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Reports have shown that interspecies differences in the metabolism and pharmacokinetics of naltrexone are a rule rather than exception. However, there is paucity of information on the disposition of naltrexone in selectively bred rat lines that reliably exhibit high and low voluntary alcohol consumption, and are often used to study alcohol-drinking behavior. We have characterized the pharmacokinetic profiles of naltrexone in selectively bred rat lines: high-alcohol-drinking (HAD-1) and low-alcohol-drinking (LAD-1) rats as well as the native Wistar strain. This study was carried out to establish a baseline pharmacokinetic profile of naltrexone in these rats prior to evaluating its pharmacokinetic profile in polymeric controlled-release formulations in our laboratory. The hypothesis is that alcohol-preferring and non-alcohol-preferring lines of rats should differ in the disposition of intravenously administered naltrexone. Naltrexone administration and blood collection were via the jugular vein. In a parallel experiment, naltrexone was administered via the jugular vein, but urine was collected using the Nalgene metabolic cage system. Data were analyzed by a noncompartmental approach. Results show a high clearance that is close to or higher than hepatic blood flow in all groups (Wistar > LAD-1 > HAD-1, but with a statistically significant difference only between Wistar and HAD-1). Volume of distribution (∼2.5–3 l/kg) and the half-life (∼1 h) were similar. Urinary elimination of naltrexone was small, but also showed differences between the rats: HAD-1 > LAD-1 > Wistar, but with a statistically significant difference only between HAD-1 and Wistar rats. This study has therefore established the baseline disposition characteristics of naltrexone in these strains of rats. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: In the present study, whole-cell patch clamp recording technique was used to investigate the action of 5-hydroxytryptamine (5-HT) on the function of native neuronal nicotinic acetylcholine receptors expressed in the rat trigeminal ganglion neurons. Inward currents (I nic) caused by externally-applied nicotine were observed in majority of the examined neurons, which were mediated by α-bungarotoxin-insensitive nicotinic acetylcholine receptors. We found that 5-HT could reversibly inhibit I nic in a concentration-dependent manner, and the inhibition did not involve 5-HT receptors. Other serotonergic agents, such as 2-methyl-5-HT, α-methyl-5-HT, sumatriptan and ICS-205,930, also had similar inhibitory effects on I nic. 5-HT inhibited nicotinic acetylcholine receptors in a non-competitive manner, as 5-HT decreased the maximal current response to nicotine but had no effect on the threshold and EC50. The inhibition of I nic by 5-HT was voltage-dependent and became stronger at hyperpolarized potentials. These results indicated that 5-HT directly inhibited nicotinic acetylcholine receptors in the trigeminal ganglion neurons. As a local modulator of the nicotinic acetylcholine receptor, 5-HT might play a role in the modulation of sensory information. [Copyright &y& Elsevier]

Prolactin (PRL) is a polypeptide hormone produced and released from the pituitary and extrapituitary tissues. It regulates activity of nociceptors and causes hyperalgesia in pain conditions, but little is known the molecular mechanism. We report here that PRL can exert a potentiating effect on the functional activity of acid-sensing ion channels (ASICs), key sensors for extracellular protons. First, PRL dose-dependently increased the amplitude of ASIC currents with an EC 50 of (5.89 ± 0.28) × 10 −8 M. PRL potentiation of ASIC currents was also pH dependent. Second, PRL potentiation of ASIC currents was blocked by Δ1-9-G129R-hPRL, a PRL receptor antagonist, and removed by intracellular dialysis of either protein kinase C inhibitor GF109203X, protein interacting with C-kinase 1(PICK1) inhibitor FSC-231, or PI3K inhibitor AS605240. Third, PRL altered acidosis-evoked membrane excitability of DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Four, PRL exacerbated nociceptive responses to injection of acetic acid in female rats. Finally, PRL displayed a stronger effect on ASIC mediated-currents and nociceptive behavior in intact female rats than OVX female and male rats and thus modulation of PRL may be gender-dependent. These results suggest that PRL up-regulates the activity of ASICs and enhances ASIC mediated nociceptive responses in female rats, which reveal a novel peripheral mechanism underlying PRL involvement in hyperalgesia. [ABSTRACT FROM AUTHOR]

