Synthesis of unnatural morphinan compounds to induce itch-like behaviors in mice: Towards the development of MRGPRX2 selective ligands.

Mas-related G protein-coupled receptor X2 (MRGPRX2) mediates the itch response in neurons and is involved in atopic dermatitis (AD)-associated inflammation and itch. Potent and MRGPRX2-selective ligands are essential to an understanding of the detailed function of the receptor and to develop new therapeutic agents for its related diseases. (+)-TAN-67 (1), the enantiomer of the δ-opioid receptor (DOR) selective ligand (-)-TAN-67 (1), has been reported to activate MRGPRX2, although (+)-1 also interacts with DOR, which prevents investigators from interrogating the function of MRGPRX2. Here, we have succeeded in developing a novel unnatural morphinan compound (+)-2a by a transformation based on the structure of (+)-1, which removes the DOR binding affinity. (+)-2a activated both human MRGPRX2 and the mouse orthologue Mrgprb2 in in vitro experiments and induced itch-like behaviors in mice to the same extent as (+)-1. The (+)-2a-induced itch response in mice was suppressed by administration of the tripeptide QWF, an MRGPRX2/Mrgprb2 antagonist, or the antipruritic drug nalfurafine. Together, (+)-2a serves as a useful tool to elucidate the itch-related function/action of MRGPRX2 and its mouse orthologue Mrgprb2.

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.

Bergamot Essential Oil Attenuates Anxiety-Like Behaviour in Rats.

Preclinical studies have recently highlighted that bergamot essential oil (BEO) is endowed with remarkable neurobiolological effects. BEO can affect synaptic transmission, modulate electroencephalographic activity and it showed neuroprotective and analgesic properties. The phytocomplex, along with other essential oils, is also widely used in aromatherapy to minimize symptoms of stress-induced anxiety and mild mood disorders. However, only limited preclinical evidences are actually available. This study examined the anxiolytic/sedative-like effects of BEO using an open field task (OFT), an elevated plus-maze task (EPM), and a forced swimming task (FST) in rats. This study further compared behavioural effects of BEO to those of the benzodiazepine diazepam. Analysis of data suggests that BEO induces anxiolytic-like/relaxant effects in animal behavioural tasks not superimposable to those of the DZP. The present observations provide further insight to the pharmacological profile of BEO and support its rational use in aromatherapy.

Analgesic Effects of 1st Generation Anti-histamines in Mice.

Pain is sensed, transmitted, and modified by a variety of mediators and receptors. Histamine is a well-known mediator of pain. In addition to their anti-histaminic effects, the classical, or 1st generation, anti-histamines (1st AHs) possess, to various degrees, anti-muscarinic, anti-serotonergic, anti-adrenergic, and other pharmacologic effects. Although there have been attempts to use 1st AHs as analgesics and/or analgesic adjuvants, the advent of non-steroidal anti-inflammatory drugs (NSAIDs) discouraged such trials. We previously reported that in patients with temporomandibular disorders, osteoporosis, and/or osteoarthritis, the analgesic effects of certain 1st AHs (chlorpheniramine and diphenhydramine) are superior to those of the NSAIDs flurbiprofen and indomethacin. Here, we compared analgesic effects among 1st AHs and NSAIDs against responses shown by mice to intraperitoneally injected 0.7% acetic acid. Since 1st AHs are water soluble, we selected water-soluble NSAIDs. For direct comparison, drugs were intravenously injected 30 min before the above tests. Histamine-H1-receptor-deficient (H1R-KO) mice were used for evaluating H1-receptor-independent effects. The tested 1st AHs (especially cyproheptadine) displayed or tended to display analgesic effects comparable to those of NSAIDs in normal and H1R-KO mice. Our data suggest that the anti-serotonergic and/or anti-adrenergic effects of 1st AHs make important contributions to their analgesic effects. Moreover, combination of a 1st AH with an NSAID (cyclooxygenase-1 inhibitor) produced remarkably potent analgesic effects. We propose that a 1st AH, by itself or in combination with a cyclooxygenase-1 inhibitor, should undergo testing to evaluate its usefulness in analgesia.

