Attempted reversal of cocaine-induced antinociceptive effects with naloxone, an opioid antagonist.

We attempted to reverse the behavioral and neuronal antinociceptive effects of cocaine with naloxone, an opioid antagonist. Cocaine (20 mg/kg i.p.) produced a strong analgesic effect in the formalin test and in the tail pinch test. These cocaine-induced analgesic effects could be reversed by naloxone at a very high dose (10 mg/kg) but not at a dose (1 mg/kg) which was sufficient to attenuate morphine (10 mg/kg)-induced analgesia. Naloxone alone at a dose of 10 mg/kg did not produce significant effects. In general, nociceptively evoked responses in medial thalamic neurons were suppressed by cocaine (20 mg/kg), and this suppression was attenuated by naloxone (10 mg/kg). The results suggest that opioid receptors which are not involved in mediating morphine-induced analgesia and which have a low sensitivity to naloxone are involved in cocaine-induced central analgesia.     

The analgesic activity of biphalin and its analog AM 94 in rats

Biphalin is an opioid linear octapeptide, which displays a broad affinity for all opioid receptors (μ, δ and κ), as well as exceptionally high antinociceptive activity. AM 94 is a biphalin analog and a selective agonist at μ and δ opioid receptors. This study investigated the antinociceptive profile of AM 94. All antinociception evaluations were made in adult male rats using the hot-plate test. AM 94 proved to induce greater and longer antinociception compared to biphalin following intracebroventricular (1 nmol/kg) and intravenous administration (1200 nmol/kg) as evaluated by % maximum possible effect (M.P.E.), when administered intracerebroventricularly and intravenously and sustained analgesia up to 210 min. The antinociceptive activities of biphalin and AM 94 were antagonized by naloxone (10mg/kg intraperitoneally). Our data suggest that AM 94 could be regarded as a novel pharmacologically active opioid compound for eliciting potent and sustained analgesia after central and peripheral administration.     

Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat

Antinociception achieved after peripheral administration of opioids has opened a new approach to the treatment of severe and chronic pain. Additionally, opioid analgesics with restricted access to the central nervous system could improve safety of opioid drugs used in clinical practice. In the present study, peripheral components of antinociceptive actions of 6-amino acid-substituted derivatives of 14-O-methyloxymorphone were investigated after local intraplantar (i.pl.) administration in rat models of inflammatory and neuropathic pain. Their antinociceptive activities were compared with those of morphine, the classical mu-opioid receptor agonist. Intraplantar administration of morphine and the 6-amino acid derivatives produced dose-dependent reduction of formalin-induced flinching of the inflamed paw, without significant effect on the paw edema. Local i.pl. administration of the new derivatives in rats with neuropathic pain induced by sciatic nerve ligation produced antiallodynic and antihyperalgesic effects; however, the antinociceptive activity was lower than that observed in inflammatory pain. In both models, the 6-amino acid derivatives and morphine at doses that produced analgesia after i.pl. administration were systemically (s.c.) much less active indicating that the antinociceptive action is due to a local effect. Moreover, the local opioid antinociceptive effects were significantly attenuated by naloxone methiodide, a peripherally acting opioid receptor antagonist, demonstrating that the effect was mediated by peripheral opioid receptors. The present data indicate that the peripherally restricted 6-amino acid conjugates of 14-O-methyloxymorphone elicit antinociception after local administration, being more potent in inflammatory than in neuropathic pain. Opioid drugs with peripheral site of action can be an important target for the treatment of long lasting pain.     

Peripheral and central antinociceptive actions of ethylketocyclazocine in the formalin test

The antinociceptive actions of ethylketocyclazocine and morphine were examined in rats in a thermal nociceptive test (tail-immersion) and a test involving minor tissue injury (formalin). In the formalin test, the antinociceptive effects of high doses of ethylketocyclazocine, but not morphine, were attenuated by the peripherally acting antagonist naloxone methylbromide. Naloxone methylbromide had no effect on antinociception produced by ethylketocyclazocine in the tail-immersion test. When ethylketocyclazocine was injected intraventricularly, only partial antinociception was observed in the formalin test. Conversely, naloxone given intraventricularly only partially attenuated the antinociception produced by ethylketocyclazocine given systemically. The data indicate that the antinociceptive effects of ethylketocyclazocine in the tissue injury-induced nociception are a result of summation of central and peripheral actions. Morphine antinociception reaches ceiling at doses that are devoid of such peripheral actions. The data imply that it may be possible to develop a new class of peripherally acting analgesics that are effective in acute inflammatory pain.     

