Characteristics of α1-adrenoceptor antagonists-induced ejaculatory dysfunction on spontaneous seminal emission in rats.

Although α1-adrenoceptor (α1-AR) antagonists used to treat benign prostatic hyperplasia can cause ejaculation disorders, the aetiology of this adverse event is still controversial. Therefore, we investigated the effects of antagonists with different affinities for α1-AR subtypes on ejaculatory function and their mechanisms of action in normal rats. In the spontaneous seminal emission (SSE) test, systemically administered prazosin, terazosin, tamsulosin and naftopidil decreased the weight of ejaculated seminal material in a dose-dependent manner; the potency order was as follows: tamsulosin > terazosin > prazosin > naftopidil. The selective α1D-AR antagonist BMY7378 had no effect on SSE. Intrathecal tamsulosin and naftopidil did not inhibit SSE. Tamsulosin, the most potent, was ineffective as a single dose and significantly increased seminal vesicle fluid in rats treated for 2 weeks but did not significantly change retrograde ejaculation. These results indicated that the difference in inhibitory potency of the five α1-AR antagonists against SSE was due to the involvement of α1A-AR subtypes. Our results further suggested that α1-AR antagonist-induced ejaculatory dysfunction at the peripheral level was mainly due to the loss of seminal emission, although some retrograde ejaculation may also be involved.

Transgenic Mice for the Translational Study of Neuropathic Pain and Dystonia.

Murine models are fundamental in the study of clinical conditions and the development of new drugs and treatments. Transgenic technology has started to offer advantages in oncology, encompassing all research fields related to the study of painful syndromes. Knockout mice or mice overexpressing genes encoding for proteins linked to pain development and maintenance can be produced and pain models can be applied to transgenic mice to model the most disabling neurological conditions. Due to the association of movement disorders with sensitivity and pain processing, our group focused for the first time on the role of the torsinA gene GAG deletion-responsible for DYT1 dystonia-in baseline sensitivity and neuropathic responses. The aim of the present report are to review the complex network that exists between the chaperonine-like protein torsinA and the baseline sensitivity pattern-which are fundamental in neuropathic pain-and to point at its possible role in neurodegenerative diseases.

Analgesic Characteristics of NanoBEO Released by an Airless Dispenser for the Control of Agitation in Severe Dementia.

Chronic pain is one of the most common causes of the need for clinical evaluation, acquiring more importance in the elderly with cognitive impairment. Reduced self-reporting capabilities cause unrelieved pain contributing to the development of agitation. Safe and effective pain treatment can afford the management of agitation without the serious increase in death risk associated with neuroleptics. To this aim, the essential oil of bergamot (BEO), proven by rigorous evidence to have strong preclinical anti-nociceptive and anti-allodynic properties, has been engineered (NanoBEO, patent EP 4003294) to allow randomized, double-blind, placebo-controlled trials (BRAINAID, NCT04321889). The present study: (1) assesses the analgesic effects of a single therapeutic dose of NanoBEO, as supplied by an airless dispenser for clinical translation, in models of inflammatory, neuropathic, and sensitization types of pain relevant to clinic; (2) provides a dose-response analysis of the efficacy of NanoBEO on scratching behavior, a typical behavioral disturbance occurring in dementia. A single therapeutic dose of NanoBEO confirms efficacy following thirty minutes pre-treatment with capsaicin and on the central sensitization phase induced by formalin. Moreover, it has an ID50 of 0.6312 mg and it is efficacious on static and dynamic mechanical allodynia. Altogether, the gathered results strengthen the potential of NanoBEO for clinical management of pain and agitation.

Translational Value of the Transdermal Administration of Bergamot Essential Oil and of Its Fractions.