The involvement of central nervous system histamine receptors in psychological stress-induced exacerbation of allergic airway inflammation in mice.

BACKGROUND: Psychological stress is one of the major risk factors for asthma exacerbation. Although histamine in the brain acts as an excitatory and inhibitory neurotransmitter associated with psychological stress, the contribution of brain histamine to psychological stress-induced exacerbation of asthma remains unclear. The objective of this study was to investigate the role of histamine receptors in the CNS on stress induced asthma aggravation. METHODS: We monitored the numbers of inflammatory cells and interleukin (IL)-13 levels in bronchoalveolar lavage fluid, airway responsiveness to inhaled methacholine, mucus secretion in airway epithelial cells, and antigen-specific IgE contents in sera in a murine model of stress-induced asthma treated with epinastine (an H1R antagonist), thioperamide (an H3/4R antagonist), or solvent. RESULTS: All indicators of stress-induced asthma exacerbation were significantly reduced in stressed mice treated with epinastine compared with those treated with solvent, whereas treatment with thioperamide did not reduce the numbers of inflammatory cells in the stressed mice. CONCLUSIONS: These results suggest that H1R, but not H3/4R, may be involved in stress-induced asthma exacerbations in the central nervous system.

Potential involvement of µ-opioid receptor dysregulation on the reduced antinociception of morphine in the inflammatory pain state in mice.

The antinociceptive effect of morphine in the inflammatory pain state was described in the von Frey filament test using the complete Freund's adjuvant (CFA)-induced mouse inflammatory pain model. After an i.pl. injection of CFA, mechanical allodynia was observed in the ipsilateral paw. The antinociceptive effect of morphine injected s.c. and i.t. against mechanical allodynia was reduced bilaterally at 1 day and 4 days after the CFA pretreatment. The expression level of mRNA for µ-opioid receptors at 1 day after the CFA pretreatment was reduced bilaterally in the lumbar spinal cord and dorsal root ganglion (DRG). In contrast, the protein level of µ-opioid receptors at 1 day after CFA pretreatment was decreased in the ipsilateral side in the DRG but not the lumbar spinal cord. Single or repeated i.t. pretreatment with the protein kinase Cα (PKCα) inhibitor Ro-32-0432 completely restored the reduced morphine antinociception in the contralateral paw but only partially restored it in the ipsilateral paw in the inflammatory pain state. In conclusion, reduced morphine antinociception against mechanical allodynia in the inflammatory pain state is mainly mediated via a decrease in µ-opioid receptors in the ipsilateral side and via the desensitization of µ-opioid receptors in the contralateral side by PKCα-induced phosphorylation.

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.

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.

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.

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.

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.

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.

The involvement of micro-opioid receptors in the central nervous system in the worsening of allergic airway inflammation by psychological stress in mice.

BACKGROUND: Psychological stress has a recognized association with asthma symptoms. However, the mechanisms linking stress to the exacerbation of asthma are not well defined. mu-Opioid receptors (MOR) have been shown to be involved in the shift of the immune system toward a Th2-predominant response caused by psychological stress. OBJECTIVE: To test the hypothesis that MOR play a role in the worsening of allergic airway inflammation evoked by psychological stress. METHODS: Sensitized mice were exposed to restraint stress followed by antigen challenge. The levels of corticosterone and ovalbumin (OVA)-specific IgE in the blood and the levels of inflammatory cells and cytokine contents in bronchoalveolar lavage fluid were compared between stressed and nonstressed mice. The effects of MOR gene deletion and MOR antagonists/agonists were also investigated. RESULTS: Stress exposure was confirmed by an increase in corticosterone levels. Although OVA-specific IgE levels were not significantly different, the numbers of inflammatory cells and Th2 cytokine levels after antigen challenge in stressed mice were significantly higher than in nonstressed mice. MOR gene deletion ameliorated the stress-induced worsening of antigen-induced airway inflammation, and the administration of morphine, a MOR agonist, reproduced the stress-induced antigen-induced airway inflammation. Selective blocking of MOR in the central nervous system (CNS) significantly reduced stress-induced inflammatory exacerbation, but the blocking of peripheral MOR did not. CONCLUSIONS: MOR in the CNS are involved in psychological stress-induced aggravation of allergic airway inflammation.