Interaction between histamine and morphine at the level of the hippocampus in the formalin-induced orofacial pain in rats

The present study explored the interaction between histaminergic and opioidergic systems at the level of the hippocampus in modulation of orofacial pain by intra-hippocampal microinjections of histamine, pyrilamine (an antagonist of histamine H(1) receptors), ranitidine (an antagonist of histamine H(2) receptors), morphine (an opioid receptor agonist) and naloxone (an opioid receptor antagonist) in separate and combined treatments. Orofacial pain was induced by subcutaneous (sc) injection of formalin (50 μl, 1%) in the upper lip region and the time spent face rubbing was recorded in 3 min blocks for 45 min. Formalin (sc) produced a marked biphasic (first phase: 0-3 min, second phase: 15-33 min) pain response. Histamine and morphine suppressed both phases of pain. Histamine increased morphine-induced antinociception. Pyrilamine and ranitidine had no effects when used alone, whereas pretreatments with pyrilamine and ranitidine prevented histamine- and morphine-induced antinociceptive effects. Naloxone alone non-significantly increased pain intensity and inhibited the antinociceptive effects of morphine and histamine. The results of the present study indicate that at the level of the hippocampus, histamine through its H(1) and H(2) receptors, mediates orofacial region pain. Moreover, morphine via a naloxone-reversible mechanism produces analgesia. In addition, both histamine H(1) and H(2) receptors, as well as opioid receptors may be involved in the interaction between histamine and morphine in producing analgesia.     

Comparison of the peripheral and central effects of the opioid agonists loperamide and morphine in the formalin test in rats.

The effects of the peripherally restricted opioid agonist loperamide were compared to those of morphine in the formalin test in rats. Both loperamide and morphine were efficacious in producing antihyperalgesia after both subcutaneous and intracisternal administration. The antihyperalgesic effects of peripherally administered loperamide and morphine were antagonized by both naloxone and its quaternary derivative naloxone methiodide. The effects of intracisternally administered loperamide and morphine were antagonized by naloxone SC. However, quaternary naloxone SC did not block the effects of intracisternally administered loperamide, and, quaternary naloxone blocked intracisternally morphine only at a dose approximately 10-fold higher than that required to block peripherally administered morphine. In addition, approximately 10-fold higher doses of naloxone administered SC were required to antagonize loperamide compared to doses required to antagonize morphine when the agonists were administered subcutaneously, suggesting that the effects of loperamide might be mediated by opioid receptors different from those which mediated the effects of morphine. However, neither the kappa-receptor selective antagonist nor-binaltorphimine nor the delta-receptor selective antagonist naltrindole blocked the effects of either opioid agonist. The present results are consistent with the interpretation that the antihyperalgesic effects of opioid agonists can have both a peripheral and a central component of action, and that the peripheral component of action is sufficient to produce antihyperalgesia in the formalin test after peripheral administration. The present results provide further evidence that peripherally restricted opioid agonists might provide clinically useful treatment of some pain states, in particular pain states that might involve sensitization of peripheral nociceptors.     

Endogenous opioid mechanisms partially mediate P2X3/P2X2/3-related antinociception in rat models of inflammatory and chemogenic pain but not neuropathic pain