The essential oil of bergamot (BEO) has consistently proven antinociceptive and antiallodynic properties. Accordingly, the analgesic efficacy of the decolored essential oil (DEC), with higher levels of limonene, and the deterpenated (DET) fraction, with higher levels of linalool and linalyl acetate, was investigated using a formalin test after inhalation. The present study was aimed at characterizing the effects of BEO, its components with the highest pharmacological activity (represented by linalool, limonene, and linalyl acetate), and its DEC and DET fractions on the formalin test after transdermal administration relevant to clinical translation through topical application. To this aim, the schedule of intervention involved administration immediately after formalin injection or as a 5 min pretreatment followed by washout in ddY-strain mice. This study demonstrates, for the first time, the significant analgesic effect of all three constituents in the first and second phases, accounting for the efficacy of the essential oil in the formalin test. While all fractions revealed equal activity toward the phytocomplex in the early phase, the reduction in time of licking/biting during the late phase was more markedly induced by DEC. Moreover, pretreatment with BEO and its fractions followed by washout did not produce a significant reduction in licking/biting time in both phases of formalin-induced nociceptive response.

Preclinical Characterization of Antinociceptive Effect of Bergamot Essential Oil and of Its Fractions for Rational Translation in Complementary Therapy.

Bergamot essential oil (BEO) is endowed with consistent and reproducible antinociceptive and anti-allodynic properties when administered via an inhalation route. However, the effects of its main constituents and of its decolored (DEC) and deterpenated (DET) fractions, which are enriched in limonene or in linalool and linalyl acetate, respectively, on spontaneous motor activity related to anxiety and on formalin-induced licking/biting biphasic behavior have never been investigated before. Therefore, the present research aims to characterize the role of BEO components on an experimental pain model that is relevant to clinical translation. Under our present experimental conditions, a paper filter disc soaked with different volumes of the phytocomplex and of its fractions that was applied at the edge of the observation chamber allowed the effects on the spontaneous motor activity and on the formalin-induced nocifensive response in ddY-strain mice to be studied. The present research demonstrated the effects of the DEC fraction of BEO on motor activity and on formalin-induced licking/biting behavior for the first time, proving that limonene is implicated in reduced motor activity and that it is important for the analgesic effect.

TRPV4 activation prevents lipopolysaccharide-induced painful bladder hypersensitivity in rats by regulating immune pathways.

Chronic inflammation in the urinary bladder is a potential risk factor for bladder dysfunction, including interstitial cystitis/bladder pain syndrome (IC/BPS). Although several studies have reported that activation of transient receptor potential vanilloid 4 (TRPV4) contributes to bladder pain and overactive bladder with a cardinal symptom of acute or chronic cystitis, others have reported its involvement in the protective response mediated by lipopolysaccharides (LPS) to secrete anti-inflammatory/pro-resolution cytokines. Therefore, we investigated the potential benefit of an intravesical TRPV4 agonist for painful bladder hypersensitivity in a rat model of LPS-induced cystitis and determined whether its effects modulate the LPS signal for inflammatory reaction, cytokine release, and macrophage phenotype change. Previously, we showed that repeated intravesical instillations of LPS induce long-lasting bladder inflammation, pain, and overactivity in rats. In the present study, concurrent instillation of the selective TRPV4 agonist GSK1016790A (GSK) with LPS into the rat bladder improved LPS-induced bladder inflammation and reduced the number of mast cells. Furthermore, co-instillation of GSK prevented an increase in bladder pain-related behavior and voiding frequency caused by LPS. Cytokine profiling showed that LPS-stimulated inflammatory events, such as the production and secretion of pro-inflammatory cytokines (CXCL1, CXCL5, CXCL9, CXCL10, CCL3, CCL5, CCL20, and CX3CL1), are suppressed by GSK. Furthermore, TRPV4 activation switched LPS-stimulated pro-inflammatory M1-type macrophages to anti-inflammatory M2-type macrophages. These results suggest that TRPV4 activation in the bladder negatively regulates the pro-inflammatory response induced by LPS and prevents bladder hypersensitivity. These TRPV4 functions may be promising therapeutic targets for refractory IC/BPS.

Development and Translation of NanoBEO, a Nanotechnology-Based Delivery System of Bergamot Essential Oil Deprived of Furocumarins, in the Control of Agitation in Severe Dementia.