Exploring µ-Opioid Receptor Splice Variants as a Specific Molecular Target for New Analgesics.

Since a µ-opioid receptor gene containing multiple exons has been identified, the variety of splice variants for µ-opioid receptors have been reported in various species. Amidino-TAPA and IBNtxA have been discovered as new analgesics with different pharmacological profiles from morphine. These new analgesics show a very potent analgesic effect but do not have dependence liability. Interestingly, these analgesics show the selectivity to the morphine-insensitive µ-opioid receptor splice variants. The splice variants, sensitive to these new analgesics but insensitive to morphine, may be a better molecular target to develop the analgesics without side effects.

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.

Effects of insulin replacement on ejaculatory dysfunction in streptozotocin-induced diabetic rats.

OBJECTIVES: To investigate the effects of insulin replacement on ejaculatory dysfunction in streptozotocin (STZ)-induced diabetic rats. METHODS: Rats were divided into three groups: (i) STZ-treated group; (ii) STZ-treated + insulin replacement (5 and 2 international units [IU]) group; and (iii) control group. The ejaculatory function in rats was evaluated using the spontaneous seminal emission (SSE) test. The amount of seminal vesicle fluid (SVF) stored in seminal vesicle was measured after the SSE test. Blood glucose was measured using a simplified blood glucose meter. RESULTS: In the SSE test, the ejaculatory capacity in STZ-induced diabetic rats deteriorated with time after the onset of diabetes, and the incidence of SSE and the amount of ejaculated seminal material (SM) were significantly decreased from 5 weeks after STZ administration. Likewise, the amount of SVF was also significantly decreased in a time-dependent manner. One week after STZ administration when ejaculatory capacity had not yet diminished, insulin replacement (for 4 weeks) completely prevented the decrease in frequency of SSE, the amount of SM and SVF. However, insulin replacement after the dysfunction had occurred (5 or 15 weeks after STZ administration) did not allow all parameters for ejaculatory function to be restored to the levels of the control group. CONCLUSION: This study demonstrates that at an early stage following the onset of diabetes, insulin replacement can prevent ejaculatory dysfunction in STZ-induced diabetic rats, but once the dysfunction occurs, treatment with insulin alone does not restore the ejaculatory capacity to normal levels. In addition, this study suggests that the loss of seminal emission that results from a decrease in SVF may be involved in the mechanism of ejaculatory dysfunction in diabetic rats.

Anxiolytic-Like Effects of Bergamot Essential Oil Are Insensitive to Flumazenil in Rats.

Anxiety disorders are one of the most common mental disorders, and benzodiazepines (BDZs), acting on gamma-aminobutyric acid type A (GABA-A) receptor complex, represent the most common antianxiety medications in the world. However, chronic BDZ use elicits several adverse reactions. Reportedly, aromatherapy is safer for the management of anxiety. Bergamot essential oil (BEO) extracted from Citrus bergamia Risso et Poiteau fruit, like other essential oils, is widely used in aromatherapy to relieve symptoms of stress-induced anxiety. Interestingly, preclinical data indicate that BEO induces anxiolytic-like/relaxant effects in animal behavioural tasks not superimposable to those of benzodiazepine diazepam. To better elucidate the involvement of GABAergic transmission, the present study examines the effects of pretreatment with flumazenil (FLZ), a benzodiazepine site antagonist, on BEO effects using open-field task (OFT) in rats. The data yielded show that FLZ does not significantly affect behavioural effects of the phytocomplex. These results demonstrate the lack of overlapping between BEO and BDZ behavioural effects, contributing to the characterization of the neurobiological profile of the essential oil for its rational use in aromatherapy.

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.

Possible involvement of dynorphin A release via mu1-opioid receptor on supraspinal antinociception of endomorphin-2.