Prokineticin 2 (PK2), a new chemokine, causes mechanical hypersensitivity in the rat hind paw, but little is known about the molecular mechanism. Here, we have found that ionotropic P2X receptor is essential to mechanical allodynia induced by PK2. First, intraplantar injection of high dose (3 or 10 pmol) of PK2 significantly increased paw withdrawal response frequency (%) to innocuous mechanical stimuli (mechanical allodynia). And the mechanical allodynia induced by PK2 was prevented by co-administration of TNP–ATP, a selective P2X receptor antagonist. Second, although low dose (0.3 or 1 pmol) of PK2 itself did not produce an allodynic response, it significantly facilitated the mechanical allodynia evoked by intraplantar injection of α,β-methylene ATP (α,β-meATP). Third, PK2 concentration-dependently potentiated α,β-meATP-activated currents in rat dorsal root ganglion (DRG) neurons. Finally, PK2 receptors and intracellular signal transduction were involved in PK2 potentiation of α,β-meATP-induced mechanical allodynia and α,β-meATP-activated currents, since the potentiation were blocked by PK2 receptor antagonist PKRA and selective PKC inhibitor GF 109203X. These results suggested that PK2 facilitated mechanical allodynia induced by α,β-meATP through a mechanism involved in sensitization of cutaneous P2X receptors expressed by nociceptive nerve endings. [ABSTRACT FROM AUTHOR]

Abstract: Acid-sensing ion channels (ASICs), a family of proton-gated cation channels, are believed to mediate pain caused by extracellular acidification. Gastrodin is a main bioactive constituent of the traditional herbal Gastrodia elata Blume, which has been widely used in Oriental countries for centuries. As an analgesic, gastrodin has been used clinically to treat pain such as migraine and headache. However, the mechanisms underlying analgesic action of gastrodin are still poorly understood. Here, we have found that gastrodin inhibited the activity of native ASICs in rat dorsal root ganglion (DRG) neurons. Gastrodin dose-dependently inhibited proton-gated currents mediated by ASICs. Gastrodin shifted the proton concentration–response curve downwards, with a decrease of 36.92±6.23% in the maximum current response but with no significant change in the pH0.5 value. Moreover, gastrodin altered acid-evoked membrane excitability of rat DRG neurons and caused a significant decrease in the amplitude of the depolarization and the number of action potentials induced by acid stimuli. Finally, peripheral applied gastrodin relieved pain evoked by intraplantar injection of acetic acid in rats. Our results indicate that gastrodin can inhibit the activity of ASICs in the primary sensory neurons, which provided a novel mechanism underlying analgesic action of gastrodin. [Copyright &y& Elsevier]

Highlights: [•] We provide evidences that the activity of ASICs is modulated by chlorogenic acid. [•] Chlorogenic acid, one of the most abundant polyphenols in the human diet, relieves acidosis-evoked pain. [•] We revealed for the first time a cellular and molecular mechanism underlying chlorogenic acid analgesia. [ABSTRACT FROM AUTHOR]

Abstract: Extracellular acidosis is a common feature in pain-generating pathological conditions. Acid-sensing ion channels (ASICs), pH sensors, are distributed in peripheral sensory neurons and participate in nociception. Morphine exerts potent analgesic effects through the activation of opioid receptors for various pain conditions. A cross-talk between ASICs and opioid receptors in peripheral sensory neurons has not been shown so far. Here, we have found that morphine inhibits the activity of native ASICs in rat dorsal root ganglion (DRG) neurons. Morphine dose-dependently inhibited proton-gated currents mediated by ASICs in the presence of the TRPV1 inhibitor capsazepine. Morphine shifted the proton concentration–response curve downwards, with a decrease of 51.4±3.8% in the maximum current response but with no significant change in the pH0.5 value. Another μ-opioid receptor agonist DAMGO induced a similar decrease in ASIC currents compared with morphine. The morphine inhibition of ASIC currents was blocked by naloxone, a specific opioid receptor antagonist. Pretreatment of forskolin, an adenylyl cyclase activator, or the addition of cAMP reversed the inhibitory effect of morphine. Moreover, morphine altered acid-evoked excitability of rat DRG neurons and decreased the number of action potentials induced by acid stimuli. Finally, peripheral applied morphine relieved pain evoked by intraplantar of acetic acid in rats. Our results indicate that morphine can inhibit the activity of ASICs via μ-opioid receptor and cAMP dependent signal pathway. These observations demonstrate a cross-talk between ASICs and opioid receptors in peripheral sensory neurons, which was a novel analgesic mechanism of morphine. [Copyright &y& Elsevier]