P2X3/P2X2/3 receptors have emerged as important components of nociception. However, there is limited information regarding the neurochemical systems that are affected by antagonism of the P2X3/P2X2/3 receptor and that ultimately contribute to the ensuing antinociception. In order to determine if the endogenous opioid system is involved in this antinociception, naloxone was administered just prior to the injection of a selective P2X3/P2X2/3 receptor antagonist, A-317491, in rat models of neuropathic, chemogenic, and inflammatory pain. Naloxone (1-10 mg kg(-1), i.p.), dose-dependently reduced the antinociceptive effects of A-317491 (1-300 micromol kg(-1), s.c.) in the CFA model of thermal hyperalgesia and the formalin model of chemogenic pain (2nd phase), but not in the L5-L6 spinal nerve ligation model of neuropathic allodynia. In comparison experiments, the same doses of naloxone blocked or attenuated the actions of morphine (2 or 8 mg kg(-1), s.c.) in each of these behavioral models. Injection of a peripheral opioid antagonist, naloxone methiodide (10 mg kg(-1), i.p.), did not affect A-317491-induced antinociception in the CFA and formalin assays, suggesting that the opioid component of this antinociception occurred within the CNS. Furthermore, this utilization of the central opioid system could be initiated by antagonism of spinal P2X3/P2X2/3 receptors since the antinociceptive actions of intrathecally delivered A-317491 (30 nmol) in the formalin model were reduced by both intrathecally (10-50 nmol) and systemically (10 mg kg(-1), i.p.) administered naloxone. This utilization of the opioid system was not specific to A-317491 since suramin-, a nonselective P2X receptor antagonist, induced antinociception was also attenuated by naloxone. In in vitro studies, A-317491 (3-100 microM) did not produce any agonist response at delta opioid receptors expressed in NG108-15 cells. A-317491 had been previously shown to be inactive at the kappa and mu opioid receptors. Furthermore, naloxone, at concentrations up to 1 mM, did not compete for [3H] A-317491 binding in 1321N1 cells expressing human P2X3 receptors. Taken together, these results indicate that antagonism of spinal P2X3/P2X2/3 receptors results in an indirect activation of the opioid system to alleviate inflammatory hyperalgesia and chemogenic nociception.     

Local analgesic efficacy of tramadol following intraplantar injection

Several studies have suggested that systemic tramadol, an opioid, can represent a valuable treatment in severe pain conditions because of their effects on central pain pathways. However, there are not enough studies supporting that tramadol is efficacious when administered locally. Therefore, we studied the potential local analgesic effects of tramadol in peripheral nociception. In addition, we tested the antinociceptive effects of tramadol-CaCl(2) or naloxone combinations after subcutaneous intraplantar injection in a validated rat model of acute thermal nociception. Local analgesic effects of tramadol were compared with those of lidocaine. The effects of tramadol on thermal paw withdrawal latencies were monitored using the plantar test. The antinociceptive potency of tramadol is higher and long-lasting than that of lidocaine. Naloxone was unable to inhibit the increased antinociceptive response produced by tramadol. Ca(2+) modified the effect of tramadol. When Ca(2+) dose was increased in the solution, thermal antinociceptive potency of tramadol, but not lidocaine was prolonged. Thermal nociceptive responses were not affected in the non-injected paws, indicating a lack of systemic effects with doses of tramadol and lidocaine that elicited local analgesia. These results suggest that intraplantar tramadol administration can produce local analgesic effect with a different action mechanism than that of lidocaine. In addition, extracellular Ca(2+) may play an important role in the local analgesic action of tramadol.     

Antinociceptive effects of herkinorin, a MOP receptor agonist derived from salvinorin A in the formalin test in rats: new concepts in mu opioid receptor pharmacology: from a symposium on new concepts in mu-opioid pharmacology

Herkinorin is the first μ opioid (MOP) selective agonist derived from salvinorin A, a hallucinogenic natural product. Previous work has shown that, unlike other opioids, herkinorin does not promote the recruitment of β-arrestin-2 to the MOP receptor and does not lead to receptor internalization. This paper presents the first in vivo evaluation of herkinorin's antinociceptive effects in rats, using the formalin test as a model of tonic inflammatory pain. Herkinorin was found to produce a dose-dependent decrease in the number of flinches evoked by formalin. These antinociceptive effects were substantially blocked by pretreatment with the nonselective antagonist naloxone, indicating that the antinociception is mediated by opioid receptors. Contralateral administration of herkinorin did not attenuate the number of flinches evoked by formalin, indicating that its effects are peripherally restricted to the site of injection. Following chronic administration (5-day), herkinorin maintained antinociceptive efficacy in both phases of the formalin test. Furthermore, unlike morphine, herkinorin was still able to inhibit flinching in both phases of the formalin test in animals made tolerant to chronic systemic morphine treatment. Collectively, these results suggest that herkinorin may produce peripheral antinociception with decreased tolerance liability and thereby represents a promising template for the development of agents for the treatment of a variety of pain states.     

