Bruno Pradier

The cannabinoid CB2 receptor-selective phytocannabinoid beta-caryophyllene exerts analgesic effects in mouse models of inflammatory and neuropathic pain

The widespread plant volatile beta-caryophyllene (BCP) was recently identified as a natural selective agonist of the peripherally expressed cannabinoid receptor 2 (CB₂). It is found in relatively high concentrations in many spices and food plants. A number of studies have shown that CB₂ is critically involved in the modulation of inflammatory and neuropathic pain responses. In this study, we have investigated the analgesic effects of BCP in animal models of inflammatory and neuropathic pain. We demonstrate that orally administered BCP reduced inflammatory (late phase) pain responses in the formalin test in a CB₂ receptor-dependent manner, while it had no effect on acute (early phase) responses. In a neuropathic pain model the chronic oral administration of BCP attenuated thermal hyperalgesia and mechanical allodynia, and reduced spinal neuroinflammation. Importantly, we found no signs of tolerance to the anti-hyperalgesic effects of BCP after prolonged treatment. Oral BCP was more effective than the subcutaneously injected synthetic CB₂ agonist JWH-133. Thus, the natural plant product BCP may be highly effective in the treatment of long lasting, debilitating pain states. Our results have important implications for the role of dietary factors in the development and modulation of chronic pain conditions.

The transcription factor Smad-interacting protein 1 controls pain sensitivity via modulation of DRG neuron excitability.

Summary Behavioral, electrophysiological, and modeling studies of Zfhx1b[+/−] mice suggest a role of Zfhx1b in regulating pain sensitivity by controlling the transduction properties of primary nociceptive neurons. Abstract The perception of pain is initiated by the transduction of noxious stimuli through specialized ion channels and receptors expressed by primary nociceptive neurons. The molecular mechanisms that orchestrate the expression and function of ion channels relevant for pain processing are poorly understood. We demonstrate here a central role of the transcription factor Smad‐interacting protein 1 (Sip1/Zfhx1b/Zeb2), a 2‐handed zinc finger DNA‐binding protein with essential functions in neural crest and forebrain development, in controlling nociceptive neuron excitability and pain sensitivity. Mutant mice lacking 1 Zfhx1b allele displayed decreased thermal pain responses, whereas mechanical pain was unaffected. In parallel, repetitive firing of capsaicin/heat‐sensitive nociceptive DRG neurons was markedly impaired. Analysis of the voltage‐gated currents underlying repetitive firing revealed a significant increase in persistent sodium currents and a reduction in delayed rectifier potassium currents. Modeling experiments in conjunction with experimental results suggest that these changes cause a depolarization‐induced block of action potential propagation past the DRG axon T‐junction. These data suggest that Sip1 controls the transduction properties of heat‐sensitive primary sensory neurons and thus thermal pain sensitivity in a novel manner via coordinated changes in DRG‐neuron voltage‐gated ion channels.

Interaction of cannabinoid receptor 2 and social environment modulates chronic alcohol consumption

Genetic and environmental factors contribute nearly in equal power to the development of alcoholism. Environmental factors, such as negative life events or emotionally disruptive conditions, initiate and promote alcohol drinking and relapse. The endocannabinoid system is involved in hedonic control and modulates stress reactivity. Furthermore, chronic alcohol drinking alters endocannabinoid signalling, which in turn influences the stress reactivity. Recently, it has been shown that CB2 receptor activity influences stress sensitivity and alcohol drinking. We hypothesized that CB2 receptors influence the impact of environmental risk factors on alcohol preference and consumption. Therefore, in this study, we investigated the alcohol-drinking pattern of wild-type and CB2-deficient animals under single- and group-housing conditions using different alcohol-drinking models, such as forced drinking, intermittent forced drinking and two-bottle choice paradigms. Our data showed that CB2 receptor modulates alcohol consumption and reward. Interestingly, we detected that lack of CB2 receptors led to increased alcohol drinking in the intermittent forced drinking paradigm under group-housing conditions. Furthermore, we found that CB2 knockout mice consumed more food and that their body weight gain was modulated by social environment. On the basis of these data, we conclude that social environment critically affects the modulatory function of CB2 receptors, especially in alcohol intake. These findings suggest that a treatment strategy targeting CB2 receptors may have a beneficial effect on pathological drinking, particularly in situations of social stress and discomfort.

