•The S1-R agonist PRE-084 altered ethanol-induced CTA at late adolescence.•PRE-084 did not alter ethanol-induced CTA at early adolescence.•S1-R may play a key role in the ontogeny of ethanol-induced ...CTA.
Ethanol-induced conditioned taste aversion (CTA) is greater in late adolescence or young adulthood than in early adolescence. The role of the sigma receptor system in this age-related difference has not been extensively explored, particularly in female rats. This study assessed the effects of the activation of sigma-1 receptors (S1-R), via the selective S1-R agonist PRE-084, on ethanol-induced CTA at early or at terminal adolescence/emerging adulthood (28 or 56 days-old at the beginning of the procedures, respectively) in female Wistar rats. The modulation of binge-like ethanol intake by PRE-084 was assessed at terminal adolescence. S1-R activation at the acquisition of ethanol-induced CTA attenuated such learning at terminal but not at early adolescence. PRE-084 did not significantly affect ethanol binge drinking in the terminal adolescents. These results highlight the role of S1-R in ethanol-induced CTA and suggest that differential functionality of this transmitter system may underlie age-specific sensitivities to the aversive effects of ethanol.
Tetrodotoxin (TTX) is a potent neurotoxin that blocks voltage-gated sodium channels (VGSCs). VGSCs play a critical role in neuronal function under both physiological and pathological conditions. TTX ...has been extensively used to functionally characterize VGSCs, which can be classified as TTX-sensitive or TTX-resistant channels according to their sensitivity to this toxin. Alterations in the expression and/or function of some specific TTX-sensitive VGSCs have been implicated in a number of chronic pain conditions. The administration of TTX at doses below those that interfere with the generation and conduction of action potentials in normal (non-injured) nerves has been used in humans and experimental animals under different pain conditions. These data indicate a role for TTX as a potential therapeutic agent for pain. This review focuses on the preclinical and clinical evidence supporting a potential analgesic role for TTX. In addition, the contribution of specific TTX-sensitive VGSCs to pain is reviewed.
Visceral pain is very common and represents a major unmet clinical need for which current pharmacological treatments are often insufficient. Tetrodotoxin (TTX) is a potent neurotoxin that exerts ...analgesic actions in both humans and rodents under different somatic pain conditions, but its effect has been unexplored in visceral pain. Therefore, we tested the effects of systemic TTX in viscero-specific mouse models of chemical stimulation of the colon (intracolonic instillation of capsaicin and mustard oil) and intraperitoneal cyclophosphamide-induced cystitis. The subcutaneous administration of TTX dose-dependently inhibited the number of pain-related behaviors in all evaluated pain models and reversed the referred mechanical hyperalgesia (examined by stimulation of the abdomen with von Frey filaments) induced by capsaicin and cyclophosphamide, but not that induced by mustard oil. Morphine inhibited both pain responses and the referred mechanical hyperalgesia in all tests. Conditional nociceptor‑specific Na
1.7 knockout mice treated with TTX showed the same responses as littermate controls after the administration of the algogens. No motor incoordination after the administration of TTX was observed. These results suggest that blockade of TTX-sensitive sodium channels, but not Na
1.7 subtype alone, by systemic administration of TTX might be a potential therapeutic strategy for the treatment of visceral pain.
Sigma-1 (σ(1)) receptors play a role in different types of pain and in central sensitization mechanisms; however, it is unknown whether they are involved in chemotherapy-induced neuropathic pain. We ...compared the ability of paclitaxel to induce cold (acetone test) and mechanical (electronic Von Frey test) allodynia in wild-type (WT) and σ(1) receptor knockout (σ(1)-KO) mice. We also tested the effect on paclitaxel-induced painful neuropathy of BD-1063 (16-64 mg/kg, subcutaneously) and S1RA (32-128 mg/kg, subcutaneously), 2 selective σ(1) receptor antagonists that bind to the σ(1) receptor with high affinity and competitively. The responses to cold and mechanical stimuli were similar in WT and σ(1)-KO mice not treated with paclitaxel; however, treatment with paclitaxel (2 mg/kg, intraperitoneally, once per day during 5 consecutive days) produced cold and mechanical allodynia and an increase in spinal cord diphosphorylated extracellular signal-regulated kinase (pERK) in WT but not in σ(1)-KO mice. The administration of BD-1063 or S1RA 30 minutes before each paclitaxel dose prevented the development of cold and mechanical allodynia in WT mice. Moreover, the acute administration of both σ(1) receptor antagonists dose dependently reversed both types of paclitaxel-induced allodynia after they had fully developed. These results suggest that σ(1) receptors play a key role in paclitaxel-induced painful neuropathy.
