Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPARγ, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPARγ-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPARγ in macrophages.

Chemotherapy-induced peripheral neuropathy (CIPN) is the main dose-limiting adverse effect of chemotherapy drugs such as paclitaxel (PTX). PTX causes marked molecular and cellular damage, mainly in the peripheral nervous system, including sensory neurons in the dorsal root ganglia (DRG). Several studies have shown the therapeutic potential of cannabinoids, including cannabidiol (CBD), the major non-psychotomimetic compound found in the Cannabis plant, to treat peripheral neuropathies. Here, we investigated the efficacy of PECS-101 (former HUF-101), a CBD fluorinated analog, on PTX-induced neuropathic pain in mice. PECS-101, administered after the end of treatment with PTX, did not reverse mechanical allodynia. However, PECS-101 (1 mg/kg) administered along with PTX treatment caused a long-lasting relief of the mechanical and cold allodynia. These effects were blocked by a PPARγ, but not CB1 and CB2 receptor antagonists. Notably, the effects of PECS-101 on the relief of PTX-induced mechanical and cold allodynia were not found in macrophage-specific PPARγ-deficient mice. PECS-101 also decreased PTX-induced increase in Tnf, Il6, and Aif1 (Iba-1) gene expression in the DRGs and the loss of intra-epidermal nerve fibers. PECS-101 did not alter motor coordination, produce tolerance, or show abuse potential. In addition, PECS-101 did not interfere with the chemotherapeutic effects of PTX. Thus, PECS-101, a new fluorinated CBD analog, could represent a novel therapeutic alternative to prevent mechanical and cold allodynia induced by PTX potentially through the activation of PPARγ in macrophages.

A series of novel cannabinoid-type derivatives were synthesized by the coupling of (1S,4R)-(+) and (1R,4S)-(-)-fenchones with various resorcinols/phenols. The fenchone-resorcinol derivatives were fluorinated using Selectfluor and demethylated using sodium ethanethiolate in dimethylformamide (DMF). The absolute configurations of four compounds were determined by X-ray single crystal diffraction. The fenchone-resorcinol analogs possessed high affinity and selectivity for the CB2 cannabinoid receptor. One of the analogues synthesized, 2-(2',6'-dimethoxy-4'-(2″-methyloctan-2″-yl)phenyl)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-ol (), had a high affinity (K = 3.51 nM) and selectivity for the human CB2 receptor (hCB2). In the [S]GTPγS binding assay, our lead compound was found to be a highly potent and efficacious hCB2 receptor agonist (EC = 2.59 nM, E = 89.6%). Two of the fenchone derivatives were found to possess anti-inflammatory and analgesic properties. Molecular-modeling studies elucidated the binding interactions of within the CB2 binding site.

Transient Receptor Potential (TRP) channels constitute a large superfamily of polymodal channel proteins with diverse roles in many physiological and sensory systems that function both as ionotropic and metabotropic receptors. From the early days of TRP channel discovery, membrane lipids were suggested to play a fundamental role in channel activation and regulation. A prominent example is the TRP and TRP-like (TRPL) channels, which are predominantly expressed in the visual system of . Light activation of the TRP and TRPL channels, the founding members of the TRP channel superfamily, requires activation of phospholipase Cβ (PLC), which hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP) into Diacylglycerol (DAG) and Inositol 1, 4,5-trisphosphate (IP). However, the events required for channel gating downstream of PLC activation are still under debate and led to several hypotheses regarding the mechanisms by which lipids gate the channels. Despite many efforts, compelling evidence of the involvement of DAG accumulation, PIP depletion or IP-mediated Ca release in light activation of the TRP/TRPL channels are still lacking. Exogeneous application of poly unsaturated fatty acids (PUFAs), a product of DAG hydrolysis was demonstrated as an efficient way to activate the TRP/TRPL channels. However, compelling evidence for the involvement of PUFAs in physiological light-activation of the TRP/TRPL channels is still lacking. Light-induced mechanical force generation was measured in photoreceptor cells prior to channel opening. This mechanical force depends on PLC activity, suggesting that the enzymatic activity of PLC converting PIP into DAG generates membrane tension, leading to mechanical gating of the channels. In this review, we will present the roles of membrane lipids in light activation of TRP channels and present the many advantages of this model system in the exploration of TRP channel activation under physiological conditions.