Dementia is one of the most common causes of disability worldwide characterized by memory loss, cognitive impairment, and behavioral and psychological symptoms (BPSD), including agitation. Treatment of the latter consists of the off-label use of harmful atypical antipsychotics, though a significant reduction is afforded by pain control. The use of an essential oil endowed with analgesic properties and devoid of toxicity would represent an important option for the management of agitation in dementia. Therefore, the aim of this study was to engineer a nanotechnology delivery system based on solid lipid nanoparticles loaded with bergamot essential oil (BEO) and devised in the pharmaceutical form of an odorless cream (NanoBEO) to confirm its analgesic efficacy for further development and application to control agitation in dementia. BEO has proven strong antinociceptive and anti-allodynic properties and, in its bergapten-free form, it is completely devoid of phototoxicity. NanoBEO has been studied in vivo confirming the previously reported analgesic activity of BEO to which is now added its anti-itching properties. Due to the nanotechnology delivery system, the stability of titrated BEO components is guaranteed. Finally, the latter invention, currently under patent consideration, is smell-devoid allowing efficacy and safety to be established in double-blind clinical trials; until now the latter studies have been impeded in aromatherapy by the strong odor of essential oils. A clinical trial NCT04321889 has been designed to provide information about the efficacy and safety of NanoBEO on agitation and pain in patients suffering from severe dementia.

Efficacy of Essential Oils in Pain: A Systematic Review and Meta-Analysis of Preclinical Evidence.

Background: The demand for essential oils (EOs) has been steadily growing over the years. This is mirrored by a substantial increase in research concerned with EOs also in the field of inflammatory and neuropathic pain. The purpose of this present systematic review and meta-analysis is to investigate the preclinical evidence in favor of the working hypothesis of the analgesic properties of EOs, elucidating whether there is a consistent rational basis for translation into clinical settings. Methods: A literature search has been conducted on databases relevant for medical scientific literature, i.e., PubMed/MEDLINE, Scopus, and Web of Science from database inception until November 2, 2020, following the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) criteria for systematic reviews and meta-analyses. Results: The search was conducted in order to answer the following PICOS (participants/population, interventions, comparisons, outcomes, and study design) question: are EOs efficacious in reducing acute nociceptive pain and/or neuropathic pain in mice experimental models? The search retrieved 2,491 records, leaving 954 studies to screen after the removal of duplicates. The title and abstract of all 954 studies were screened, which left 127 records to evaluate in full text. Of these, 30 articles were eligible for inclusion. Conclusion: Most studies (27) assessed the analgesic properties of EOs on acute nociceptive pain models, e.g. the acetic acid writhings test, the formalin test, and the hot plate test. Unfortunately, efficacy in neuropathic pain models, which are a more suitable model for human conditions of chronic pain, had fewer results (only three studies). Moreover, some methodologies raised concerns in terms of the risk of bias. Therefore, EOs with proven efficacy in both types of pain were corroborated by methodologically consistent studies, like the EO of bergamot, which should be studied in clinical trials to enhance the translational impact of preclinical modeling on clinical pain research.

Effect of Gabapentin in a Neuropathic Pain Model in Mice Overexpressing Human Wild-Type or Human Mutated Torsin A.

BACKGROUND: DYT1 dystonia is the most common form of early-onset inherited dystonia, which is caused by mutation of torsin A (TA) belonging to the "ATPases associated with a variety of cellular activities" (AAA + ATPase). Dystonia is often accompanied by pain, and neuropathic pain can be associated to peripherally induced movement disorder and dystonia. However, no evidence exists on the effect of gabapentin in mice subjected to neuropathic pain model overexpressing human normal or mutated TA. METHODS: Mice subjected to L5 spinal nerve ligation (SNL) develop mechanical allodynia and upregulation of the α2δ-1 L-type calcium channel subunit, forming a validated experimental model of neuropathic pain. Under these experimental conditions, TA is expressed in dorsal horn neurons and astrocytes and colocalizes with α2δ-1. Similar to this subunit, TA is overexpressed in dorsal horn 7 days after SNL. This model has been used to investigate (1) basal mechanical sensitivity; (2) neuropathic pain phases; and (3) the effect of gabapentin, an α2δ-1 ligand used against neuropathic pain, in non-transgenic (NT) C57BL/6 mice and in mice overexpressing human wild-type (hWT) or mutant (hMT) TA. RESULTS: In comparison to non-transgenic mice, the threshold for mechanical sensitivity in hWT or hMT does not differ (Kruskal-Wallis test = 1.478; p = 0.4777, although, in the latter animals, neuropathic pain recovery phase is delayed. Interestingly, gabapentin (100 mg/Kg) reduces allodynia at its peak (occurring between post-operative day 7 and day 10) but not in the phase of recovery. CONCLUSIONS: These data lend support to the investigation on the role of TA in the molecular machinery engaged during neuropathic pain.