Antagonists of the σ(1) receptor may have therapeutic value for the treatment and/or prevention of paclitaxel-induced neuropathic pain. This possibility is especially interesting in the context of chemotherapy-induced neuropathy, where the onset of nerve damage is predictable and preventive treatment could be administered.
Binge drinking at adolescence is a risk factor for problematic alcohol (ethanol) consumption later in life, yet the murine studies that modelled this phenomenon via ethanol self-administration have ...provided mixed findings. Antagonism of the sigma-1 receptor (S1-R) system at adolescence modulates ethanol’s motivational effects and intake. It is still unknown, however, whether this antagonism would protect against enhanced ethanol intake at adulthood after adolescent binge ethanol exposure.
Exp. 1 and 2 tested adults male or female Wistar rats -exposed or not to ethanol self-administration at adolescence (postnatal days 31–49; nine 2-hour sessions of access to 8–10% ethanol)- for ethanol intake using 24-h two-bottle choice test (Exp. 1) or time restricted, single-bottle, tests (Exp. 2). Experiments 2–5 evaluated, in adolescent or adult rats, the effects of the S1-R antagonist S1RA on ethanol intake and on ethanol-induced conditioned taste or place aversion. Ancillary tests (e.g., novel object recognition, ethanol-induced locomotor activity) were also conducted.
Adolescent ethanol exposure promoted ethanol consumption at both the restricted, single-bottle, and at the two-bottle choice tests conducted at adulthood. S1RA administration reduced ethanol intake at adulthood and facilitated the development of ethanol-induced taste (but not place) aversion.
S1RA holds promise for lessening ethanol intake after chronic and substantial ethanol exposure in adolescence that results in heightened ethanol exposure at adulthood. This putative protective effect of S1-R antagonism may relate to S1RA exacerbating the aversive effects of this drug.
•Binge adolescent ethanol exposure heightened ethanol drinking at adulthood.•Recognition memory was preserved after binge ethanol exposure.•S1RA administration inhibited ethanol drinking at adulthood.•S1RA promoted ethanol-induced taste aversion.•S1RA did not affect ethanol-induced place aversion.
We evaluated the effect of low doses of systemically administered tetrodotoxin (TTX) on the development and expression of neuropathic pain induced by paclitaxel in mice. Treatment with paclitaxel ...(2mg/kg, i.p., once daily during 5 days) produced long-lasting (2-4 weeks) heat hyperalgesia (plantar test), mechanical allodynia (electronic Von Frey test) and cold allodynia (acetone drop method), with maximum effects observed on days 7, 10 and 10-14, respectively. Acute subcutaneous treatment with 1 or 3 microg/kg of TTX reduced the expression of mechanical allodynia, whereas higher doses (3 or 6 microg/kg) were required to reduce the expression of cold allodynia and heat hyperalgesia. In contrast, TTX (3 or 6 microg/kg, s.c.) did not affect the response to the same thermal and mechanical stimuli in control animals, which indicates that the antihyperalgesic and antiallodynic effects of TTX were not due to unspecific inhibition of the perception of these stimuli. Administration of TTX (6 microg/kg, s.c.) 30 min before each of the 5 doses of paclitaxel did not modify the development of heat hyperalgesia produced by the antineoplastic, but abolished the development of mechanical and cold allodynia. Coadministration of a lower dose of TTX (3 microg/kg) also prevented the development of mechanical allodynia. No signs of TTX-induced toxicity or motor incoordination were observed. These data suggest that low doses of TTX can be useful to prevent and treat paclitaxel-induced neuropathic pain, and that TTX-sensitive subtypes of sodium channels play a role in the pathogenesis of chemotherapy-induced neuropathic pain.