Sleep spindles are crucial for learning in the cortex and basal ganglia (BG) because they facilitate the reactivation of previously active neuronal ensembles. Studying field potentials (FPs) and spiking in the cortex and BG during sleep in non-human primates following pre-sleep learning, we show that FP sleep spindles are widespread in the BG and are similar to cortical spindles in morphology, spectral content, and response to the pre-sleep task. Further, BG spindles are concordant with electroencephalogram (EEG) spindles and associated with increased cortico-BG correlation. However, spindles across the BG differ markedly in their entrainment of local spiking. The spiking activity of striatal projection neurons exhibits consistent phase locking to striatal and EEG spindles, producing phase windows of peaked cross-region spindling. In contrast, firing in other BG nuclei is not entrained to either local or EEG sleep spindles. These results suggest corticostriatal synapses as the main hub for offline cortico-BG communication.

The light-activated Transient Receptor Potential (TRP) channel is the founding member of a large and diverse family of channel proteins. The TRP (dTRP) channel, which generates the electrical response to light has been investigated in a great detail two decades before the first mammalian TRP channel was discovered. Thus, dTRP is unique among members of the TRP channel superfamily because its physiological role and the enzymatic cascade underlying its activation are established. In this article we outline the research leading to elucidation of dTRP as the light activated channel and focus on a major physiological property of the dTRP channel, which is indirect activation via a cascade of enzymatic reactions. These detailed pioneering studies, based on the genetic dissection approach, revealed that light activation of the TRP channel is mediated by G-Protein-Coupled Receptor (GPCR)-dependent enzymatic cascade, in which phospholipase C β (PLC) is a crucial component. This physiological mechanism of TRP channel activation was later found in mammalian TRPC channels. However, the initial studies on the mammalian TRPV1 channel indicated that it is activated directly by capsaicin, low pH and hot temperature (>42 °C). This mechanism of activation was apparently at odds with the activation mechanism of the TRPC channels in general and the light activated TRP/TRPL channels in particular, which are target of a GPCR-activated PLC cascade. Subsequent studies have indicated that under physiological conditions TRPV1 is also target of a GPCR-activated PLC cascade in the generation of inflammatory pain. The light-activated TRP channel is still a useful experimental paradigm because its physiological function as the light-activated channel is known, powerful genetic techniques can be applied to its further analysis, and signaling molecules involved in the activation of these channels are available.

Spontaneous pauses in firing are the hallmark of external pallidum (GPe) neurons. However, the role of GPe pauses in the basal ganglia network remains unknown. Pupil size and saccadic eye movements have been linked to attention and exploration. Here, we recorded GPe spiking activity and the corresponding pupil sizes and eye positions in non-human primates. We show that pauses, rather than the GPe discharge rate per se, were associated with dilated pupils. In addition, following pause initiation there was a considerable increase in the rate of spontaneous saccades. These results suggest that pauses are a powerful mechanism by which the GPe may influence basal ganglia downstream structures and play a role in exploratory behavior.

Early-life adversity (ELA) increases the likelihood of neuropsychiatric diagnoses, which are more prevalent in women than men. Since changes in reproductive hormone levels can also increase the probability of anxiety disorders in women, we examined the effects of ELA on adult female mice across the estrous cycle. We found that during diestrus, when progesterone levels are relatively high, ELA mice exhibit increased avoidance behavior and increased theta oscillation power in the ventral hippocampus (vHIP). We also found that diestrus ELA mice had higher levels of progesterone and lower levels of allopregnanolone, a neurosteroid metabolite of progesterone, in the vHIP compared with control-reared mice. Progesterone receptor antagonism normalized avoidance behavior in ELA mice, while treatment with a negative allosteric modulator of allopregnanolone promoted avoidance behavior in control mice. These results suggest that altered vHIP progesterone and allopregnanolone signaling during diestrus increases avoidance behavior in ELA mice.

Emerging research indicates that physical activity can ameliorate chronic pain, but the underlying mechanisms are still largely obscure. In particular, little is known on the mechanisms behind exercise-induced analgesia in the setting of inflammatory pain. In our previous studies on systemic inflammation in mice using lipopolysaccharide (LPS) administration, we characterized satellite glial cells (SGCs) and neurons in dorsal root ganglia (DRG). We found that a week post-LPS injection, the sensitivity to mechanical stimulation was lowered, SGCs were activated and coupling among SGCs increased 3 to 4.5-fold. In the present work, we examined the effects of exercise (free wheel running) on tactile sensitivity and on pathological changes in mouse DRG in the LPS model. We found that exercise prevented tactile hypersensitivity, and also reversed the cellular changes in the DRG induced by LPS that were listed above. We propose that the analgesic effect of exercise is at least partly mediated by reversing the pathological changes in SGCs.

