Additive Antinociceptive Effect Research Articles

Cannabinoid receptor-mediated antinociception with acetaminophen drug combinations in rats with neuropathic spinal cord injury pain

Pre-clinical evidence demonstrates that neuropathic spinal cord injury (SCI) pain is maintained by a number of neurobiological mechanisms, suggesting that treatments directed at several pain-related targets may be more advantageous compared to a treatment focused on a single target. The current study evaluated the efficacy of the non-opiate analgesic acetaminophen, which has several putative analgesic mechanisms, combined with analgesic drugs used to treat neuropathic pain in a rat model of below-level neuropathic SCI pain. Following an acute compression of the mid-thoracic spinal cord, rats exhibited robust hind paw hypersensitivity to innocuous mechanical stimulation. Fifty percent antinociceptive doses of gabapentin, morphine, tramadol or memantine were combined with an ineffective dose of acetaminophen; acetaminophen alone was not antinociceptive. The combination of acetaminophen with either tramadol or memantine resulted in an additive antinociceptive effect. Acetaminophen combined with either morphine or gabapentin, however, resulted in supra-additive (synergistic) efficacy. One of the analgesic mechanisms of acetaminophen is inhibiting the uptake of endocannabinoids from the extracellular space. Pre-treatment with AM251, a cannabinoid-1 receptor (CB1) antagonist, significantly diminished the antinociceptive effect of the acetaminophen + gabapentin combination. Pre-treatment with AM630, a cannabinoid-2 receptor (CB2) antagonist, did not have an effect on this combination. By contrast, both AM251 and AM630 reduced the efficacy of the acetaminophen + morphine combination. None of the active drugs alone were affected by either CB receptor antagonist. The results imply that modulation of the endocannabinoid system in addition to other mechanisms mediate the synergistic antinociceptive effects of acetaminophen combinations. Despite the presence of a cannabinoid mechanism, synergism was not present in all acetaminophen combinations. The combination of currently available drugs may be an appropriate option in ameliorating neuropathic SCI pain if single drug therapy is ineffective.

Modulation of Morphine-induced Antinociception in Acute and Chronic Opioid Treatment by Ibudilast

Opioid analgesics are effective in relieving chronic pain, but they have serious adverse effects, including development of tolerance and dependence. Ibudilast, an inhibitor of glial activation and cyclic nucleotide phosphodiesterases, has shown potential in the treatment of neuropathic pain and opioid withdrawal. Because glial cell activation could also be involved in the development of opioid tolerance in rats, the authors studied the antinociceptive effects of ibudilast and morphine in different models of coadministration. Antinociception was assessed using male Sprague- Dawley rats in hot plate and tail-flick tests. The effects of ibudilast on acute morphine-induced antinociception, induction of morphine tolerance, and established morphine tolerance were studied. Systemic ibudilast produced modest dose-related antinociception and decreased locomotor activity at the studied doses of 2.5-22.5 mg/kg. The highest tested dose of 22.5 mg/kg produced 52% of the maximum possible effect in the tail-flick test. It had an additive antinociceptive effect when combined with systemic morphine. Coadministration of ibudilast with morphine did not attenuate the development of morphine tolerance. However, in morphine-tolerant rats, ibudilast partly restored morphine-induced antinociception. Ibudilast produces modest antinociception, and it is effective in restoring but not in preventing morphine tolerance. The mechanisms of the effects of ibudilast should be better understood before it is considered for clinical use.

The addition of fentanyl to 1.5 mg/ml ropivacaine has no advantage for paediatric epidural analgesia

Epidural opioids are frequently combined with local anaesthetics for an additive antinociceptive effect. We investigated the efficacy of epidural fentanyl to 1.25 or 1.5 mg/ml ropivacaine for post-operative epidural analgesia in children. One hundred and eight children undergoing hypospadias repair were randomized to receive 1.25 mg/ml ropivacaine (R1.25 group), 1.25 mg/ml ropivacaine with 0.2 mcg/kg/h of fentanyl (R1.25F group), 1.5 mg/ml ropivacaine (R1.5 group) or 1.5 mg/ml ropivacaine with 0.2 mcg/kg/h of fentanyl (R1.5F group) for post-operative epidural analgesia. The epidural catheter was threaded caudally through the L4-5 interspace. The face, legs, activity, cry, consolability (FLACC) score was assessed at every hour and at FLACC score >4, an epidural bolus of 0.5 ml/kg of ropivacaine 1.5 mg/ml was given as the rescue analgesia. The incidence of side effects such as hypoxia, sedation, pruritus, nausea and/or vomiting was recorded. The need for rescue analgesia was higher in the R1.25 group compared with that in the other three groups (all P<0.05). The incidence of side effects was higher in the R1.5F group compared with that in the R1.25 and R1.5 groups (both P=0.010). The addition of 0.2 mcg/kg/h fentanyl to 1.5 mg/ml ropivacaine increased the incidence of side effects without improvement of analgesia in infants and children undergoing hypospadias repair. The use of plain 1.25 mg/ml ropivacaine increased the need for rescue analgesia and this could be compensated by addition of fentanyl.