Central Mechanisms of Apomorphine and m-Chlorophenylpiperazine on Synergistic Action for Ejaculation in Rats.

BACKGROUND: We previously reported that the combination of the dopamine (DA) receptor agonist apomorphine and the 5-hydroxytryptamine (5-HT2) receptor agonist m-chlorophenylpiperazine (m-CPP) in rats potently and selectively facilitates the ejaculatory response through activation of D2-like and 5-HT2C receptors, respectively. AIM: The aim of this study was to clarify the target level of the proejaculatory effects induced by combination of these agonists. METHODS: For in vivo behavioral studies, apomorphine and m-CPP were given intracerebroventricularly and intrathecally alone or in combination with either drug administered systemically. Male rats were acclimated to observational cages bedded in paper towels, and the occurrence of ex copula ejaculation was assessed by evaluating the presence and weight of ejaculatory plugs dropped from the tip of the penis to the paper towels or adhered to the tip of the penis at 30 min after drug administration. For in vitro contraction studies, seminal vesicles isolated from rats were suspended in an organ bath to test contractile responses to drug combinations, and the effects of the combined drugs on the contractile response of noradrenaline were also tested. MAIN OUTCOME MEASURES: The presence and weight of ejaculatory plugs produced by drug-induced ejaculation and the contractile responses of the seminal vesicle were evaluated. RESULTS: Intrathecal m-CPP (10 µg), but not intracerebroventricular m-CPP, evoked the synergistic effects on ejaculation when used in combination with systemically administered apomorphine (0.1 mg/kg, subcutaneous). Moreover, the synergy between m-CPP and apomorphine was completely abolished by the intrathecal 5-HT2C receptor antagonist SB242084 (10 µg). Intrathecal or intracerebroventricular apomorphine (1-10 µg) evoked proejaculatory effects in combination with systemically administered m-CPP (0.3 mg/kg, intraperitoneal). The selective peripherally acting D2-like receptor agonist carmoxirole did not evoke ejaculation when used in combination with m-CPP. Furthermore, isolated rat seminal vesicles were completely insensitive to the combination of apomorphine and m-CPP. CONCLUSION: These results indicated that the synergistic effects of the drugs on ejaculation were induced at the central level but not at peripheral sites. Our findings also suggested that the 5-HT2C receptor mediated the stimulation of the spinal ejaculatory pattern generator and was synergistically potentiated by the spinal DA receptor and that activation of the supraspinal DA receptor was also involved in mediating these synergistic effects. Yoshizumi M, Yonezawa A, Kimura Y, et al. Central Mechanisms of Apomorphine and m-Chlorophenylpiperazine on Synergistic Action for Ejaculation in Rats. J Sex Med 2021;18:231-239.

Gabapentin reduces painful bladder hypersensitivity in rats with lipopolysaccharide-induced chronic cystitis.

Although interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic condition causing bladder pain and urinary symptoms, effective treatments have not been established. The aim of this study was to adapt a chronic cystitis model in rats using lipopolysaccharide (LPS), which reflects IC/BPS pathology, and characterize the model's histological and behavioral effects. Furthermore, we investigated the effect of an α2 δ subunit ligand, gabapentin (GBP), on bladder hypersensitivity of rats with chronic cystitis. Cystitis models were created by repeated intravesical injections of LPS. In the histological examination, the LPS-injected group had greater inflammatory response, fibrosis, and abnormally thick re-epithelialization. In the LPS-injected group, LPS prompted hyperalgesia in both the lower abdomen and hind paw regions after day 1 of the first injection compared with the saline-injected controls, without any recovery for 21 days at least. During cystometry, the LPS-injected group showed bladder hyperactivity at all times. Systemic administration of GBP reduced cystitis-related pain due to chronic inflammation and reduced the increased frequency of voiding in the LPS-injected group. These results suggest that repeated intravesical injections of LPS induce long-lasting bladder inflammation, pain, and overactivity in rats, while GBP is effective in the management of those symptoms in this chronic cystitis model. The current study identifies a relatively simple method to develop an animal model for chronic cystitis and provides evidence that GBP may be an effective treatment option for patients with IC/BPS.