Role of central opioid on the antinociceptive effect of sulfated polysaccharide from the red seaweed Solieria filiformis in induced temporomandibular joint pain

This study aimed to investigate the effect of sulfated polysaccharide from red seaweed Solieria filiformis (Fraction F II) in the inflammatory hypernociception in the temporomandibular joint (TMJ) of rats. Male Wistar rats were pretreated (30 min) with a subcutaneous injection (s.c.) of vehicle or FII (0.03, 0.3 or 3.0 mg/kg) followed by intra-TMJ injection of 1.5% Formalin or 5-hydroxytryptamine (5-HT, 225 μg/TMJ). In other set of experiments rats were pretreated (15 min) with an intrathecal injection of the non-selective opioid receptors Naloxone, or μ-opioid receptor antagonist CTOP, or δ-opioid receptor Naltridole hydrochloride, or κ-opioid receptor antagonist Nor-Binaltorphimine (Nor-BNI) followed by injection of FII (s.c.). After 30 min, the animals were treated with an intra-TMJ injection of 1.5% formalin. After TMJ treatment, behavioral nociception response was evaluated for a 45-min observation period, animals were terminally anesthetized and periarticular tissue, trigeminal ganglion and subnucleus caudalis (SC) were collected plasma extravasation and ELISA analysis. Pretreatment with F II significantly reduced formalin- and serotonin-induced TMJ nociception, inhibit the plasma extravasation and inflammatory cytokines release induced by 1.5% formalin in the TMJ. Pretreatment with intrathecal injection of Naloxone, CTOP, Naltridole or Nor-BNI blocked the antinociceptive effect of F II in the 1.5% formalin-induced TMJ nociception. In addition, F II was able to significantly increase the β-endorphin release in the subnucleus caudalis. The results suggest that F II has a potential antinociceptive and anti-inflammatory effect in the TMJ mediated by activation of opioid receptors in the subnucleus caudalis and inhibition of the release of inflammatory mediators in the periarticular tissue.     

Peripheral interaction of opioid and NMDA receptors in inflammatory pain in rats

Both opioid and NMDA receptors have been known to be involved in pain processing in the central nervous system as well as in the periphery. The effect of drugs acting on opioid and NMDA receptors, and their role in modulation of pain response was observed in the formalin model of inflammatory pain in rats. We have demonstrated that morphine has significant antinociceptive effect in the formalin model and this effect was enhanced when given in combination with ketamine. We have also reported modulation of pain response when naloxone or NMDA were co-administered with morphine or ketamine in various combinations. A noteworthy observation in our study is that low dose naloxone when co-administered with ketamine and morphine, or with ketamine and NMDA, caused decrease in the pain response. These observations may suggest that low dose naloxone can cause modulation of opioid and NMDA receptors resulting in antinociceptive effect. Our study thus introduces a new concept of more than two drugs acting on opioid and NMDA receptors to modulate pain response.     

3-Methyl-5-hydroxy-5-trichloromethyl-1H-1-pyrazolcarboxyamide induces antinociception

The antinociceptive action of a novel pyrazole-derived compound, 3-methyl-5-hydroxy-5-trichloromethyl-1H-1-pyrazolcarboxyamide (MPCA) was evaluated using the formalin and tail-immersion tests in mice. Anti-inflammatory activity was assessed by paw plethysmometry in adult rats using the carrageenin-induced paw edema test. Subcutaneous administration of MPCA (22, 66, and 200 mg/kg) induced a dose-dependent decrease in the time spent licking during the neurogenic and inflammatory phases of the formalin test, and preadministration of naloxone (1 mg/kg, sc) did not prevent MPCA-induced (200 mg/kg, sc) antinociception. Naloxone decreased the spontaneous locomotor activity of mice, while MPCA had no effect on locomotion. In contrast, administration of the opioid antagonist caused a significant increase in the locomotor behavior of mice previously injected with MPCA. MPCA was devoid of antinociceptive action by the tail-immersion test and of anti-inflammatory activity. Moreover, MPCA had no effect on the motor performance of mice in the rotarod test. These results suggest that MPCA induces antinociception in the neurogenic and inflammatory phases of the formalin test, an effect that does not involve opioid receptors.     