The synthesis and pharmacological activity of a new series of pyrazoles that led to the identification of 1-(4-(2-((1-(3,4-difluorophenyl)-1H-pyrazol-3-yl)methoxy)ethyl)piperazin-1-yl)ethanone ...(9k, EST64454) as a σ1 receptor (σ1R) antagonist clinical candidate for the treatment of pain are reported. The compound 9k is easily obtained through a five-step synthesis suitable for the production scale and shows an outstanding aqueous solubility, which together with its high permeability in Caco-2 cells will allow its classification as a BCS class I compound. It also shows high metabolic stability in all species, linked to an adequate pharmacokinetic profile in rodents, and antinociceptive properties in the capsaicin and partial sciatic nerve ligation models in mice.
The present study assessed the effects of ethanol exposure during adolescence or adulthood. We exposed Wistar rats, males or females, to self-administered 8-10% (v/v) ethanol (BINGE group) during the ...first 2 h of the dark cycle, three times a week (Monday, Wednesday, and Friday) during postnatal days (PDs) 32-54 or 72-94 (adolescent and adults, respectively). During this period, controls were only handled, and a third (IP) condition was given ethanol intraperitoneal administrations, three times a week (Monday, Wednesday, and Friday), at doses that matched those self-administered by the BINGE group. The rats were tested for ethanol intake and preference in a two-bottle (24 h long) choice test, shortly before (PD 30 or 70) and shortly after (PD 56 or 96) exposure to the binge or intraperitoneal protocol; and then tested for free-choice drinking during late adulthood (PDs 120-139) in intermittent two-bottle intake tests. Binge drinking was significantly greater in adolescents vs. adults, and was blocked by naloxone (5.0 mg/kg) administered immediately before the binge session. Mean blood ethanol levels (mg/dl) at termination of binge session 3 were 60.82 ± 22.39. Ethanol exposure at adolescence, but not at adulthood, significantly reduced exploration of an open field-like chamber and significantly increased shelter-seeking behavior in the multivariate concentric square field. The rats that had been initially exposed to ethanol at adolescence drank, during the intake tests conducted at adulthood, significantly more than those that had their first experience with ethanol at adulthood, an effect that was similar among BINGE, IP and control groups. The study indicates that binge ethanol drinking is greater in adolescent that in adults and is associated with heightened ethanol intake at adulthood. Preventing alcohol access to adolescents should reduce the likelihood of problematic alcohol use or alcohol-related consequences.
Background: Prenatal ethanol exposure (PEE) induces heightened ethanol intake at adolescence in preclinical studies. Ethanol intake alters the absorption of folate, a methyl-group donor critical for ...numerous cellular functions. The prenatal administration of folate is, therefore, a promising approach to reduce the effects of PEE.
Objectives: Experiment 1 determined if prenatal folate modulated the effects of PEE on ethanol intake, anxiety-like response, and exploratory behaviors (Experiment 1) in Wistar rats. Experiment 2 assessed, in rats not given PEE, if postnatal folate reversed effects of ethanol exposure at postnatal days 28-42. Experiment 3 assessed if folate altered blood ethanol levels (BELs).
Methods: Experiment 1 involved 242 (125 male) adolescent Wistar rats derived from dams given folate (20 mg/kg, gestational days - GD- 13-20) + ethanol (2.0 g/kg, GD 17-20), ethanol, or vehicle only at pregnancy. Experiment 2 involved 29 male adolescents administered vehicle or ethanol doses co-administered or not with folate. In Experiment 3 twelve adult females were tested for BELs after folate administration. These tests were applied: intake tests, light dark box (LDB), elevated plus maze, open field and concentric square field.
Results: PEE heightened ethanol intake (η
2
ps = 0.06-07) and induced hyperactivity and a reduced latency to exit the white area of the LDB (η
2
ps = 0.12-17). These effects were partially inhibited by folate (p > .05). Rats exposed to ethanol exposure at adolescence exhibited reduced motor activity (η
2
p = .17), regardless of folate treatment. Folate did not affect BELs.
Conclusion: Folate administration should be considered as a preventive or acute treatment to attenuate the neurobehavioral effects of PEE.
The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4H,6H-pyrrolo3,4-b1,2,3triazolo1,5-d1,4oxazine derivatives as potent sigma-1 receptor (σ1R) ligands are ...reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σ1R antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic pK a (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, 12lR and 12qS, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.
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