Morphine Antinociception Restored by Use of Methadone in the Morphine-Resistant Inflammatory Pain State.

The antinociceptive effect of methadone in the morphine-resistant inflammatory pain state was described in the paw-withdrawal test using the complete Freund's adjuvant (CFA)-induced mouse inflammatory pain model. After intraplantar (i.pl.) injection of CFA, thermal hyperalgesia was observed in the ipsilateral paw. The antinociceptive effects of subcutaneous (s.c.) injection of morphine, fentanyl, and oxycodone against thermal hyperalgesia in the inflammatory pain state were reduced in the ipsilateral paw 7 days after CFA pretreatment. On the contrary, the antinociceptive effect of s.c. injection of methadone was maintained in the ipsilateral paw 7 days after CFA pretreatment. The suppressed morphine antinociception in the CFA model mice was bilaterally restored following s.c. treatment with methadone 20 min prior to or 3 days after CFA pretreatment. The suppressed morphine antinociception was also bilaterally restored by intraperitoneal treatment with MK-801 30 min prior to CFA pretreatment; however, the s.c. injection of morphine 30 min prior to CFA pretreatment failed to restore the suppressed morphine antinociception in the CFA model mice. The expression level of mRNA for µ-opioid receptors 7 days after i.pl. pretreatment was not significantly changed by i.pl. pretreatment with CFA or s.c. pretreatment with methadone. In conclusion, methadone is extremely effective against thermal hyperalgesia in the morphine-resistant inflammatory pain state, and restores suppressed morphine antinociception in the inflammatory pain state without altering the expression level of mRNA for µ-opioid receptors.

Contribution of Histamine to Nociceptive Behaviors Induced by Intrathecally Administered Cholecystokinin-8.

The involvement of spinal release of histamine in the nociceptive behaviors induced by cholecystokinin-8 (CCK-8) was investigated in mice. Intrathecal (i.t.) injection of CCK-8 elicited the nociceptive behaviors consisting of biting and licking. The nociceptive behaviors induced by i.t. treatment with CCK-8 showed two bell-shaped patterns. The histamine H3 receptor antagonist significantly promoted the nociceptive behaviors induced by CCK-8 at doses of 1-100 fmol and 100 pmol. The nociceptive behaviors elicited by CCK-8 was inhibited by i.t. administration of the CCK-B receptor antagonist in a dose-dependent manner, but not by the CCK-A receptor antagonist. The nociceptive behaviors induced by CCK-8 were markedly suppressed by i.t. pretreatment with antiserum against histamine and were abolished in histidine decarboxylase-deleted gene mice. In histamine H1 receptor-deleted gene mice, the nociceptive behaviors induced at both 10 amol and 10 pmol of CCK-8 were not affected. The tachykinin neurokinin-1 (NK1) receptor antagonists inhibited CCK-8 (10 pmol)-induced nociceptive behaviors in a dose-dependent manner. CCK-8 (10 amol)-induced nociceptive behaviors was not antagonized by co-administration with the tachykinin NK1 receptor antagonists. The nociceptive behaviors elicited by CCK-8 were inhibited by i.t. administration of the antagonist for the N-methyl-D-aspartate (NMDA) receptor in a dose-dependent manner. Our results suggest that the nociceptive behaviors induced by i.t. administration of CCK-8 (10 pmol) are mediated through the spinal release of histamine and are elicited via activation of the tachykinin NK1 and NMDA receptors, whereas the nociceptive behaviors induced by i.t. administration of CCK-8 (10 amol) are mediated through the spinal release of histamine and elicited via NMDA receptor activation.

