 8 days post-CCI nerve injury, acute systemic administration of gabapentin produced a dose-dependent decrease in CCI-induced mechanical and cold allodynia, and increased motor incoordination. Coadministration of THC and gabapentin in a fixed-ratio dose-dependently reduced mechanical and cold allodynia, and produced all the side-effects observed for THC, including motor incoordination, catalepsy and sedation. Isobolographic analysis indicated that the ED50 for the THC:gabapentin induced reduction in allodynia was 1.7 times less than that predicted for an additive interaction. The therapeutic window of combination THC:gabapentin was greater than that for THC alone. These findings indicate that gabapentin synergistically enhances the anti-allodynic actions of THC and improves its therapeutic window. Thus, THC may represent a potential adjuvant for neuropathic pain medications such as gabapentin.

Opioid and cannabinoid synergy in a mouse neuropathic pain model.

BACKGROUND AND PURPOSE: Clinical studies have reported that pan-cannabinoid receptor agonists may have efficacy in neuropathic pain states and that this might be enhanced by co-administration with opioids. While cannabinoid-opioid analgesic synergy has been demonstrated in animal models of acute pain, it has not been examined in neuropathic pain models. We examined the effect of combination treatment with cannabinoid and opioid receptor agonists on allodynia and side effects in a nerve injury-induced neuropathic pain model. EXPERIMENTAL APPROACH: C57BL/6 mice were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of morphine and the pan-cannabinoid receptor agonist, WIN55212, on allodynia and side effects were examined at 7-10 days post-CCI surgery. Isobolographic analysis was used to determine whether the effects of the combination were synergistic. KEY RESULTS: The opioid agonist morphine reduced CCI-induced mechanical and cold allodynia and produced motor incoordination, in a dose-dependent manner. WIN55212 reduced CCI-induced allodynia and produced motor incoordination, catalepsy and sedation, in a dose-dependent manner, as we have observed previously. When administered together, WIN55212 and morphine reduced allodynia in a synergistic manner but had only an additive effect on motor incoordination. CONCLUSIONS AND IMPLICATIONS: These findings indicate that administration of a combination of a non-selective opioid and cannabinoid receptor agonist synergistically reduces nerve injury-induced allodynia, while producing side effects in an additive manner. This suggests that this combination treatment has an improved anti-allodynic potency and therapeutic index in a neuropathic pain model.

Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model.

BACKGROUND AND PURPOSE: While cannabinoids have been proposed as a potential treatment for neuropathic pain, they have limitations. Cannabinoid receptor agonists have good efficacy in animal models of neuropathic pain; they have a poor therapeutic window. Conversely, selective fatty acid amide hydrolase (FAAH) inhibitors that enhance the endocannabinoid system have a better therapeutic window, but lesser efficacy. We examined whether JZL195, a dual inhibitor of FAAH and monacylglycerol lipase (MAGL), could overcome these limitations. EXPERIMENTAL APPROACH: C57BL/6 mice underwent the chronic constriction injury (CCI) model of neuropathic pain. Mechanical and cold allodynia, plus cannabinoid side effects, were assessed in response to systemic drug application. KEY RESULTS: JZL195 and the cannabinoid receptor agonist WIN55212 produced dose-dependent reductions in CCI-induced mechanical and cold allodynia, plus side effects including motor incoordination, catalepsy and sedation. JZL195 reduced allodynia with an ED50 at least four times less than that at which it produced side effects. By contrast, WIN55212 reduced allodynia and produce side effects with similar ED50s. The maximal anti-allodynic effect of JZL195 was greater than that produced by selective FAAH, or MAGL inhibitors. The JZL195-induced anti-allodynia was maintained during repeated treatment. CONCLUSIONS AND IMPLICATIONS: These findings suggest that JZL195 has greater anti-allodynic efficacy than selective FAAH, or MAGL inhibitors, plus a greater therapeutic window than a cannabinoid receptor agonist. Thus, dual FAAH/MAGL inhibition may have greater potential in alleviating neuropathic pain, compared with selective FAAH and MAGL inhibitors, or cannabinoid receptor agonists.

Leveraging the Power of Knowledge Management to Transform Global Health and Development.

Good knowledge is essential to prevent disease and improve health. Knowledge management (KM) provides a systematic process and tools to promote access to and use of knowledge among health and development practitioners to improve health and development outcomes. KM tools range from publications and resources (briefs, articles, job aids) and products and services (websites, eLearning courses, mobile applications), to training and events (workshops, webinars, meetings) and approaches and techniques (peer assists, coaching, after-action reviews, knowledge cafés).

Development of an efficient trapping system for New Zealand flower thrips, Thrips obscuratus.