Additive Antinociceptive Effects of the Selective Nav1.8 Blocker A-803467 and Selective TRPV1 Antagonists in Rat Inflammatory and Neuropathic Pain Models

Evidence implicating Nav1.8 and TRPV1 ion channels in various chronic pain states is extensive. In this study, we used isobolographic analysis to examine the in vivo effects of the combination of the Nav1.8 blocker A-803467 [5-(4-Chloro-phenyl)-furan-2-carboxylic acid (3,5-dimethoxy-phenyl)-amide] with 2 structurally distinct TRPV1 antagonists, A-840257 [1-(1H-Indazol-4-yl)-3-([R]-4-piperidin-1-yl-indan-1-yl)-urea] or A-425619 [1-Isoquinolin-5-yl-3-(4-trifluoromethyl-benzyl)-urea]. The antinociceptive effects of the Nav1.8 blocker alone and in combination with each TRPV1 antagonist were examined in an inflammatory (complete Freund's adjuvant, CFA) and a neuropathic (spinal nerve ligation, SNL) pain model after systemic (intraperitoneal) administration. Alone, A-803467 was efficacious in both CFA and SNL models with ED(50) values of 70 (54.2 to 95.8) mg/kg and 70 (38.1 to 111.9) mg/kg, respectively. The ED(50) values of the TRPV1 antagonists A-840257 and A-425619 alone in the CFA model were 10 (3.6 to 14.9) mg/kg and 43 (24.1 to 62.2) mg/kg, respectively; both were without significant effect in the SNL model. A series of experiments incorporating 1:1, 3:1, or 0.3:1 ED(50) dose-ratio combinations of A-840257 and A-803467, or A-425619 and A-803467 were performed in both pain models, and the effective doses of mixtures that produced 50% antinociception (ED(50, mix)) were determined by isobolographic analysis. The ED(50, mix) in each case was not found to be statistically different than ED(50, add), the theoretical ED(50) calculated assuming additive effects. These data demonstrate that Nav1.8 blockers and TRPV1 antagonists administered in combination produce an additive effect in rat pain models. Using such a combination strategy to produce analgesia may potentially provide an improved therapeutic separation from unwanted in vivo side effects associated with blockade of either Nav1.8 or TRPV1 alone. In this report, effects of coadministration of TRPV1 antagonists and A-803467, a Nav1.8 blocker, were investigated in preclinical rodent models of neuropathic and inflammatory pain. The 2 classes of novel antinociceptive agents produced an additive interaction in attenuating CFA-induced thermal hyperalgesia, providing a rationale for their use as a combination strategy in the clinic for treating inflammatory pain.

Co-administration of rofecoxib and tramadol results in additive or sub-additive interaction during arthritic nociception in rat

Over the decades, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. In order to assess a possible antinociceptive interactions, the antinociceptive effects of rofecoxib p.o., a preferential inhibitor of cyclooxygenase-2, and tramadol-hydrochloride p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The SSI was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally rofecoxib alone (1.0, 1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg), tramadol alone (1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg) or 12 different combinations of rofecoxib plus tramadol. Five combinations exhibited various degrees of sub-additive (i.e. less than the sum of the effects produced by the each drug alone) antinociceptive effects (3.2 mg/kg tramadol with 7.8 mg/kg rofecoxib; 5.6 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib; 10.0 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib), whereas the other 7 combinations showed additive antinociceptive effects (i.e. the sum of the effects produced by each agent alone). Three combination of rofecoxib + tramadol (10.0 + 5.6, 10.0 + 10.0, and 17.8 + 5.6 mg/kg respectively) presented high sub-additive interactions ( P < 0.002: Q = 9.5). The combination rofecoxib (17.8 mg/kg) + tramadol (10.0 mg/kg) caused gastric injuries less severe than those observed with indomethacin, but more severe than those obtained with rofecoxib or tramadol in single administration. The antinociceptive interaction of rofecoxib and tramadol suggests that combinations with these drugs may have no clinical utility in pain therapy.

