Activity-Dependent Modulation of Tonic GABA Currents by Endocannabinoids in Hirudo verbana

Paulsen, Riley T.; Burrell, Brian D.

doi:10.3389/fnsyn.2022.760330

Cited by 4 publications

(1 citation statement)

References 82 publications

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“…NMDA receptors are known to contribute to wind-up sensitization in mammals and repeated high-frequency stimulation of Hirudo nociceptors is known to produce NMDA receptor-dependent synaptic potentiation in nociceptive and non-nociceptive synapses ( Franzen et al, 2023 ; Yuan and Burrell, 2019 ). Other physiological mechanisms potentially contributing to sensitization in Hirudo include decreases in GABAergic tone (disinhibition) ( Baca et al, 2008 ; Paulsen and Burrell, 2022 ), endocannabinoid-based modulation ( Jorgensen and Burrell, 2022 ; Wang and Burrell, 2018 ) and serotonergic modulation ( Burrell and Sahley, 2005 ; Burrell et al, 2001 ; Ehrlich et al, 1992 ; Lockery and Kristan, 1991 ; Zaccardi et al, 2004 ).…”

Section: Discussionmentioning

confidence: 99%

Repetitive nociceptive stimulation elicits complex behavioral changes in Hirudo: evidence of arousal and motivational adaptations

Hoynoski,

Dohn,

Franzen

et al. 2023

Journal of Experimental Biology

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Appropriate responses to real or potential damaging stimuli to the body (nociception) are critical to an animal's short- and long-term survival. The initial goal of this study was to examine habituation of withdrawal reflexes (whole-body and local shortening) to repeated mechanical nociceptive stimuli (needle pokes) in the medicinal leech, Hirudo verbana, and assess whether injury altered habituation to these nociceptive stimuli. While repeated needle pokes did reduce shortening in Hirudo, a second set of behaviors changes was observed. Specifically, animals began to evade subsequent stimuli by either hiding their posterior sucker underneath adjacent body segments or by engaging in locomotion (crawling). Animals differed in terms of how quickly they adopted evasion behaviors during repeated stimulation, exhibiting a multi-modal distribution for early, intermediate, and later evaders. Prior injury had a profound effect on this transition, decreasing the time frame in which animals began to carry out evasion and increasing the magnitude of these evasion behaviors (more locomotory evasion). The data indicate the presence in Hirudo of a complex and adaptive defensive arousal process to avoid noxious stimuli that is influenced by differences in internal states, prior experience with injury of the stimulated areas, and possibly learning-based processes.

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Section: Discussionmentioning

confidence: 99%

Repetitive nociceptive stimulation elicits complex behavioral changes in Hirudo: evidence of arousal and motivational adaptations

Hoynoski,

Dohn,

Franzen

et al. 2023

Journal of Experimental Biology

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Characterization of a Fatty Acid Amide Hydrolase (FAAH) in Hirudo Verbana

Kabeiseman,

Paulsen,

Burrell

2024

Neurochem Res

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The endocannabinoid system plays a critical role in modulating both peripheral and central nervous system function. Despite being present throughout the animal kingdom, there has been relatively little investigation of the endocannabinoid system beyond traditional animal models. In this study, we report on the identification and characterization of a putative fatty acid amide hydrolase (FAAH) in the medicinal leech, Hirudo verbana. FAAH is the primary enzyme responsible for metabolizing the endocannabinoid signaling molecule arachidonoyl ethanolamide (anandamide or AEA) and therefore plays a critical role in regulating AEA levels in the nervous system. mRNA encoding Hirudo FAAH (HirFAAH) is expressed in the leech central nervous system (CNS) and sequence analysis suggests that this is an orthologue of FAAH-2 observed in vertebrates. Functionally, HirFAAH has serine hydrolase activity based on activity-based protein profiling (ABPP) studies using the fluorophosphonate probe TAMRA-FP. HirFAAH also hydrolyzes arachidonyl 7-amino, 4-methyl coumarin amide (AAMCA), a substrate specific to FAAH. Hydrolase activity during both the ABPP and AAMCA assays was eliminated by a mutation at a conserved catalytic serine. Activity was also blocked by the known FAAH inhibitor, URB597. Treatment of Hirudo ganglia with URB597 potentiated synapses made by the pressure-sensitive mechanosensory neuron (P cell), mimicking the effects of exogenously applied AEA. The Hirudo CNS has been a useful system in which to study properties of endocannabinoid modulation of nociception relevant to vertebrates. Therefore, this characterization of HirFAAH is an important contribution to comparative studies of the endocannabinoid system.

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Heterosynaptic long-term potentiation of non-nociceptive synapses requires endocannabinoids, NMDARs, CamKII, and PKCζ

Franzen

Paulsen

Kabeiseman

et al. 2023

Journal of Neurophysiology

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Noxious stimuli or injury can trigger long-lasting sensitization to non-nociceptive stimuli (referred to as allodynia in mammals). Long-term potentiation (LTP) of nociceptive synapses has been shown to contribute to nociceptive sensitization (hyperalgesia) and there is even evidence of heterosynaptic spread of LTP contributing to this type of sensitization. However, it is not clear whether activation of nociceptors elicits heterosynaptic LTP (hetLTP) in non-nociceptive synapses. Previous studies in the medicinal leech (Hirudo verbana) have demonstrated that high frequency stimulation (HFS) of nociceptors produce both homosynaptic LTP as well as hetLTP in non-nociceptive afferent synapses. This hetLTP involves endocannabinoid-mediated disinhibition of non-nociceptive synapses at the presynaptic level, but it is not clear if there are additional processes contributing to this synaptic potentiation. In this study, we found evidence for the involvement of postsynaptic level change and observed that postsynaptic NMDA receptors (NMDAR) were found to be required for this potentiation. Next Hirudo orthologues for known LTP signaling proteins, CamKII and PKCζ, were identified based on sequences from humans, mice, and the marine mollusk Aplysia. In electrophysiological experiments, inhibitors of CamKII (AIP) and PKCζ (ZIP) were found to interfere with hetLTP. Interestingly, CamKII was found to be necessary for both induction and maintenance of hetLTP, while PKCζ was only necessary for maintenance. These findings show activation of nociceptors can elicit a potentiation of non-nociceptive synapses through a process that involves both endocannabinoid-mediated disinhibition and NMDAR-initiated signaling pathways.

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Activity-Dependent Modulation of Tonic GABA Currents by Endocannabinoids in Hirudo verbana

Cited by 4 publications

References 82 publications

Repetitive nociceptive stimulation elicits complex behavioral changes in Hirudo: evidence of arousal and motivational adaptations

Repetitive nociceptive stimulation elicits complex behavioral changes in Hirudo: evidence of arousal and motivational adaptations

Characterization of a Fatty Acid Amide Hydrolase (FAAH) in Hirudo Verbana

Heterosynaptic long-term potentiation of non-nociceptive synapses requires endocannabinoids, NMDARs, CamKII, and PKCζ

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