Smad‐interacting protein 1 affects acute and tonic, but not chronic pain

Smad‐interacting protein 1 (also named Zeb2 and Zfhx1b) is a transcription factor that plays an important role in neuronal development and, when mutated, causes Mowat–Wilson syndrome (MWS). A corresponding mouse model carrying a heterozygous Zeb2 deletion was comprehensively analysed in the German Mouse Clinic. The most prominent phenotype was the reduced pain sensitivity. In this study, we investigated the role of Zeb2 in inflammatory and neuropathic pain.

Enhanced microglial activity in FAAH(-/-) animals.

AIMS Several lines of evidence suggest that the endocannabinoid system is involved in the regulation of glial activity. Enhanced levels of the endocannabinoid N-arachidonoyl ethanolamine (AEA, also referred to as anandamide) as well as non-cannabinoid lipids like palmitoylethanolamine (PEA) due to genetic deletion or pharmacologic blockade of its degrading enzyme fatty acid amide hydrolase (FAAH) reduced neuroinflammatory changes in models of neurodegeneration. Now we addressed the question if genetic deletion of FAAH also influences age-related neuroinflammation. MAIN METHODS To answer this question we compared the number and size of microglia in young and old wild-type and FAAH(-/-) mice and analysed the distribution of microglia sizes in the four groups. Additionally, we analysed IL-6 and IL-1β levels with ELISA and astrocyte activities as ratio of GFAP-positive areas in the hippocampus. KEY FINDINGS Ageing was associated with an increased number and activity of microglia, elevated IL-6 and IL-1β levels and enhanced area covered by astrocytes in wild-type animals. Unexpectedly, in FAAH(-/-) animals the number of microglia and the ratio of activated microglia and IL-1β level were already higher in young animals than in age-matched wild-type controls. There was no further age-related increase in these inflammation markers in the knockout line. SIGNIFICANCE Our results suggest that AEA is involved in the regulation of microglia activity. Life-long elevation of AEA levels disturbs microglial regulation and leads to pro-inflammatory changes.

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Short-term synaptic plasticity contributes to many computations in the brain and allows synapses to keep a finite record of recent activity. Here we have investigated the mechanisms underlying an intriguing form of short-term plasticity termed labile LTP, at hippocampal and PFC synapses in male rats and male and female mice. In the hippocampus, labile LTP is triggered by high-frequency activation of presynaptic axons and is rapidly discharged with further activation of those axons. However, if the synapses are quiescent, they remain potentiated until further presynaptic activation. To distinguish labile LTP from NMDAR-dependent forms of potentiation, we blocked NMDARs in all experiments. Labile LTP was synapse-specific and was accompanied by a decreased paired pulse ratio, consistent with an increased release probability. Presynaptic Ca2+ and protein kinase activation during the tetanus appeared to be required for its initiation. Labile LTP was not reversed by a PKC inhibitor and did not require either RIM1α or synaptotagmin-7, proteins implicated in other forms of presynaptic short-term plasticity. Similar NMDAR-independent potentiation could be elicited at synapses in mPFC. Labile LTP allows for rapid information storage that is erased under controlled circumstances and could have a role in a variety of hippocampal and prefrontal cortical computations related to short-term memory. SIGNIFICANCE STATEMENT Changes in synaptic strength are thought to represent information storage relevant to particular nervous system tasks. A single synapse can exhibit multiple overlapping forms of plasticity that shape information transfer from presynaptic to postsynaptic neurons. Here we investigate the mechanisms underlying labile LTP, an NMDAR-independent form of plasticity induced at hippocampal synapses. The potentiation is maintained for long periods as long as the synapses are infrequently active, but with regular activation, the synapses are depotentiated. Similar NMDAR-independent potentiation can also be induced at L2/3-to-L5 synapses in mPFC. Labile LTP requires a rise in presynaptic Ca2+ and protein kinase activation but is unaffected in RIM1α or synaptotagmin-7 mutant mice. Labile LTP may contribute to short-term or working memory in hippocampus and mPFC.