The antinociceptive effects of intraplantar injections of 2‐arachidonoyl glycerol are mediated by cannabinoid CB2 receptors

2-arachidonoyl glycerol (2-AG) is an endogenous cannabinoid with central antinociceptive properties. Its degradation is catalysed by monoacylglycerol lipase (MGL) whose activity is inhibited by URB602, a new synthetic compound. The peripheral antinociceptive effects of 2-AG and URB602 in an inflammatory model of pain are not yet determined. We have evaluated these effects with and without the cannabinoid CB(1) (AM251) and CB(2) (AM630) receptor antagonists. Inflammation was induced in rat hind paws by intraplantar injection of formalin. Nociception was assessed behaviourally over the next 60 min, in 19 experimental groups: (1) control; (2-6) 2-AG (0.01-100 microg); (7) AM251 (80 microg); (8) AM251+2-AG (10 microg); (9) AM630 (25 microg); (10) AM630+2-AG (10 microg); (11-16) URB602 (0.1-500 microg); (17) 2-AG+URB602 (ED(50)); (18) AM251+URB602 (ED(50)); (19) AM630+URB602 (ED(50)). Drugs were injected s.c. in the dorsal surface of the hind paw (50 microl), 15 min before formalin injection into the same paw. 2-AG and URB602 produced dose-dependent antinociceptive effects for the late phases of the formalin test with ED(50) of 0.65+/-0.455 mug and 68+/-14.3 microg, respectively. Their combination at ED(50) doses produced an additive antinociceptive effect. These effects were inhibited by AM630 but not by AM251 for 2-AG and by the two cannabinoid antagonists for URB602. Locally injected 2-AG and URB602 decreased pain behaviour in a dose-dependent manner in an inflammatory model of pain. The antinociceptive effect of 2-AG was mediated by the CB(2) receptor.

Additive antinociceptive effect of the combination of diazoxide, an activator of ATP-sensitive K + channels, and sodium nitroprusside and dibutyryl-cGMP

Using the rat paw pressure test, in which increased sensitivity is induced by intraplantar injection of prostaglandin E 2, we assessed the antinociceptive effect of the ATP-sensitive K + channel opener diazoxide and the large-conductance Ca 2+-activated K + channel opener NS-1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl) phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one) on the peripheral hyperalgesia induced by prostaglandin E 2. Diazoxide, administered locally into the right hindpaw (20, 38, 75, 150, 300 and 600 μg), elicited a dose-dependent antinociceptive effect on prostaglandin E 2-induced hyperalgesia (2 μg/paw). The effect of diazoxide at the dose of 300 μg/paw was shown to be local since it did not produce any effect when administered in the contralateral paw. The action of diazoxide (300 μg/paw) as an ATP-sensitive K + channel opener seems to be specific, since its effect was antagonized in a dose-dependent manner by glibenclamide (40, 80 and 160 μg/paw), a specific blocker of these channels, while tetraethylammonium (7.5, 15 and 30 μg/paw), dequalinium (12.5, 25 and 50 μg/paw) or charybdotoxin (0.5, 1 and 2 μg/paw), blockers of voltage-dependent K + channels and of small- and large-conductance Ca 2+-activated K + channels, respectively, were not able to abolish the antinociception induced by diazoxide. The peripheral antinociceptive effect of diazoxide was not prevented by prior administration of naloxone (12.5, 25 and 50 μg/paw), an opioid receptor antagonist, or methylene blue (75, 125 and 300 μg/paw), an agent that inhibits the activation of guanylate cyclase by nitric oxide. A low dose of diazoxide (20 μg/paw) administered together with a low dose of sodium nitroprusside (125 μg/paw) or dibutyryl cGMP (db-cGMP, 50 μg/paw) induced a marked antinociceptive effect similar to that observed when each drug was administered alone. NS1619 (75, 150 and 300 μg/paw), a specific opener of large-conductance Ca 2+-activated K + channels, had no antinociceptive action on prostaglandin E 2-induced hyperalgesia. This series of experiments provides evidence for a peripheral antinociceptive action of diazoxide and supports the suggestion that the activation of ATP-sensitive K + channels could be the mechanism by which sodium nitroprusside and db-cGMP induce peripheral antinociception, excluding the involvement of large-contuctance Ca 2+-activated K + channels in the process.

