Ulises Coffeen

Dopamine receptors in the anterior insular cortex modulate long-term nociception in the rat

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 D1 and D2 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 D1 receptor antagonist (SCH‐23390), a dopamine D1 receptor agonist (SKF‐38393), a dopamine D2 receptor agonist (TNPA) and a dopamine D2 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 D2 or the blockade of D1 receptors elicit antinociception.

Dopamine and NMDA systems modulate long-term nociception in the rat anterior cingulate cortex

&NA; The anterior cingulate cortex (ACC) plays a key role in pain processing. It has been reported that increased activity of glutamatergic projections into the ACC intensifies nociception; whereas dopaminergic projections inhibit it. The aim of this study was to evaluate the role of dopaminergic and NMDA systems of the ACC in the modulation of long‐term nociception elicited by sciatic denervation in the rat. Score, onset and incidence of long‐term nociception were measured by the autotomy behavior. The effects of a single microinjection into the ACC of different doses of dopamine (100 nM, 100 &mgr;M and 100 mM), a NMDA receptor antagonist (MK801 200 nM and 9.34 mM) and amantadine, a dopamine agonist and NMDA receptor antagonist (10, 100 and 1000 &mgr;M) were tested on long‐term nociception. Dopamine diminished autotomy behavior in an inverse dose‐dependent manner, with dopamine 100 nM as most effective concentration. MK801 and amantadine elicited a significant reduction on autotomy score. Prior injections of D1 and D2 receptor antagonists blocked the antinociceptive effects of amantadine on long‐term nociceptive behavior. The present study suggests an interaction between dopaminergic and glutamatergic systems within the ACC in the genesis and maintenance of long‐term nociception.

Taurine in the anterior cingulate cortex diminishes neuropathic nociception: A possible interaction with the glycineA receptor

Taurine is an inhibitory amino‐acid which has been proposed as a nociceptive process neuromodulator. The glycineA receptor (glyRA) 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 glyRA is responsible for taurine actions, we microinjected strychnine, a glyRA 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 glyRA is evidenced by the fact that strychnine antagonises the antinociceptive effect of taurine.

Inflammatory nociception diminishes dopamine release and increases dopamine D2 receptor mRNA in the rat's insular cortex

BackgroundThe insular cortex (IC) receives somatosensory afferent input and has been related to nociceptive input. It has dopaminergic terminals and D1 (D1R) -excitatory- and D2 (D2R) -inhibitory- receptors. D2R activation with a selective agonist, as well as D1R blockade with antagonists in the IC, diminish neuropathic nociception in a nerve transection model. An intraplantar injection of carrageenan and acute thermonociception (plantar test) were performed to measure the response to inflammation (paw withdrawal latency, PWL). Simultaneously, a freely moving microdyalisis technique and HPLC were used to measure the release of dopamine and its metabolites in the IC. Plantar test was applied prior, one and three hours after inflammation. Also, mRNA levels of D1 and D2Rs were measured in the IC after three hours of inflammation.ResultsThe results showed a gradual decrease in the release of dopamine, Dopac and HVA after inflammation. The decrease correlates with a decrease in PWL. D2Rs increased their mRNA expression compared to the controls. In regard of D1Rs, there was a decrease in their mRNA levels compared to the controls.ConclusionsOur results showed that the decreased extracellular levels of dopamine induced by inflammation correlated with the level of pain-related behaviour. These results also showed the increase in dopaminergic mediated inhibition by an increase in D2Rs and a decrease in D1Rs mRNA. There is a possible differential mechanism regarding the regulation of excitatory and inhibitory dopaminergic receptors triggered by inflammation.

Scopolamine into the anterior cingulate cortex diminishes nociception in a neuropathic pain model in the rat: an interruption of 'nociception-related memory acquisition'?

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 ( in ) 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.

Expression of muscarinic M1 and M2 receptors in the anterior cingulate cortex associated with neuropathic pain

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 M2Rs 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.

Inhibition of Peripheral Nociceptors by Aminoglycosides Produces Analgesia in Inflammatory Pain Models in the Rat

Aminoglycosides (AGs) modulate nociceptors and ionic channels expressed in sensory neurons. The AG applied in situ could be useful to alleviate hyperalgesia in animal models of inflammatory pain. We tested streptomycin (ST) and neomycin (NEO) as analgesic agents applied in situ in rat paw inflammation caused by formalin or carrageenan administration. The action of ST and NEO on the action potential discharge produced by acidic stimuli in isolated dorsal root ganglion neurons was also studied in current-clamp recordings. In the formalin test, ST and NEO significantly reduced the nociceptive behaviour. ST reduced the N-(4-methyl-2-quinazolinyl)-guanidine (GMQ)-induced nociceptive behaviour, and NEO diminished the hyperalgesia to thermonociception and mechanonociception produced by CAR. In the current-clamp experiments, ST and NEO reduced the generation of action potentials when an acidic solution was applied. We conclude that ST and NEO produce analgesia to inflammatory pain, an effect that is due in part to the inhibition of ASIC activation in sensory neurons.

A D2-like receptor family agonist produces analgesia in mechanonociception but not in thermonociception at the spinal cord level in rats

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.

Neuropathic and inflammatory antinociceptive effects and electrocortical changes produced by Salvia divinorum in rats

ETHNOPHARMACOLOGICAL RELEVANCE Salvia divinorum is a medicinal plant traditionally used in hallucinogenic ethnopharmacological practices and for its analgesic and antinflammatory properties. Its active compounds include diterpenes known as salvinorins which act as potent κ opioid receptor agonists. AIM OF THE STUDY Given its effects in acute animal models of pain, as well as its antinflammatory attributes, we decided to investigate the analgesic effects of an SD extract in neuropathic (sciatic loose nerve ligature) and inflammatory (intra plantar carrageenan) pain models in rats. We also determined in this study the electrocorticographic changes to correlate similar hallucinogenic state and behavior as those produced in humans. MATERIAL AND METHODS Mechanical and thermonociceptive responses, plantar test and von Frey assay, respectively, were measured in adult Wistar rats 30min, 3h and 24h after the intraperitoneal administration of saline or an hydroponic SD extract. We also evaluated carbamazepine and celecoxib, as gold reference drugs, to compare its antinociceptive effects. RESULTS Our results showed that administration of SD extract induced antialgesic effects in both neuropathic and inflammatory pain models. All those effects were blocked by nor-binaltorphimine (a Kappa opioid receptor antagonist). Moreover, it was observed an increase of the anterior power spectral density and a decrease in the posterior region as electrocorticographic changes. CONCLUSION The present investigation give evidence that SD is capable to reduce algesic response associated to neuropathic and inflammatory nociception. This study support therapeutic alternatives for a disabling health problem due to the long term pain with high impact on population and personal and social implications.

Salvinorin A reduces neuropathic nociception in the insular cortex of the rat

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.