Impact of nutraceuticals on glaucoma: A systematic review.

BACKGROUND: glaucoma is a remarkable social issue being the leading cause of irreversible blindness worldwide. It is a progressive neuropathy characterized by the death of the retinal ganglion cells, of which the most important risk factor is represented by the increase of intraocular pressure (IOP). The role of nutraceutical supplementations with anti-oxidant activity has been extensively tested in preclinical models of glaucoma. The clinical efficacy of nutraceuticals in glaucoma is still controversial. OBJECTIVES: the aim of this systematic review is to assess the efficacy of nutraceuticals with anti-oxidant activity in glaucoma through the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) rigorous criteria. DATA SOURCES: the literature search has been performed on the electronic databases currently recognized of most relevance for medical scientific literature, i.e. PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials (CENTRAL) with access to EMBASE, ClinicalTrials.gov and Scopus. The date of last search is April 8th, 2020. Study eligibility criteria, participants, and interventions: prospective randomized clinical trials assessing the effects of nutraceuticals and anti-oxidants on IOP and/or visual field in patients with glaucoma. The eligible papers must be published in English and available in full text. STUDY APPRAISAL AND SYNTHESIS METHODS: the evaluation of the eligibility of the studies has been carried out independently by two authors. The selection process has followed the PRISMA flow diagram, assessing the quality of the body of evidence and the risk of bias. RESULTS: the search of literature has retrieved 1615 papers and 2 clinical trials with results, among which only 6 are eligible for inclusion in the present systematic review to address the preset participants, interventions, comparisons, outcomes and study design (PICOS) "are the nutraceuticals effective in glaucoma?". In 5 out of 6 studies the nutraceutical supplementation is effective in providing additional decrease of IOP to current usual therapy, without the occurrence of side effects. However, all the studies present high heterogeneity and some concerns in terms of risk of bias, apart from one trial for which the risk of bias is low. CONCLUSIONS: the evidence of effectiveness of nutraceutical formulations is still uncertain and inconclusive. Therefore, large double-blind randomized clinical trials with adequate design, methodology and statistical power are needed to support the use of nutraceuticals in glaucoma.

Pharmacokinetic Interactions between Herbal Medicines and Drugs: Their Mechanisms and Clinical Relevance.

The therapeutic efficacy of a drug or its unexpected unwanted side effects may depend on the concurrent use of a medicinal plant. In particular, constituents in the medicinal plant extracts may influence drug bioavailability, metabolism and half-life, leading to drug toxicity or failure to obtain a therapeutic response. This narrative review focuses on clinical studies improving knowledge on the ability of selected herbal medicines to influence the pharmacokinetics of co-administered drugs. Moreover, in vitro studies are useful to anticipate potential herbal medicine-drug interactions. In particular, they help to elucidate the cellular target (metabolic or transporter protein) and the mechanism (induction or inhibition) by which a single constituent of the herbal medicine acts. The authors highlight the difficulties in predicting herbal-drug interactions from in vitro data where high concentrations of extracts or their constituents are used and pharmacokinetics are missed. Moreover, the difficulty to compare results from human studies where different kinds of herbal extracts are used is discussed. The herbal medicines discussed are among the best sellers and they are reported in the "Herbal Medicines for Human Use" section of the European Medicinal Agency (EMA).

Role of 5-HT1A Receptor in the Anxiolytic-Relaxant Effects of Bergamot Essential Oil in Rodent.

The essential oil obtained by the fresh fruit of Citrus bergamia Risso et Poiteau is used worldwide in aromatherapy to reduce pain, facilitate sleep induction, and/or minimize the effects of stress-induced anxiety. Preclinical pharmacological data demonstrate that bergamot essential oil (BEO) modulates specific neurotransmissions and shows an anxiolytic-relaxant effect not superimposable to that of the benzodiazepine diazepam, suggesting that neurotransmissions, other than GABAergic, could be involved. Several studies on essential oils indicate a role for serotonergic (5-HT) neurotransmission in anxiety. Interestingly, among serotonergic receptors, the 5-HT1A subtype seems to play a key role in the control of anxiety. Here, we report that modulation of the 5-HT1A receptor by selective agonist ((±)8-OH-DPAT) or antagonist (WAY-100635) may influence some of the anxiolytic-relaxant effects of BEO in Open Field and Elevated Plus Maze tests.

