RESUMO

Intrathecal (i.t.) administration of quinpirole, a dopamine (DA) D2-like receptor agonist, produces antinociception to mechanonociceptive stimuli but not to thermonociceptive stimuli. To determine a cellular mechanism for the specific antinociceptive effect of D2-like receptor activation on mechanonociception, we evaluated the effect of quinpirole on voltage-gated Ca2+ influx in cultured dorsal root ganglion (DRG) neurons and the D2 DA receptor distribution in subpopulations of rat nociceptive DRG neurons. Small-diameter DRG neurons were classified into IB4+ (nonpeptidergic) and IB4- (peptidergic). Intracellular [Ca2+] microfluorometry and voltage-clamp experiments showed that quinpirole reduced Ca2+ influx and inhibited the high voltage-activated Ca2+ current (HVA-ICa) in half of IB4+ neurons, leaving Ca2+ entry and HVA-ICa in IB4- neurons nearly unaffected. Pretreatment with ω-conotoxin MVIIA prevented the effect of quinpirole on HVA-ICa from IB4+ neurons, indicating that quinpirole mainly inhibits CaV2.2 channels. Immunofluorescence experiments showed that D2 DA receptor was present mainly in IB4+ small DRG neurons. Finally, in behavioral experiments in rats, the clinically approved D2-like receptor agonist pramipexole produced spinal antinociception in a similar fashion to quinpirole, with a significant effect only in the mechanonociceptive test. Our results explain, at least in part, why D2-like receptor agonists produce antinociception on mechanonociceptors.

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RESUMO

The administration of dopaminergic drugs produces analgesia in individuals experiencing different types of pain. Analgesia induced by these drugs at the spinal cord level is mediated by D2-like agonists, which specifically inhibit the detection of nociceptive stimuli by sensory afferents. The extent of the analgesia provided by spinal dopamine agonists remains controversial, and the cellular mechanism of this analgesic process is poorly understood. The objective of this study was to evaluate the analgesic effect of quinpirole, a D2-like agonist, based on two nociceptive tests and at various doses that were selected to specifically activate dopamine receptors. We found that intrathecal quinpirole administration produces analgesia of mechanical but not thermal nociception and that the analgesic effect of quinpirole is reversed by a mix of D2, D3, and D4 receptor-specific antagonists, suggesting that the activation of all D2-like receptors is involved in the analgesia produced by intrathecal quinpirole. The differential effect on thermal and mechanical nociception was also tested upon the activation of µ-opioid receptors. As reported previously, low doses of the µ-opioid receptor agonist DAMGO produced analgesia of only thermonociception. This evidence shows that a D2-like receptor agonist administered at the spinal cord level produces analgesia specific to mechanonociception but not thermonociception.

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Benzodiazepines (BZD) are a group of psychiatric drugs widely prescribed since their introduction in the clinical practice in the early 60's. These drugs have a high therapeutic efficacy in the anxiety treatment. The pharmacological action of BZD at molecular level over the Central Nervous System is very well established. However, there has always been a strong concern from different health systems about the addictive effects that the BZD may cause. The aim of this article is to give a precise description about the BZD molecular mechanism of addiction that has been resolved in recent time, based on results obtained in basic research, as well provide information about the epidemiological impact of the medical use of the BZD over the population.

Las benzodiacepinas (BZD) son un grupo de psicofármacos ampliamente prescritos desde su introducción en la práctica clínica a principios de los años 1960. Estos fármacos cuentan con una alta eficacia terapéutica en el tratamiento de la ansiedad. Su mecanismo de acción sobre el Sistema Nervioso Central a nivel molecular es bien conocido, sin embargo siempre ha existido preocupación entre distintos sistemas de salud por los efectos de adicción farmacológica que provocan. El objetivo de este trabajo es abordar los resultados obtenidos recientemente en investigación básica y describir el mecanismo por el cual las benzodiacepinas producen sus efectos adictivos a nivel molecular, así como informar sobre el impacto epidemiológico que tiene su uso.

RESUMO

The temporal activation of the sensory systems, especially in pain, determines intermediate states that define the future of the response to sensory stimulation. In this work, we interfere pharmacologically with those states that produce peripheral and central sensitisation after an acute inflammatory process, inhibiting at the periphery the COX-2 with celecoxib and using taurine (glycine A receptor agonist) for central pain relief. We tested the paw withdrawal reflex latencies to thermo- and mechanonociception after the induction of an acute inflammatory process with carrageenan. Celecoxib at low doses [0.13 and 1.3 mg/kg, intraperitoneal (i.p.)] in combination with taurine (300 mg/kg, i.p.) produces a decrease of the nociceptive response in thermo- and mechanonociception, as compared with the effect of both drugs alone. We propose that the enhancement of the analgesic effect of celecoxib in combination with taurine could be due the simultaneous action of these drugs at both, peripheral and central levels.

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Injury to the insular cortex in humans produces a lack of appropriate response to pain. Also, there is controversial evidence on the lateralization of pain modulation. The aim of this study was to test the effect of insular cortex lesions in three models of pain in the rat. An ipsilateral, contralateral or bilateral radiofrequency lesion of the rostral agranular insular cortex (RAIC) was performed 48h prior to acute, inflammatory or neuropathic pain models in all the experimental groups. Acute pain was tested with paw withdrawal latency (PWL) after thermal stimulation. Inflammation was induced with carrageenan injected in the paw and PWL was tested 1h and 24h afterwards. Neuropathic pain was tested after ligature of the sciatic nerve by measuring mechanical nociceptive response after stimulation with the von Frey filaments. Another model of neuropathy consisted of thermo stimulation followed by right sciatic neurectomy prior to the recording of autotomy behaviour. Acute pain was not modified by the RAIC lesion. All the RAIC lesion groups showed diminished pain-related behaviours in inflammatory (increased PWL) and neuropathic models (diminished mechanical nociceptive response and autotomy score). The lesion of the RAIC produces a significant decrease in pain-related behaviours, regardless of the side of the lesion. This is a clear evidence that the RAIC plays an important role in the modulation of both inflammatory and neuropathic - but not acute - pain.

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The anterior cingulate cortex (ACC) and muscarinic receptors modulate pain. This study investigates changes in the expression of muscarinic-1 and -2 receptors (M1R, M2R) in rats' ACC (cg1-rostral- and cg2-caudal) using a model of neuropathic pain by denervation, measured as autotomy score (AS) for 8 days. Changes were analysed with painful stimuli and with scopolamine into the ACC prior to this scheme. We used reverse transcriptase-polymerase chain reaction (RT-PCR) and immunofluorescence to determine M1R and M2R's mRNA and protein levels, respectively. Animals were divided in low, medium and high AS groups. Cg1 showed decreased mRNA levels for both M1R and M2R in the low AS group, as opposed to an increased expression in the medium and high AS groups. Both receptors correlated positively with AS in these groups. In the scopolamine-treated animals there was an increase in mRNA levels for both receptors in cg1, whereas in cg2, mRNA levels of M1R decreased in all the AS and scopolamine groups. The increased M2R mRNA in cg2 correlated with AS in the low, medium and high AS groups whereas all the scopolamine groups showed an increase. Immunoreactivity of the M2R in cg1 decreased in the medium AS group in comparison to controls but scopolamine treatment produced an increase in the medium scopolamine AS group compared to the medium AS group. The M1R in cg1 and both receptors in cg2 showed no immunoreactivity changes. These results highlight the role of the M2R in cg1 related to the degree of autotomy.

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