Search

Background: Neuropathic pain is one of the most important challenges in public health. The search for novel treatments is important for an adequate relief without adverse effects. In this sense salvinorin A (SA), the main diterpene of the medicinal plant Salvia divinorum is an important antinociceptive compound, which acts as a potent agonist of kappa opioid receptor (KOR) and cannabinoid CB1 receptors., Methods: We evaluated nociceptive responses in a neuropathic pain model induced by the sciatic nerve ligature (SNL) in the right hind paw, after the microinjection of SA, Salvinorin B (SB), KOR and CB1 antagonists directly in the insular cortex (IC) in male wistar rats., Results: We found a potent antinociceptive effect with the administration of SA. Moreover, this effect was blocked by the administration of a KOR antagonist as well as the administration of a CB1 antagonist., Conclusion: Salvinorin A has a potent antinociceptive effect when is administered centrally in the IC by the interaction with KOR and CB1 receptors., Significance: We show evidence on the effectiveness of the administration of salvinorin A in the IC in a rodent model of neuropathic pain. These results support the use of novel compounds like SA as a therapeutic alternative for neuropathic pain relief., (© 2017 European Pain Federation - EFIC®.)

Although Salvia divinorum is traditionally known as a 'mind-altering' or psychoactive herb used, among others things, as a tranquilizer, this property has not been validated with regard to its efficacy and safety. The objective of this study is to provide evidence for the sedative effects of S. divinorum and discriminate the nature of the responsible constituents by examining different experimental models. A battery of tests, including the open-field, hole-board, exploration cylinder, plus-maze and sodium pentobarbital-induced hypnosis potentiation, were used in mice after administration of non-polar, medium polar and/or polar extracts of the plant (10, 30 and 100 mg/kg). Polysomnographic analysis in rats receiving an active medium polar extract (10 and 100 mg/kg) containing salvinorins was also assessed to study the effects of this plant on sleep architecture. All tested extracts produced significant sedative-like responses, although those of the medium polar extract were more pronounced in mice. The sedative effect of this latter extract, which contains a mixture of salvinorins, caused fragmented sleep architecture in rats by diminishing rapid eye movement (REM) sleep and increased the quiet awake stage at 10 and 100 mg/kg. Our results provide evidence that S. divinorum exhibits sedative-like depressant properties that alter physiological sleep architecture. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

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., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.)

The rostral agranular insular cortex (RAIC) receives dopaminergic projections from the mesolimbic system, which has been involved in the modulation of nociceptive processes. In this study we determined the contribution of dopamine D(1) and D(2) receptors in the RAIC regarding nociception processing in a neuropathic pain model, as well as inflammatory articular nociception measured as pain-induced functional impairment in the rat (PIFIR). Microinjection of vehicle or substances into the RAIC was performed after the induction of nociception. The groups were treated with: a dopamine D(1) receptor antagonist (SCH-23390), a dopamine D(1) receptor agonist (SKF-38393), a dopamine D(2) receptor agonist (TNPA) and a dopamine D(2) receptor antagonist (spiperone). Chronic nociception, induced by denervation, was measured by the autotomy score in which onset and incidence were also determined. The SCH-23390 and TNPA groups showed a decrease in the autotomy score and a delay on the onset as compared to control, whereas the PIFIR groups did not show statistical differences. This work shows the differential role of dopamine receptors within the RAIC in which the activation of D(2) or the blockade of D(1) receptors elicit antinociception.

Taurine is an inhibitory amino-acid which has been proposed as a nociceptive process neuromodulator. The glycine(A) receptor (glyR(A)) has been postulated as a receptor in which taurine exerts its function. Functional image studies have documented the role of the anterior cingulate cortex (ACC) in the affective component of pain. The aim of this study was to investigate the role of taurine as a glycinergic agonist in the ACC using a neuropathic pain model related to autotomy behaviour (AB). In order to test whether glyR(A) is responsible for taurine actions, we microinjected strychnine, a glyR(A) antagonist. We used taurine microinjected into the ACC, followed by a thermonociceptive stimulus and a sciatic denervation. Chronic nociception was measured by the autotomy score, onset and incidence. The administration of taurine 7 days after denervation modifies the temporal course of AB by inhibiting it. Our results showed a decreased autotomy score and incidence in the taurine groups, as well as a delay in the onset. Those experimental groups in which strychnine was microinjected into the ACC, either on its own or before the microinjection of taurine, showed no difference as compared to the control group. When taurine was microinjected prior to strychnine, the group behaved as if only taurine had been administered. Our results evidence a significant neuropathic nociception relief measured as an AB decrease by the microinjection of taurine into the ACC. Besides, the role of the glyR(A) is evidenced by the fact that strychnine antagonises the antinociceptive effect of taurine.

The cingulate cortex plays a key role in the affective component related to pain perception. This structure receives cholinergic projections and also plays a role in memory processing. Therefore, we propose that the cholinergic system in the anterior cingulate cortex is involved in the nociceptive memory process. We used scopolamine (10 microg in 0.25 mircrol/saline) microinjected into the anterior cingulate cortex, either before thermonociception followed by a sciatic denervation, between thermonociception and denervation or after both procedures (n=10 each). The vehicle group (saline solution 0.9%, n=14) was microinjected before thermonociception. Chronic nociception was measured by the autotomy score, which onset and incidence were also determined. Group scopolamine-thermonociception-denervation (STD) presented the lowest autotomy score as compared to vehicle and group thermonociception-denervation-scopolamine (TDS) (vehicle vs. STD, p=0.002, STD vs. TDS, p=0.001). Group thermonociception-scopolamine-denervation (TSD) showed a diminished autotomy score when compared to TDS (p=0.053). STD group showed a delay in the onset of AB as compared to the rest of the groups. Group TSD presented a significative delay (p=0.048) in AB onset when compared to group TDS. There were no differences in the incidence between groups. The results show that nociception-related memory processed in the anterior cingulate cortex is susceptible of being modified by the cholinergic transmission blockade. When scopolamine is microinjected prior to the nociceptive stimuli, nociception-related memory acquisition is prevented. The evidence obtained in this study shows the role of the anterior cingulate cortex in the acquisition of nociception-related memory.

The purpose of this work was to test if electric stimulation of the cingulum bundle in animals subjected to a hindpaw inflammatory process precipitates the onset and enhances autotomy behaviour. Wistar rats were implanted with bipolar parallel electrodes in the boundary of the cingulum bundle. The inflammatory process was induced in all subjects by injection of carrageenan. The groups were: A, sham; B, implanted and stimulated 10 min daily for 7 days; C, implanted and stimulated 2 h daily, for 7 days. Both groups were injected with CAR 2 days after ending the stimulation period; and D, implanted and stimulated 10 min daily for 5 days, the first stimulation being simultaneous to CAR injection. Results show that 100% of the subjects in stimulated groups presented autotomy as compared with 66% in the sham group. A significant shortening of the onset and increased rates in autotomy were observed in experimental groups (B, C and D) as compared to the sham group. We did not find differences between groups B and C, but there was an increment of autotomy in group D when compared with both B and C groups. We conclude that it is possible to facilitate the onset and to increase the intensity of the autotomy triggered by the inflammatory process with cingulum bundle electrical stimulation. The results also suggest that a fundamental condition to the development of the autotomy in this model is the presence of the noxious inflammatory process. Copyright 1999 European Federation of Chapters of the International Association for the Study of Pain.