BACKGROUND: New Zealand flower thrips (NZFT), Thrips obscuratus (Crawford), is an economic pest of various horticultural crops in New Zealand and is recognised as a quarantine pest globally. Two chemical attractants (ethyl nicotinate and 6-pentyl-2H-pyran-2-one), three dispensers, three trap designs and four trap heights were investigated to determine the most effective method for monitoring NZFT. Phenology of NZFT at two locations was compared. RESULTS: 6-Pentyl-2H-pyran-2-one in a polyethylene bag dispenser was the most attractive lure formulation and exhibited high stability in release rate trials. There was no difference in NZFT catch between vertical-panel and cross-panel traps, but both caught significantly more than delta traps. However, both types of panel trap had unacceptably high by-catch of native insects. Catch of thrips increased with height from 0 to 3 m. Phenology of NZFT showed similar population trends at both locations, but with a timing difference of around 50 days. CONCLUSIONS: Delta traps containing 6-pentyl-2H-pyran-2-one in a polyethylene bag at 2 m above the ground is the recommended method for monitoring NZFT, significantly improving the sensitivity, accuracy and labour input compared with prior methods. Long-term monitoring of NZFT could lead to more accurate economic damage thresholds and timing for when to apply insecticides. © 2014 Society of Chemical Industry.

Nordihydroguaiaretic acid activates hTRPA1 and modulates behavioral responses to noxious cold in mice.

Nordihydroguaiaretic acid (NDGA) is a major biologically active component of the creosote bush, Larrea tridentate, widely used in unregulated therapies. NDGA is a lipoxygenase inhibitor while a derivative, terameprocol, has been trialed as a chemotherapeutic agent. When investigating fatty acid activation of the human transient receptor potential cation channel subfamily A, member 1 (hTRPA1), we found that NDGA activated the channel. Here we investigate the actions of NDGA and terameprocol at hTRPA1 and the consequences of this for noxious cold sensitivity in mice. hTRPA1 was stably expressed in HEK 293 cells (HEK 293-TRPA1) and channel activity examined by measuring changes in intracellular calcium ([Ca]i) using a fluorescent dye and activation of membrane currents using patch clamp electrophysiology. The effects of local NDGA and terameprocol application on acetone-induced paw flinching were examined in mice. NDGA (pEC50 of 5.4 ± 0.1, maximum change in fluorescence of 385 ± 30%) and terameprocol (pEC50 4.5 ± 0.2, maximum 550 ± 75%) increased [Ca]i in HEK 293-hTRPA1 cells. NDGA also induced an increase in membrane conductance in HEK 293-hTRPA1 cells. These effects were prevented by the TRPA1 antagonist HC-030031, and were dependent on the presence of Cys621, Cys 641, and Cys 665 in hTRPA1. Neither NDGA nor terameprocol alone produced spontaneous pain behaviors in mice after hind paw injection, but both enhanced responses to acetone. NDGA and terameprocol are efficacious activators of TRPA1. NDGA should be used with care to probe lipoxygenase involvement in nociception while TRPA1 activity should be considered when considering use of these drugs in humans.

Endocannabinoid modulation by FAAH and monoacylglycerol lipase within the analgesic circuitry of the periaqueductal grey.

BACKGROUND AND PURPOSE: Endogenous cannabinoids (endocannabinoids) in the periaqueductal grey (PAG) play a vital role in mediating stress-induced analgesia. This analgesic effect of endocannabinoids is enhanced by pharmacological inhibition of their degradative enzymes. However, the specific effects of endocannabinoids and the inhibitors of their degradation are largely unknown within this pain-modulating region. EXPERIMENTAL APPROACH: In vitro electrophysiological recordings were conducted from PAG neurons in rat midbrain slices. The effects of the major endocannabinoids and their degradation inhibitors on inhibitory GABAergic synaptic transmission were examined. KEY RESULTS: Exogenous application of the endocannabinoid, anandamide (AEA), but not 2-arachidonoylglycerol (2-AG), produced a reduction in inhibitory GABAergic transmission in PAG neurons. This AEA-induced suppression of inhibition was enhanced by the fatty acid amide hydrolase (FAAH) inhibitor, URB597, whereas a 2-AG-induced suppression of inhibition was unmasked by the monoacylglycerol lipase (MGL) inhibitor, JZL184. In addition, application of the CB1 receptor antagonist, AM251, facilitated the basal GABAergic transmission in the presence of URB597 and JZL184, which was further enhanced by the dual FAAH/MGL inhibitor, JZL195. CONCLUSIONS AND IMPLICATIONS: Our results indicate that AEA and 2-AG act via disinhibition within the PAG, a cellular action consistent with analgesia. These actions of AEA and 2-AG are tightly regulated by their respective degradative enzymes, FAAH and MGL. Furthermore, individual or combined inhibition of FAAH and/or MGL enhanced tonic disinhibition within the PAG. Therefore, the current findings support the therapeutic potential of FAAH and MGL inhibitors as a novel pharmacotherapy for pain.

Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine inflammatory pain model.

The analgesic efficacy of cannabinoids in chronic pain models is limited by side-effects. It has been proposed that this might be overcome by using agents which indirectly activate the endocannabinoid system. We examined the analgesic and side-effect profile of the dual FAAH/MAGL inhibitor JZL195 in an inflammatory pain model. The effect of systemic injections of a range of doses of JZL195 and the pan-cannabinoid receptor agonist WIN55212 were performed 1 day following intraplantar injection of CFA in C57BL/6 mice. JZL195 and WIN55212 both reduced mechanical allodynia and thermal hyperalgesia, and produced catalepsy and sedation in a dose dependent manner. Unlike WIN55212, JZL195 reduced allodynia at doses below those at which side-effects were observed. The effects of JZL195 and WIN55212 were abolished by co-application with the CB1 antagonist AM251. The CB2 antagonist also reduced the JZL195 anti-allodynia, and reversed the WIN55212 anti-allodynia. The reduction in allodynia produced by JZL195 was greater than that produced individually by the FAAH and MAGL inhibitors, URB597 and JZL184. These findings suggest that JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects.

Upregulation of α1-adrenoceptors on cutaneous nerve fibres after partial sciatic nerve ligation and in complex regional pain syndrome type II.

After peripheral nerve injury, nociceptive afferents acquire an abnormal excitability to adrenergic agents, possibly due to an enhanced expression of α1-adrenoceptors (α1-ARs) on these nerve fibres. To investigate this in the present study, changes in α1-AR expression on nerve fibres in the skin and sciatic nerve trunk were assessed using immunohistochemistry in an animal model of neuropathic pain involving partial ligation of the sciatic nerve. In addition, α1-AR expression on nerve fibres was examined in painful and unaffected skin of patients who developed complex regional pain syndrome (CRPS) after a peripheral nerve injury (CRPS type II). Four days after partial ligation of the sciatic nerve, α1-AR expression was greater on dermal nerve fibres that survived the injury than on dermal nerve fibres after sham surgery. This heightened α1-AR expression was observed on nonpeptidergic nociceptive afferents in the injured sciatic nerve, dermal nerve bundles, and the papillary dermis. Heightened expression of α1-AR in dermal nerve bundles after peripheral nerve injury also colocalized with neurofilament 200, a marker of myelinated nerve fibres. In each patient examined, α1-AR expression was greater on nerve fibres in skin affected by CRPS than in unaffected skin from the same patient or from pain-free controls. Together, these findings provide compelling evidence for an upregulation of α1-ARs on cutaneous nociceptive afferents after peripheral nerve injury. Activation of these receptors by circulating or locally secreted catecholamines might contribute to chronic pain in CRPS type II.

Serotonergic modulation of neuronal activity in rat midbrain periaqueductal gray.

Serotonin (5-HT) modulates pain and anxiety from within the midbrain periaqueductal gray (PAG). In the present study, the effects of 5-HT- and 5-HT(1/2) subtype-selective ligands on rat PAG neurons were examined using whole cell patch-clamp recordings in brain slices. In voltage clamp, 5-HT produced outward and inward currents in distinct subpopulations of neurons that varied throughout different subregions of the PAG. The 5-HT(1A) agonist R(+)-8-OH-DPAT (1 µM) produced outward currents in subpopulations of PAG neurons. By contrast, sumatriptan (1 µM) and other 5-HT(1B, -D), and (-F) subtype agonists had little or no postsynaptic activity. The 5-HT(2A/C) agonists DOI (3 µM) and TCB-2 (1 µM) produced inward currents in subpopulations of PAG neurons, and DOI enhanced evoked inhibitory postsynaptic currents via a presynaptic mechanism. In current clamp, both R(+)-8-OH-DPAT and sumatriptan produced an excitatory increase in evoked mixed postsynaptic potentials (PSPs). In addition, R(+)-8-OH-DPAT, but not sumatriptan, directly hyperpolarized PAG neurons. By contrast, the 5-HT(2) agonist DOI depolarized subpopulations of neurons and produced an inhibitory decrease in evoked mixed PSPs. These findings indicate that 5-HT(1A) and 5-HT(1B/D) ligands have partly overlapping inhibitory effects on membrane excitability and synaptic transmission within the PAG, which are functionally opposed by 5-HT(2A/C) actions in specific PAG subregions.

Postsynaptic mGluR mediated excitation of neurons in midbrain periaqueductal grey.