The peripheral L-arginine-nitric oxide-cyclic GMP pathway and ATP-sensitive K⁺ channels are involved in the antinociceptive effect of crotalphine on neuropathic pain in rats

Crotalphine, a 14 amino acid peptide first isolated from the venom of the South American rattlesnake Crotalus durissus terrificus, induces a peripheral long-lasting and opioid receptor-mediated antinociceptive effect in a rat model of neuropathic pain induced by chronic constriction of the sciatic nerve. In the present study, we further characterized the molecular mechanisms involved in this effect, determining the type of opioid receptor responsible for this effect and the involvement of the nitric oxide-cyclic GMP pathway and of K? channels. Crotalphine (0.2 or 5 μg/kg, orally; 0.0006 μg/paw), administered on day 14 after nerve constriction, inhibited mechanical hyperalgesia and low-threshold mechanical allodynia. The effect of the peptide was antagonized by intraplantar administration of naltrindole, an antagonist of δ-opioid receptors, and partially reversed by norbinaltorphimine, an antagonist of κ-opioid receptors. The effect of crotalphine was also blocked by 7-nitroindazole, an inhibitor of the neuronal nitric oxide synthase; by 1H-(1,2,4) oxadiazolo[4,3-a]quinoxaline-1-one, an inhibitor of guanylate cyclase activation; and by glibenclamide, an ATP-sensitive K? channel blocker. The results suggest that peripheral δ-opioid and κ-opioid receptors, the nitric oxide-cyclic GMP pathway, and ATP-sensitive K? channels are involved in the antinociceptive effect of crotalphine. The present data point to the therapeutic potential of this peptide for the treatment of chronic neuropathic pain.     

The antinociceptive effect of fluvoxamine

The authors conducted a study in order to evaluate the antinociceptive effects of the serotonin-selective reuptake inhibitor (SSRI) antidepressant fluvoxamine and its interaction with various opioid receptor subtypes. Male ICR mice were tested with a hotplate analgesia meter. Fluvoxamine elicited antinociceptive effect in a dose-dependent manner following i.p., i.t. and i.c.v. injection. Naloxone 10 mg/kg s.c. did not abolish the fluvoxamine antinociceptive effect. At the next stage fluvoxamine was administered together with various agonists of opioid receptors. When administered together with opiates, fluvoxamine significantly potentiated analgesia at the K_j-opioid receptor subtype (P<.005) and to a lesser extent, at the μ-, δ-, and K₁-opioid receptors. We conclude that fluvoxamine alone induces an antinociceptive effect. This effect is mediated by a non-opioid mechanism of action. These results suggest a potential role for fluvoxamine in the management of pain when co-administered with opioids at low doses.     

JB-9322, a new selective histamine H2-receptor antagonist with potent gastric mucosal protective properties.

1. The opioid activity of the amphibian peptide, [Lys7]dermorphin, was studied in rats and mice. When administered intracerebroventricularly (i.c.v.), intravenously (i.v.) or subcutaneously (s.c.) it produced a long lasting analgesia. Its antinociceptive potency exceeded that of morphine 290 times by i.c.v. injection, and 25-30 times by peripheral administration. 2. The dose-response curves of [Lys7]dermorphin antinociception were shifted to the right by the pretreatment with naloxone (0.1 mg kg-1, s.c.) or with the mu 1-selective antagonist, naloxonazine (10 mg kg-1, i.v. 24 h before peptide injection). 3. The peptide also displayed potent antinociceptive effects in a chronic inflammatory pain model (rat Freund's adjuvant arthritis). In this pain model, systemic administration of the peptide raised the nociceptive threshold more in inflamed than in healthy paw. 4. High central and peripheral doses of [Lys7]dermorphin in rats produced catalepsy. The cataleptic response was antagonized by naloxone but left unchanged by naloxonazine pretreatment. 5. In rats and mice, central or peripheral administration of [Lys7]dermorphin induced a significantly slower development of tolerance to the antinociceptive effect than did morphine. 6. Upon naloxone precipitation of the withdrawal syndrome, [Lys7]dermorphin-dependent mice made fewer jumps and lost less weight than the morphine-dependent animals. Withdrawal hyperalgesia did not develop in [Lys7]dermorphin-dependent mice. 7. In conclusion, [Lys7]dermorphin seems to be a unique opioid peptide having a high penetration into the blood-brain barrier despite its low lipid solubility. This peptide causes fewer side-effects than other opioids and appears less likely than morphine to cause physical dependence in rats and mice.     