Primary sensory neurons in dorsal root ganglia (DRG) are wrapped by satellite glial cells (SGCs), and neuron-SGC interaction may affect somatosensation, especially nociceptive transmission. P2-purinergic receptors (P2Rs) are key elements in the two-way interactions between DRG neurons and SGCs. However, because the cell types are in such close proximity, conventional approaches such as in vitro culture and electrophysiologic recordings are not adequate to investigate the physiologically relevant responses of these cells at a population level. Here, we performed in vivo calcium imaging to survey the activation of hundreds of DRG neurons in Pirt-GCaMP6s mice and to assess SGC activation in GFAP-GCaMP6s mice in situ. By combining pharmacologic and electrophysiologic techniques, we investigated how ganglionic purinergic signaling initiated by α,β-methyleneadenosine 5'-triphosphate (α,β-MeATP) modulates neuronal activity and excitability at a population level. We found that α,β-MeATP induced robust activation of small neurons-likely nociceptors-through activation of P2X3R. Large neurons, which are likely non-nociceptive, were also activated by α,β-MeATP, but with a delay. Blocking pannexin 1 channels attenuated the late phase response of DRG neurons, indicating that P2R stimulation may subsequently induce paracrine ATP release, which could further activate cells in the ganglion. Moreover, ganglionic α,β-MeATP treatment in vivo sensitized small neurons and enhanced responses of spinal wide-dynamic-range neurons to subsequent C-fiber inputs, suggesting that modulation via ganglionic P2R signaling could significantly affect nociceptive neuron excitability and pain transmission. Therefore, targeting functional P2Rs within ganglia may represent an important new strategy for pain modulation.

Itch (pruritus) is a common chronic condition with a lifetime prevalence of over 20%. The mechanisms underlying itch are poorly understood, and its therapy is difficult. There is recent evidence that following nerve injury or inflammation, intercellular communications in sensory ganglia are augmented, which may lead to abnormal neuronal activity, and hence to pain, but there is no information whether such changes take place in an itch model. We studied changes in neurons and satellite glial cells (SGCs) in trigeminal ganglia in an itch model in mice using repeated applications of 2,4,6-trinitro-1-chlorobenzene (TNCB) to the external ear over a period of 11 days. Treated mice showed augmented scratching behavior as compared with controls during the application period and for several days afterwards. Immunostaining for the activation marker glial fibrillary acidic protein in SGCs was greater by about 35% after TNCB application, and gap junction-mediated coupling between neurons increased from about 2% to 13%. The injection of gap junction blockers reduced scratching behavior, suggesting that gap junctions contribute to itch. Calcium imaging studies showed increased responses of SGCs to the pain (and presumed itch) mediator ATP. We conclude that changes in both neurons and SGCs in sensory ganglia may play a role in itch.

Lorcaserin, a selective serotonin 5-HT receptor agonist, was developed as an appetite suppressant with the rationale of minimizing the risk of cardiovascular toxicity associated with non-selective serotoninergic agents such as fenfluramine. Eight years after FDA approval, however, it was withdrawn from the market, when a large safety study suggested a potential cancer risk. Following in the fenfluramine footsteps and utilizing the repurposing approach coupled with the regulatory orphan drug designation, lorcaserin is currently in clinical development for the treatment of epilepsy. This potential novel indication builds on the evidence that 5-HT receptor stimulation can protect against seizures, and accounts at least in part for fenfluramine's antiseizure effects in Dravet syndrome models. In animal models, lorcaserin shows a narrower range of antiseizure activity than fenfluramine. In particular, lorcaserin is inactive in classical acute seizure tests such as maximal electroshock and subcutaneous pentylenetetrazole in mice and rats, and the 6-Hz stimulation model in mice. However, it is active in the GAERS absence seizure model, and in mutant zebrafish models of Dravet syndrome. Preliminary uncontrolled studies in patients with Dravet syndrome have yielded promising results, and a phase III, double-blind, placebo-controlled, parallel group trial is currently ongoing to assess its efficacy and safety in children and adults with Dravet syndrome.