Analysis of the analgesic interactions between ketorolac and tramadol during arthritic nociception in rat

The potential advantage of using combination therapy is that analgesia can be maximized while minimizing the incidence of adverse effects. In order to assess a possible synergistic antinociceptive interactions, the antinociceptive effects of ketorolac tromethamine, p.o., a nonsteroidal anti-inflammatory drug (NSAID), and tramadol hydrochloride, p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The surface of synergistic interaction was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally ketorolac alone (0.18, 0.32, 0.56, 1.0, 1.78, 3.16, and 5.62 mg/kg), tramadol alone (3.16, 5.62, 10.0, 17.78, 31.62, 56.23, and 100.0 mg/kg), or 24 different combinations of ketorolac plus tramadol. Ten combinations exhibited various degrees of potentiation of antinociceptive effects (17.78 mg/kg tramadol with either 0.18, 0.32, or 0.56 mg/kg ketorolac; 10.0 mg/kg tramadol with either 0.18, 0.32, 0.56, or 1.8 mg/kg ketorolac; 5.6 mg/kg tramadol with either 0.32 or 0.56 mg/kg ketorolac; and 3.16 mg/kg tramadol with 0.32 mg/kg ketorolac), whereas the other 14 combinations showed additive antinociceptive effects. Three combinations of ketorolac+tramadol (1.0+17.78, 1.78+10, and 1.78+17.78, mg/kg respectively) produced the maximum antinociceptive effects, and two combinations (0.32+10.0 and 0.56+10.0 mg/kg, respectively) presented effects of high potentiation ( P<0.001). This combination caused gastric injuries less severe than those observed with indomethacin. The synergistic antinociceptive effects of ketorolac and tramadol were important and suggest that combinations with these drugs may have clinical utility in pain therapy.

Enhancement of antinociception by co-administration of an opioid drug (morphine) and a preferential cyclooxygenase-2 inhibitor (rofecoxib) in rats

Synergism has been used to obtain analgesia at doses at which side effects are minimal. In addition, it has been demonstrated that inhibition of cyclooxygenase-2 is responsible for the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs). The aim of this study was to evaluate the antinociceptive interaction between the preferential COX-2 inhibitor, rofecoxib and morphine. Several combinations were evaluated using the pain-induced functional impairment model (PIFIR), a rat model of arthritic pain. Surface of synergistic interaction (SSI) analysis and an isobolographic method were used to detect the antinociceptive potency of the drugs, given either individually or in combination. The surface of synergistic interaction was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Male rats received orally morphine alone (10, 17.8, 31.6, 56.2 and 100.0 mg/kg), rofecoxib alone (3.2, 5.6, 10, 31.6, 56.2 and 74.0 mg/kg) or 12 different combinations of morphine and rofecoxib. Three combinations exhibited potentiation of antinociceptive effects (10 mg/kg of morphine with either 5.6, 10 or 31.6 mg/kg of rofecoxib), whereas the other nine combinations showed additive antinociceptive effects. The combination of morphine, 56.2 mg/kg (p.o.), and rofecoxib, 31.6 mg/kg (p.o.), produced the maximum antinociceptive effect ( P<0.05). This combination caused gastric injuries less severe than those observed with indomethacin, i.e. it reduced ulcers and erosion formation. The synergistic antinociceptive effects of rofecoxib and morphine are important and suggest that combinations with drugs may decrease the side effects associated with the use of nonselective NSAIDs. Furthermore, the present results suggest that combinations containing opioid drugs and selective COX-2 inhibitors may have clinical utility in pain therapy.

Isobolographic analysis of the analgesic interactions between ketamine and tramadol.