Neuropharmacological Properties of the Essential Oil of Bergamot for the Clinical Management of Pain-Related BPSDs.

BACKGROUND: Alzheimer's Disease (AD) accounts for approximately 50% of all cases of dementia and, in spite of the great effort for the development of disease-modifying drugs, a definitive treatment of cognitive impairment is not available yet. A perfect adherence to the current therapy of cognitive decline is needed for a better control of the disease and this is proven to reduce, though not completely abolish, the associated Behavioural and Psychological Symptoms of Dementia (BPSDs) from occurring. This cluster of symptoms, remarkably affecting patients' health-related quality of life (HRQL), is tightly associated with pain states. Antipsychotics are the only treatment for BPSDs. However, these drugs are more effective and safer in the short-term (6-12 weeks), they are able to manage aggression but not agitation and they cannot control pain. Aromatherapy with Melissa officinalis and Lavandula officinalis has been employed to handle BPSDs, but it has not provided strong evidence to offer relief from pain. OBJECTIVE: Bergamot Essential Oil (BEO) exerts antinociceptive activity through several pharmacological mechanisms: in particular, it is able to enhance autophagy, a process undergoing derangement in chronic pain. Thus, the sound pharmacological basis for clinical translation of aromatherapy with BEO in the treatment of BPSDs has been pointed out. CONCLUSION: The antinociceptive effects elicited by BEO in experimental pain models make it a possible candidate for the pharmacological management of pain-related BPSDs.

Antinociceptive effect of inhalation of the essential oil of bergamot in mice.

Bergamot essential oil (BEO) has proven wide evidence of pharmacological antinociceptive effectiveness both in nociceptive and in neuropathic pain models. The antinociceptive properties of BEO for inhalation have not been investigated. The purpose of this study is to evaluate the effects of the inhalation of BEO on formalin-induced nociceptive response in mice. Male ddY-strain mice (Japan SLC, Hamamatsu, Japan) of 23-25 g of weight at the time the experiments underwent the formalin test. Twenty µl of formalin (2% in saline) were administered into the plantar surface of the mice hindpaw and the time of licking/biting was observed and recorded at intervals of 5 min. The device for BEO inhalatory delivery consisted in a filter paper disc soaked with known volume of BEO placed on the edge of the cage. Inhalation of BEO exerted antinociceptive activity. In particular, it reduced the formalin-induced licking/biting behaviour in a manner that was dependent on the volume of BEO used in the device for its release and on the time of exposure to the phytocomplex. The results support the use of BEO in aromatherapy for complementary management of chronic pain relief in a stepwise therapeutic programme.

The involvement of spinal release of histamine on nociceptive behaviors induced by intrathecally administered spermine.

The involvement of spinal release of histamine on nociceptive behaviors induced by spermine was examined in mice. Intrathecal spermine produced dose-dependent nociceptive behaviors, consisting of scratching, biting and licking. The nociceptive behaviors induced by spermine at 0.02 amol and 10 pmol were markedly suppressed by i.t. pretreatment with antiserum against histamine and were abolished in histidine decarboxylase-deficient mice. In histamine H1 receptor-deficient mice, the nociceptive behaviors induced by spermine were completely abolished after treatment with 0.02 amol of spermine and significantly suppressed after treatment with 10 pmol of spermine. The i.t. pretreatment with takykinin NK1 receptor antagonists eliminated the nociceptive behaviors induced by 0.02 amol of spermine, but did not affect the nociceptive behaviors induced by 10 pmol of spermine. On the other hand, the nociceptive behaviors induced by spermine at both 0.02 amol and 10 pmol were suppressed by i.t. pretreatment with antagonists for the NMDA receptor polyamine-binding site. The present results suggest that the nociceptive behaviors induced by i.t. administration of spermine are mediated through the spinal release of histamine and are elicited via activation of NMDA receptors.