The Eilat Conferences have provided a forum for discussion of novel treatments of epilepsy among basic and clinical scientists, clinicians, and representatives from regulatory agencies as well as from the pharmaceutical industry for 3 decades. Initially with a focus on pharmacological treatments, the Eilat Conferences now also include sessions dedicated to devices for treatment and monitoring. The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain, on May 22-25, 2022 and was attended by 157 delegates from 26 countries. As in previous Eilat Conferences, the core of EILAT XVI consisted of a sequence of sessions where compounds under development were presented and discussed. This progress report summarizes preclinical and, when available, phase 1 clinical data on five different investigational compounds in preclinical or early clinical development, namely GAO-3-02, GRT-X, NBI-921352 (formerly XEN901), OV329, and XEN496 (a pediatric granular formulation of retigabine/ezogabine). Overall, the data presented in this report illustrate novel strategies for developing antiseizure medications, including an interest in novel molecular targets, and a trend to pursue potential new treatments for rare and previously neglected severe epilepsy syndromes.

The Sixteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVI) was held in Madrid, Spain on May 22-25, 2022 and was attended by 157 delegates from 26 countries representing basic and clinical science, regulatory agencies, and pharmaceutical industries. One day of the conference was dedicated to sessions presenting and discussing investigational compounds under development for the treatment of seizures and epilepsy. The current progress report summarizes recent findings and current knowledge for seven of these compounds in more advanced clinical development for which either novel preclinical or patient data are available. These compounds include bumetanide and its derivatives, darigabat, ganaxolone, lorcaserin, soticlestat, STK-001, and XEN1101. Of these, ganaxolone was approved by the US Food and Drug Administration in March 2022 for the treatment of seizures associated with cyclin-dependent kinase-like 5 deficiency disorder in patients 2 years of age and older.

BACKGROUND: the endocannabinoid system (ECS) participates in many physiological and pathological processes including pain generation, modulation, and sensation. Its involvement in chronic orofacial pain (OFP) in general, and the reflection of its involvement in OFP in salivary endocannabinoid (eCBs) levels in particular, has not been examined.

OBJECTIVES: to evaluate the association between salivary (eCBs) levels and chronic OFP.

METHODS: salivary levels of 2 eCBs, anandamide (AEA), 2-arachidonoylglycerol (2-AG), 2 endocannabinoid-like compounds-palmitoylethanolamine (PEA), -oleoylethanolamine (OEA), and their endogenous precursor and breakdown product, arachidonic acid (AA), were analyzed using liquid chromatography/tandem mass spectrometry in 83 chronic OFP patients and 43 pain-free controls. The chronic OFP patients were divided according to diagnosis into musculoskeletal, neurovascular/migraine, and neuropathic pain types.

RESULTS: chronic OFP patients had lower levels of OEA ( = 0.02) and 2-AG = 0.01). Analyzing specific pain types revealed lower levels of AEA and OEA in the neurovascular group 0.04, 0.02, respectively), and 2-AG in the neuropathic group compared to controls ( 0.05). No significant differences were found between the musculoskeletal pain group and controls. Higher pain intensity was accompanied by lower levels of AA ( = 0.028), in neuropathic group.

CONCLUSIONS: lower levels of eCBs were found in the saliva of chronic OFP patients compared to controls, specifically those with neurovascular/migraine, and neuropathic pain. The detection of changes in salivary endocannabinoids levels related to OFP adds a new dimension to our understanding of OFP mechanisms, and may have diagnostic as well as therapeutic implications for pain.