Metabotropic glutamate (mGlu) receptors modulate pain from within the midbrain periaqueductal grey (PAG). In the present study, the postsynaptic mGlu receptor mediated effects on rat PAG neurons were examined using whole-cell patch-clamp recordings in brain slices. The selective group I agonist DHPG (10 µM) produced an inward current in all PAG neurons tested which was associated with a near parallel shift in the current-voltage relationship. By contrast, the group II and III mGlu receptor agonists DCG-IV (1 µM) and l-AP4 (3 µM) produced an outward current in only 10-20% of PAG neurons tested. The DHPG induced current was concentration dependent (EC(50) = 1.4 µM), was reduced by the mGlu1 antagonist CPCCOEt (100 µM), and was further reduced by CPCCOEt in combination with the mGlu5 antagonist MPEP (10 µM). The glutamate transport blocker TBOA (30 µM) also produced an inward current, however, this was largely abolished by CNQX (10 µM) plus AP5 (25 µM). Slow EPSCs were evoked following train, but not single shock stimulation, which were enhanced by TBOA (30 µM). The TBOA enhancement of slow EPSCs was abolished by MPEP plus CPCCOEt. These findings indicate that endogenously released glutamate, under conditions in which neurotransmitter spill-over is enhanced, activates group I mGlu receptors to produce excitatory currents within PAG. Thus, postsynaptic group I mGlu receptors have the potential to directly modulate the analgesic, behavioural and autonomic functions of the PAG. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

Development of single-dispenser pheromone suppression of Epiphyas postvittana, Planotortrix octo and Ctenopseustis obliquana in New Zealand stone fruit orchards.

BACKGROUND: Pheromones of two native leafrollers of economic importance to the New Zealand horticulture industry, Planotortrix octo [(Z)-8-tetradecenyl acetate and tetradecyl acetate] and Ctenopseustis obliquana [(Z)-5-tetradecenyl acetate and (Z)-8-tetradecenyl acetate], were reinvestigated and combined with pheromone of Epiphyas postvittana [light-brown apple moth, (E)-11-tetradecenyl actetate and (E, E)-9,11-tetradecen-1-yl acetate] to develop a single dispenser for mating disruption of three pest species for integrated pest management. RESULTS: Additional compounds identified from pheromone gland extracts were characterised as repellents for P. octo. However, for C. obliquana from Central Otago, a change in ratio of (Z)-5-tetradecenyl acetate and (Z)-8-tetradecenyl acetate and the addition of three compounds found in the gland (dodecyl acetate, tetradecyl acetate and hexadecanal) led to a significant improvement in catch over previous lures. Males from Central Otago showed antennal electrophysiological responses to hexadecanal, unlike C. obliquana from Auckland, which did not. Three multiple-species disruption blends were devised in a single dispenser to target E. postvittana, P. octo and C. obliquana. Disruption of traps was recorded in single-tree replicates with all three blends, but the five-component blend was overall most effective at disruption and was deployed area wide in commercial orchard plots. CONCLUSIONS: Deployment of single dispensers into commercial stone fruit orchards led to disruption of trapping for the three species and measurable reductions in insecticide use in cherries, peaches and nectarines without increased fruit damage (assessed in apricots).

Role of 5-HT(1) receptor subtypes in the modulation of pain and synaptic transmission in rat spinal superficial dorsal horn.

BACKGROUND AND PURPOSE: 5-HT receptor agonists have variable nociceptive effects within the spinal cord. While there is some evidence for 5-HT(1A) spinally-mediated analgesia, the role of other 5-HT(1) receptor subtypes remains unclear. In the present study, we examined the spinal actions of a range of 5-HT(1) agonists, including sumatriptan, on acute pain, plus their effect on afferent-evoked synaptic transmission onto superficial dorsal horn neurons. EXPERIMENTAL APPROACH: For in vivo experiments, 5-HT agonists were injected via chronically implanted spinal catheters to examine their effects in acute mechanical and thermal pain assays using a paw pressure analgesymeter and a Hargreave's device. For in vitro experiments, whole-cell patch-clamp recordings of primary afferent-evoked glutamatergic EPSC were made from lamina II neurons in rat lumbar spinal slices. KEY RESULTS: Intrathecal (i.t.) delivery of the 5-HT(1A) agonist R ± 8-OH-DPAT (30-300 nmol) produced a dose-dependent thermal, but not mechanical, analgesia. Sumatriptan and the 5-HT(1B), 5-HT(1D), 5-HT(1F) agonists CP93129, PNU109291 and LY344864 (100 nmol) had no effect on either acute pain assay. R ± 8-OH-DPAT (1 µM) and sumatriptan (3 µM) both reduced the amplitude of the evoked EPSC. In contrast, CP93129, PNU109291 and LY344864 (0.3-3 µM) had no effect on the evoked EPSC. The actions of both R ± 8-OH-DPAT and sumatriptan were abolished by the 5-HT(1A) antagonist WAY100635 (3 µM). CONCLUSIONS AND IMPLICATIONS: These findings indicate that the 5-HT(1A) receptor subtype predominantly mediates the acute antinociceptive and cellular actions of 5-HT(1) ligands within the rat superficial dorsal horn.