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Short-term synaptic plasticity contributes to many computations in the brain and allows synapses to keep a finite record of recent activity. Here we have investigated the mechanisms underlying an intriguing form of short-term plasticity termed labile LTP, at hippocampal and PFC synapses in male rats and male and female mice. In the hippocampus, labile LTP is triggered by high-frequency activation of presynaptic axons and is rapidly discharged with further activation of those axons. However, if the synapses are quiescent, they remain potentiated until further presynaptic activation. To distinguish labile LTP from NMDAR-dependent forms of potentiation, we blocked NMDARs in all experiments. Labile LTP was synapse-specific and was accompanied by a decreased paired pulse ratio, consistent with an increased release probability. Presynaptic Ca2+ and protein kinase activation during the tetanus appeared to be required for its initiation. Labile LTP was not reversed by a PKC inhibitor and did not require either RIM1α or synaptotagmin-7, proteins implicated in other forms of presynaptic short-term plasticity. Similar NMDAR-independent potentiation could be elicited at synapses in mPFC. Labile LTP allows for rapid information storage that is erased under controlled circumstances and could have a role in a variety of hippocampal and prefrontal cortical computations related to short-term memory. SIGNIFICANCE STATEMENT Changes in synaptic strength are thought to represent information storage relevant to particular nervous system tasks. A single synapse can exhibit multiple overlapping forms of plasticity that shape information transfer from presynaptic to postsynaptic neurons. Here we investigate the mechanisms underlying labile LTP, an NMDAR-independent form of plasticity induced at hippocampal synapses. The potentiation is maintained for long periods as long as the synapses are infrequently active, but with regular activation, the synapses are depotentiated. Similar NMDAR-independent potentiation can also be induced at L2/3-to-L5 synapses in mPFC. Labile LTP requires a rise in presynaptic Ca2+ and protein kinase activation but is unaffected in RIM1α or synaptotagmin-7 mutant mice. Labile LTP may contribute to short-term or working memory in hippocampus and mPFC.

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Short-term synaptic plasticity contributes to many computations in the brain and allows synapses to keep a finite record of recent activity. Here we have investigated the mechanisms underlying an intriguing form of short-term plasticity termed labile LTP, at hippocampal and PFC synapses in male rats and male and female mice. In the hippocampus, labile LTP is triggered by high-frequency activation of presynaptic axons and is rapidly discharged with further activation of those axons. However, if the synapses are quiescent, they remain potentiated until further presynaptic activation. To distinguish labile LTP from NMDAR-dependent forms of potentiation, we blocked NMDARs in all experiments. Labile LTP was synapse-specific and was accompanied by a decreased paired pulse ratio, consistent with an increased release probability. Presynaptic Ca2+ and protein kinase activation during the tetanus appeared to be required for its initiation. Labile LTP was not reversed by a PKC inhibitor and did not require either RIM1α or synaptotagmin-7, proteins implicated in other forms of presynaptic short-term plasticity. Similar NMDAR-independent potentiation could be elicited at synapses in mPFC. Labile LTP allows for rapid information storage that is erased under controlled circumstances and could have a role in a variety of hippocampal and prefrontal cortical computations related to short-term memory. SIGNIFICANCE STATEMENT Changes in synaptic strength are thought to represent information storage relevant to particular nervous system tasks. A single synapse can exhibit multiple overlapping forms of plasticity that shape information transfer from presynaptic to postsynaptic neurons. Here we investigate the mechanisms underlying labile LTP, an NMDAR-independent form of plasticity induced at hippocampal synapses. The potentiation is maintained for long periods as long as the synapses are infrequently active, but with regular activation, the synapses are depotentiated. Similar NMDAR-independent potentiation can also be induced at L2/3-to-L5 synapses in mPFC. Labile LTP requires a rise in presynaptic Ca2+ and protein kinase activation but is unaffected in RIM1α or synaptotagmin-7 mutant mice. Labile LTP may contribute to short-term or working memory in hippocampus and mPFC.