Evidence for a peripheral mechanism of action for the potentiation of the antinociceptive effect of morphine by dipyrone

The potentiation of the antinociceptive effect of morphine by dipyrone (metamizol) and the possible participation of a peripheral mechanism on such synergism were studied with the use of the formalin test in the rat. Nociception was induced by the intraplantar injection of diluted formalin (1%) in the right hind paw. Local administration of either dipyrone or morphine in the site of injury produced a dose-dependent antinociceptive effect. When combined, noneffective doses of morphine (1.25 microg/paw) and dipyrone (100 microg/paw) produced a significantly greater antinociceptive effect compared with either drug alone or saline. The opioid antagonist naloxone partly reversed the effect of the dipyrone-morphine combination. On the other hand, the inhibitor of nitric oxide (NO) synthesis, N(G)-L-nitro-arginine methylester (L-NAME), but not its inactive isomer, D-NAME, completely antagonized the effect of the dipyrone-morphine combination. These results suggest that the potentiation of morphine-induced antinociception by dipyrone in the formalin test requires an important participation of local release of NO, activating the NO-cyclic GMP pathway at the peripheral level.     

Antinociceptive properties of Micrurus lemniscatus venom

The therapeutic potential of snake venoms for pain control has been previously demonstrated. In the present study, the antinociceptive effects of Micrurus lemniscatus venom (MlV) were investigated in experimental models of pain. The antinociceptive activity of MIV was evaluated using the writhing, formalin, and tail flick tests. Mice motor performance was assessed in the rota rod and open field tests. In a screening test for new antinociceptive substances - the writhing test - oral administration of MlV (19.7-1600 μg/kg) produced significant antinociceptive effect. The venom (1600 μg/kg) also inhibited both phases of the formalin test, confirming the antinociceptive activity. The administration of MlV (1600 μg/kg) did not cause motor impairment in the rota rod and open field tests, which excluded possible non-specific muscle relaxant or sedative effects of the venom. The MIV (177-1600 μg/kg) also increases the tail flick latency response, indicating a central antinociceptive effect for the venom. In this test, the MlV-induced antinociceptive effect was long-lasting and higher than that of morphine, an analgesic considered the gold standard. In another set of experiments, the mechanisms involved in the venom-induced antinociception were investigated through the use of pharmacological antagonists. The MlV (1600 μg/kg) antinociceptive effect was prevented by naloxone (5 mg/kg), a non-selective opioid receptor antagonist, suggesting that this effect is mediated by activation of opioid receptors. In addition, the pre-treatment with the μ-opioid receptor antagonist CTOP (1 mg/kg) blocked the venom antinociceptive effect, while the k-opioid receptor antagonist nor-BNI (0.5 mg/kg) or the δ-opioid receptor antagonist naltrindole (3 mg/kg) only partially reduced the venom-induced antinociception. The present study demonstrates, for the first time, that oral administration of M. lemniscatus venom, at doses that did not induce any motor performance alteration, produced potent and long-lasting antinociceptive effect mediated by activation of opioid receptors.     