Abstract: Acid-sensing ion channels (ASICs), as key sensors for extracellular protons, are expressed in nociceptive sensory neurons and contribute to signalling pain caused by tissue acidosis. ASICs are also the subject of various factors. Here, we further provide evidence that the activity of ASICs is potentiated by the activation of 5-HT2 receptors in rat dorsal root ganglion neurons. A specific 5-HT2 receptor agonist, α-methyl-5-HT, dose-dependently enhanced proton-gated currents with an EC50 of 0.13 ± 0.07 nM. The α-methyl-5-HT enhancing effect on proton-gated currents was blocked by cyproheptadine, a 5-HT2 receptor antagonist, and removed by intracellular dialysis of either GDP-β-S or protein kinase C inhibitor GF109203X. Moreover, α-methyl-5-HT altered acid-evoked membrane excitability of rat DRG neurons and caused a significant increase in the amplitude of the depolarization and the number of spikes induced by acid stimuli. Finally, α-methyl-5-HT increased nociceptive responses to injection of acetic acid in rats. These results suggest that α-methyl-5-HT up-regulates the activity of ASICs via 5-HT2 receptor and protein kinase C dependent signal pathways in rat primary sensory neurons and this potentiation contributed to acid- mediated pain in tissue injury and inflammation. [Copyright &y& Elsevier]

Abstract: Prokineticin 2 (PK2) is a newly identified regulatory protein, which is involved in a wide range of physiological processes including pain perception in mammals. However, the precise role of PK2 in nociception is yet not fully understood. Here, we investigate the effects of PK2 on GABAA receptor function in rat trigeminal ganglion neurons using whole-cell patch clamp technique. PK2 reversibly depressed inward currents produced by GABAA receptor activation (IGABA ) with an IC50 of 0.26 ± 0.02 nM. PK2 appeared to decrease the efficacy of GABA to GABAA receptor but not the affinity. The maximum response of the GABA dose–response curve decreased to 71.2 ± 7.0% of control after pretreatment with PK2, while the threshold value and EC50 of curve did not alter significantly. The effects of PK2 on IGABA were voltage independent. The PK2-induced inhibition of IGABA was removed by intracellular dialysis of either GDP-β-S (a non-hydrolyzable GDP analog), EGTA (a Ca2+ chelator) or GF109203X (a selective protein kinase C inhibitor), but not by H89 (a protein kinase A inhibitor). These results suggest that PK2 down-regulates the function of the GABAA receptor via G-protein and protein kinase C dependent signal pathways in primary sensory neurons and this depression might underlie the hyperalgesia induced by PK2. [ABSTRACT FROM AUTHOR]

Background and Purpose: Although both natural and synthetic cannabinoid compounds have been shown to exert an antinociceptive effect on acute and persistent pain, the anatomical locus of the target of cannabinoid-induced analgesia has not been fully elucidated. Here, we investigated the effects of the cannabinoid agonist WIN 55,212-2 on GABA-activated currents (I(GABA)) in rat primary sensory neurones.Experimental Approach: In the present study, experiments were performed on neurones freshly isolated from rat trigeminal ganglion (TG) by using whole-cell patch clamp and repatch techniques.Key Results: GABA-evoked inward currents were potentiated by pretreatment with WIN 55,212-2 in a concentration-dependent manner (10(-10)-10(-8) M). WIN 55,212-2 shifted the GABA concentration-response curve upwards, with an increase of 30.3 +/- 3.7% in the maximal current response but with no significant change in the EC(50) (agonist concentration producing a half-maximal response) value. WIN 55,212-2 potentiated the responses to GABA in a manner independent of holding potential and in the absence of any change in the reversal potential of the current. This potentiation of I(GABA) induced by WIN 55,212-2 was almost completely blocked by AM 251 (3 x 10(-8) M), a CB(1) receptor antagonist, and, using the repatch technique, was found to be abolished after intracellular dialysis with the protein kinase A (PKA) activator cAMP or the PKA inhibitor H89.Conclusions and Implications: The potentiation by WIN 55,212-2 of I(GABA) in primary sensory neurones may help to elucidate the mechanism underlying the modulation of analgesia by cannabinoids in the spinal dorsal horn. [ABSTRACT FROM AUTHOR]