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Short-term synaptic plasticity contributes to many computations in the brain and allows synapses to keep a finite record of recent activity. Here we have investigated the mechanisms underlying an intriguing form of short-term plasticity termed labile LTP, at hippocampal and PFC synapses in male rats and male and female mice. In the hippocampus, labile LTP is triggered by high-frequency activation of presynaptic axons and is rapidly discharged with further activation of those axons. However, if the synapses are quiescent, they remain potentiated until further presynaptic activation. To distinguish labile LTP from NMDAR-dependent forms of potentiation, we blocked NMDARs in all experiments. Labile LTP was synapse-specific and was accompanied by a decreased paired pulse ratio, consistent with an increased release probability. Presynaptic Ca2+ and protein kinase activation during the tetanus appeared to be required for its initiation. Labile LTP was not reversed by a PKC inhibitor and did not require either RIM1α or synaptotagmin-7, proteins implicated in other forms of presynaptic short-term plasticity. Similar NMDAR-independent potentiation could be elicited at synapses in mPFC. Labile LTP allows for rapid information storage that is erased under controlled circumstances and could have a role in a variety of hippocampal and prefrontal cortical computations related to short-term memory. SIGNIFICANCE STATEMENT Changes in synaptic strength are thought to represent information storage relevant to particular nervous system tasks. A single synapse can exhibit multiple overlapping forms of plasticity that shape information transfer from presynaptic to postsynaptic neurons. Here we investigate the mechanisms underlying labile LTP, an NMDAR-independent form of plasticity induced at hippocampal synapses. The potentiation is maintained for long periods as long as the synapses are infrequently active, but with regular activation, the synapses are depotentiated. Similar NMDAR-independent potentiation can also be induced at L2/3-to-L5 synapses in mPFC. Labile LTP requires a rise in presynaptic Ca2+ and protein kinase activation but is unaffected in RIM1α or synaptotagmin-7 mutant mice. Labile LTP may contribute to short-term or working memory in hippocampus and mPFC.

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Short-term synaptic plasticity contributes to many computations in the brain and allows synapses to keep a finite record of recent activity. Here we have investigated the mechanisms underlying an intriguing form of short-term plasticity termed labile LTP, at hippocampal and PFC synapses in male rats and male and female mice. In the hippocampus, labile LTP is triggered by high-frequency activation of presynaptic axons and is rapidly discharged with further activation of those axons. However, if the synapses are quiescent, they remain potentiated until further presynaptic activation. To distinguish labile LTP from NMDAR-dependent forms of potentiation, we blocked NMDARs in all experiments. Labile LTP was synapse-specific and was accompanied by a decreased paired pulse ratio, consistent with an increased release probability. Presynaptic Ca2+ and protein kinase activation during the tetanus appeared to be required for its initiation. Labile LTP was not reversed by a PKC inhibitor and did not require either RIM1α or synaptotagmin-7, proteins implicated in other forms of presynaptic short-term plasticity. Similar NMDAR-independent potentiation could be elicited at synapses in mPFC. Labile LTP allows for rapid information storage that is erased under controlled circumstances and could have a role in a variety of hippocampal and prefrontal cortical computations related to short-term memory. SIGNIFICANCE STATEMENT Changes in synaptic strength are thought to represent information storage relevant to particular nervous system tasks. A single synapse can exhibit multiple overlapping forms of plasticity that shape information transfer from presynaptic to postsynaptic neurons. Here we investigate the mechanisms underlying labile LTP, an NMDAR-independent form of plasticity induced at hippocampal synapses. The potentiation is maintained for long periods as long as the synapses are infrequently active, but with regular activation, the synapses are depotentiated. Similar NMDAR-independent potentiation can also be induced at L2/3-to-L5 synapses in mPFC. Labile LTP requires a rise in presynaptic Ca2+ and protein kinase activation but is unaffected in RIM1α or synaptotagmin-7 mutant mice. Labile LTP may contribute to short-term or working memory in hippocampus and mPFC.