Paradoxical effects of opioid antagonist naloxone on SSRI-induced analgesia and tolerance in mice

Selective serotonin reuptake inhibitors (SSRIs) have been used clinically as co-analgesics in various devastating painful conditions. Upon chronic treatment tolerance develops to their analgesic effect, which is often refractory to increasing dose. Although modulation of serotonergic pathways considerably explains their clinical efficacy, numerous reports nevertheless indicate the direct/indirect role of the opioidergic pathway in SSRI-induced analgesia. The present study was designed to investigate the effect, if any, of the opioid antagonist naloxone on SSRIs-induced analgesia and tolerance employing acetic acid-induced writhing assay. Two SSRIs, fluoxetine (FLX), and citalopram (CTP) were used in the study. Acute systemic (5-40 mg kg(-1) i.p.), or intrathecal (5-40 microg per mouse, i.t.) administration of fluoxetine or citalopram exhibited a dose-dependent and significant (p < 0.05) antinociceptive effect. Single systemic (2-5 mg kg(-1) i.p.) or intrathecal (1 microg per mouse, i.t.) administration of opioid antagonist naloxone blocked where as systemic ultra-low dose (10 ng/kg) or intrathecal (0.05 ng) naloxone potentiated the acute antinociceptive effect of both SSRIs (10 mg kg(-1) i.p. and 10 microg i.t.). Animals treated chronically over a 7-day period with SSRIs developed tolerance to their antinociceptive effect. Further, chronic administration of ultra-low dose of naloxone intrathecal (0.05 ng per mouse, i.t.) or systemic (10 ng kg(-1) i.p.) with fluoxetine or citalopram (10 microg i.t.; 5 mg kg(-1) i.p.) over a 7-day period reversed the tolerance to the antinociceptive effect of SSRIs. Thus, in ultra-low doses, naloxone paradoxically enhances SSRIs-induced analgesia and reverse tolerance through spinal and peripheral action. These effects of opioid antagonist naloxone on SSRIs-induced antinociception may have an implication in refractory cases upon chronic use of SSRIs as co-analgesics.     

Probable activation of the opioid receptor-nitric oxide-cyclic GMP-K+ channels pathway by codeine

There is evidence that local peripheral administration of morphine produces antinociception through the activation of the nitric oxide (NO)-cyclic GMP-K(+) channels pathway. Therefore we evaluated the possible participation of this pathway in the antinociceptive action produced by codeine in the rat 5% formalin test. Local peripheral injection of codeine produced a dose-dependent antinociception during the first and second phases of the test. Local pretreatment of the paws with the NO synthase inhibitor N(G)-L-nitro-arginine methyl ester (L-NAME), the soluble guanylyl cyclase inhibitor methylene blue, the ATP-sensitive K(+) channel inhibitors glibenclamide and tolbutamide, the non-selective voltage-gated K(+) channel inhibitors 4-aminopyridine (4-AP) and tetraethylammonium (TEA) and the opioid receptor blocker naloxone prevented codeine-induced antinociception in both phases of the test. L-NAME, methylene blue, K(+) channel blockers and naloxone by themselves did not modify formalin-induced nociceptive behavior. Our data suggest that codeine could activate the opioid receptor-NO-cyclic GMP-K(+) channels pathway in order to produce its peripheral antinociceptive effect in the formalin test.     

Contributions of peripheral and central opioid receptors to antinociception in rat muscle pain models

Administration of hypertonic saline (HS) is an accepted model to study muscular pain. HS-induced nociceptive responses were tested in masseter, already described, and in two new pain models of spinally innervated muscles (gastrocnemius and triceps) developed in rats at our laboratory. HS administration in the masseter induced vigorous hindpaw shaking and in the gastrocnemius or triceps, paw withdrawal or flexing. Participation of the central and peripheral opioid receptors in HS-induced pain is compared in these muscles: masseter, innervated by trigeminal nerve, and gastrocnemius and triceps by spinal nerves. Morphine and loperamide were used to reveal peripheral and central components of opioid analgesia. Both agonists reduced HS-induced nociceptive behaviours in the masseter and were antagonised by the opioid antagonist naloxone and by naloxone methiodide, an opioid receptor antagonist that poorly penetrates the blood-brain barrier. Unexpectedly, in the gastrocnemius and triceps, morphine, but not loperamide, decreased the nociceptive behaviour and this effect was only reversed by naloxone. So, peripheral opioid receptors seem to participate in HS-induced masseter pain, whereas only central opioid receptors reduced the nociception in gastrocnemius and triceps. Our results suggest that the use of peripheral opioids can be more advantageous than central opioids for treatment of orofacial muscular pain.