The endocannabinoid system is involved in physiological and pathological processes, including pain generation, modulation, and sensation. Its role in certain types of chronic orofacial pain (OFP) has not been thoroughly examined. By exploring the profiles of specific salivary endocannabinoids (eCBs) in individuals with different types of OFP, we evaluated their use as biomarkers and the influence of clinical parameters and pain characteristics on eCB levels. The salivary levels of anandamide (AEA), 2-arachidonoyl glycerol (2-AG), and their endogenous breakdown product arachidonic acid (AA), as well as the eCB-like molecules N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), were assessed in 83 OFP patients and 43 pain-free controls using liquid chromatography/tandem mass spectrometry. Patients were grouped by diagnosis: post-traumatic neuropathy (PTN), trigeminal neuralgia (TN), temporomandibular disorder (TMD), migraine, tension-type headache (TTH), and burning mouth syndrome (BMS). Correlation analyses between a specific diagnosis, pain characteristics, and eCB levels were conducted. Significantly lower levels of 2-AG were found in the TN and TTH groups, while significantly lower PEA levels were found in the migraine group. BMS was the only group with elevated eCBs (AEA) versus the control. Significant correlations were found between levels of specific eCBs and gender, health-related quality of life (HRQoL), BMI, pain duration, and sleep awakenings. In conclusion, salivary samples exhibited signature eCBs profiles for major OFP disorders, especially migraine, TTH, TN, and BMS. This finding may pave the way for using salivary eCBs biomarkers for more accurate diagnoses and management of chronic OFP patients.

OBJECTIVES: Burning mouth syndrome is an intraoral chronic pain condition characterized by a moderate to severe sensation of burning from the oral mucosa. No clinical signs are found and there is no efficient treatment.

METHOD AND MATERIALS: This pilot study included 10 women that were resistant to other previous treatments or noncompliant to systemic medications. Patients were asked to apply tretinoin gel 0.05% on their tongues twice daily for 14 days. Treatment effectiveness was assessed by completing a pre-study psychologic questionnaire and recording a daily wellbeing and pain log.

RESULTS: Significant pain-score decrease in 50% of the patients (delta numerical rating score -3.15 ± 3.02, P value = .005) was recorded. This finding was in concordance with the verbal statements including major quality-of-life improvement (P value = .05), without any treatment positive or negative predictive factors.

CONCLUSIONS: Topical tretinoin exhibits potential efficacy in patients with treatment resistant burning mouth syndrome and may also be used as a primary treatment modality.

It is nearly axiomatic that pain, among other examples of conscious experience, is an outcome of still-uncertain forms of neural processing that occur in the cerebral cortex, and specifically within thalamo-cortical networks. This belief rests largely on the dramatic relative expansion of the cortex in the course of primate evolution, in humans in particular, and on the fact that direct activation of sensory representations in the cortex evokes a corresponding conscious percept. Here we assemble evidence, drawn from a number of sources, suggesting that pain experience is unlike the other senses and may not, in fact, be an expression of cortical processing. These include the virtual inability to evoke pain by cortical stimulation, the rarity of painful auras in epileptic patients and outcomes of cortical lesions. And yet, pain perception is clearly a function of a conscious brain. Indeed, it is perhaps the most archetypical example of conscious experience. This draws us to conclude that conscious experience, at least as realized in the pain system, is seated subcortically, perhaps even in the "primitive" brainstem. Our conjecture is that the massive expansion of the cortex over the course of evolution was not driven by the adaptive value of implementing consciousness. Rather, the cortex evolved because of the adaptive value of providing an already existing subcortical generator of consciousness with a feed of critical information that requires the computationally intensive capability of the cerebral cortex.

Differences between therapeutic effects of medical cannabis inflorescences and those of their extracts are generally attributed to the differences in administration form and in the resultant pharmacokinetics. We hypothesized that difference may further extend to the composition of the actually consumed drug. Cannabinoid and terpene contents were compared between commercial cannabis inflorescences ( = 19) and decarboxylated extracts ( = 12), and between inflorescences and decarboxylated extracts produced from them ( = 10). While cannabinoid content was preserved in the extracts, a significant loss of terpenes was evident, mainly in the more volatile monoterpenes and monoterpenoids (representing a loss of about 90%). This loss changes the total terpene content, the proportion of monoterpenes out of the total terpenes, and the monoterpene/cannabinoid ratio. Terpene deficiency might impair extracts' pharmacological efficacy and might contribute to the patients' preference to inflorescences-smoking. This argues against the validity of terms such as "whole plant" and "full spectrum" extracts and creates a misleading assumption that extracts represent the pharmacological profile of the sourced inflorescences. Furthermore, it reduces the diversity in extracts, such as loss of differences between sativa-type and indica-type. Enriching cannabis extracts with selected terpenes may provide a suitable solution, generating a safe, precise, and reproducible drug with tailored cannabinoid and terpene contents. Careful selection of terpenes to be added enables tailor-made extracts, adjusted for various medicinal aims and for different populations.