It has been demonstrated that the antinociception induced by i.t. or i.c.v. administration of endomorphins is mediated through mu-opioid receptors. Moreover, though endomorphins do not have appreciable affinity for kappa-opioid receptors, pretreatment with the kappa-opioid receptor antagonist nor-binaltorphimine markedly blocks the antinociception induced by i.c.v.- or i.t.-injected endomorphin-2, but not endomorphin-1. These evidences propose the hypothesis that endomorphin-2 may initially stimulate the mu-opioid receptors, which subsequently induces the release of dynorphins acting on kappa-opioid receptors to produce antinociception. The present study was performed to determine whether the release of dynorphins by i.c.v.-administered endomorphin-2 is mediated through mu-opioid receptors for producing antinociception. Intracerebroventricular pretreatment with an antiserum against dynorphin A, but not dynorphin B or alpha-neo-endorphin, and s.c. pretreatment with kappa-opioid receptor antagonist nor-binaltorphimine dose-dependently attenuated the antinociception induced by i.c.v.-administered endomorphin-2, but not endomorphin-1 and DAMGO. The attenuation of endomorphin-2-induced antinociception by pretreatment with antiserum against dynorphin A or nor-binaltorphimine was dose-dependently eliminated by additional s.c. pretreatment with a selective mu-opioid receptor antagonist beta-funaltrexamine or a selective mu1-opioid receptor antagonist naloxonazine at ultra low doses, which are inactive against micro-opioid receptor agonists in antinociception, suggesting that endomorphin-2 stimulates distinct subclass of micro1-opioid receptor that induces the release of dynorphin A acting on kappa-opioid receptors in the brain. It concludes that the antinociception induced by supraspinally administered endomorphin-2 is in part mediated through the release of endogenous kappa-opioid peptide dynorphin A, which is caused by the stimulation of distinct subclass of micro1-opioid receptor.

Intrathecal high-dose histamine induces spinally-mediated nociceptive behavioral responses through a polyamine site of NMDA receptors.

Previous research has demonstrated that a high dose of histamine (1600 pmol) injected i.t. in mice can evoke nociceptive behaviors consisting of biting/licking along with occasional scratching. The present study was undertaken to examine the involvement of spinal N-methyl-d-aspartate (NMDA) and histamine H(1) and H(2) receptors in the nociceptive behaviors evoked by high-dose histamine. Co-administration of the histamine H(1) receptor antagonists, d-chlorpheniramine and pyrilamine, or the histamine H(2) receptor antagonists, ranitidine and zolantidine, failed to suppress the histamine-evoked nociceptive behaviors. Moreover, following histamine administration, nociceptive behaviors in histamine H(1) receptor-knockout and histamine H(2) receptor-knockout mice were indistinguishable from those in wild-type mice, suggesting that histamine-induced nociceptive behaviors are not mediated through histamine H(1) and H(2) receptors in the spinal cord. The histamine-induced nociceptive behaviors were inhibited by co-administration of the competitive NMDA receptor antagonists, d-(-)-2-amino-5-phosphonovaleric acid (D-APV) and 3-((+)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPPA), and the ion channel blocker, (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine maleate (MK-801). Co-administration of ifenprodil, an antagonist for both the polyamine site and the NR2B subunit of NMDA receptors, also inhibited the histamine-induced nociceptive behaviors. (R-[R, S])-alpha-(4-hydroxyphenyl)-beta-methyl-4-(phenylmethyl)-1-piperidinepropanol hydrochloride (Ro25-6981), an antagonist of the NMDA receptor subtype containing the NR2B subunit, did not inhibit histamine-induced nociceptive behaviors, whereas these behaviors were attenuated by pretreatment with an antisense oligodeoxynucleotide against the mRNA for the NR1 subunit of the NMDA receptor. Moreover, agmatine and arcaine, antagonists for a polyamine site on the NMDA receptor, inhibited nociceptive behaviors induced by histamine. These results suggest that a polyamine site on spinal NMDA receptors is involved in eliciting the nociceptive behavioral episode following intrathecal injection of histamine.