Owing to different mechanisms of analgesia, we hypothesized that the combination of ketamine and tramadol could produce synergistic or additive antinociceptive effects. Swiss albino mice were administered intraperitoneally with ketamine, tramadol, a combination of ketamine and tramadol, or saline, and the resulting antinociceptive effects were tested in the mouse tail-flick and formalin tests. The potencies of the two drugs alone or in combination were obtained by fitting data to the Sigmoid Emax equation. Isobolographic analysis was performed to evaluate the interaction. CNS depression was also monitored. Results showed that tramadol exhibited apparent dose-dependent effects in the tail-flick test, and in phase 1 and phase 2 of the formalin test. Ketamine dose-dependently inhibited the phase 2 responses, but failed to modify the phase 1 and tail-flick responses. Combination of tramadol and ketamine produced significant synergistic interactions only in phase 2 of the formalin test (P < 0.05). The synergistic combinations also displayed less CNS depression than when an equianalgesic dose of ketamine was administered alone. We conclude that in the acute thermal or chemical pain model, ketamine is not effective and the net effect of ketamine and tramadol in combination was simply additive after systemic administration. However, the coadministration produced synergistic antinociception in the chemical-induced persistent pain model.

Effects of intracerebroventricularly administered chimeric peptide of metenkephalin and FMRFa—[D-Ala 2]YFa—on antinociception and its modulation in mice

An enzymatically stable analog of YGGFMKKKFMRFamide (YFa), a chimeric peptide of metenkephalin and FMRFa, was synthesised. The antinociceptive effects of intracerebroventricular injections of this analog—[D-Ala 2]YAGFMKKKFMRFamide ([D-Ala 2]YFa)—was then investigated using the mouse radiant-heat tail-flick test. [D-Ala 2]YFa produced modest to good antinociception at 1, 2, and 5 μg/mouse (0.64, 1.28, and 3.22 nmol, respectively). This antinociceptive effect was completely reversed by the opioid receptor antagonist naloxone (1.5 μg/mouse: 4.12 nmol, intracerebroventricular [i.c.v.]), administered 5 min prior. Pretreatment (5 min) with either neuropeptides FF (1 μg/mouse: 0.92 nmol, i.c.v.) or FMRFa (1 μg/mouse: 1.69 nmol, i.c.v.) significantly attenuated the antinociceptive effects induced by [D-Ala 2]YFa (1 μg/mouse, i.c.v.). Intracerebroventricular administration of [D-Ala 2]YFa at 1 μg/mouse dose with morphine (2 μg/mouse: 5.86 nmol, i.c.v.) produced an additive antinociceptive effect, suggesting that [D-Ala 2]YFa may have a modulatory effect on opioid (morphine) analgesia. These results provide further support for a role of such amphiactive sequences in antinociception and its modulation.

Spinal potentiation and supraspinal additivity in the antinociceptive interaction between systemically administered alpha 2-adrenoceptor agonist and cocaine in the rat.

We studied the antinociceptive interaction of systemically administered medetomidine, a selective alpha 2-adrenoceptor agonist, with cocaine in the tailflick and hotplate tests in rats. In intact rats, both medetomidine alone (25-300 micrograms/kg subcutaneously [SC]) and cocaine alone (10-30 mg/kg intraperitoneally [IP]) produced a dose-dependent antinociception in the supraspinally mediated hotplate test, and their combination (medetomidine 25 micrograms/kg+cocaine 10-20 mg/kg) produced an additive antinociceptive effect. In the spinally mediated tailflick test, only medetomidine alone produced a significant antinociceptive effect both in intact and spinal rats, whereas cocaine alone produced a marginally significant antinociceptive effect in the tailflick test only at the highest dose used (30 mg/kg) and only in intact rats. The combination of medetomidine (25 micrograms/kg SC) with cocaine (10-20 mg/kg IP) produced potentiation of antinociception in the tailflick test both in intact and spinal rats. The results indicate that at the supraspinal level there is an additive antinociceptive interaction between cocaine and medetomidine, whereas at the spinal level cocaine potentiates the medetomidine-induced antinociception independent of supraspinal mechanisms. The results further support previous evidence indicating that antinociception produced by a systemically administered alpha 2-adrenergic drug alone is mainly due to spinal mechanisms, whereas that by systemically administered cocaine alone is mainly due to supraspinal mechanisms.

Antinociception produced by receptor selective opioids. Modulation of supraspinal antinociceptive effects by spinal opioids

This study evaluated the antinociceptive effects produced when different combinations of supraspinal μ- and δ-opioid agonist were co-administered with spinal μ-, δ-, and κ-opioid agonist. Using the Randall-Selitto paw-withdrawal test, in the rat, changes in nociceptive thresholds were measured following co-administration of sequentially increasing i.c.b. doses of either DAMGO or DPDPE with a low-antinociceptive dose of intrathecal DAMGO, DPDPE, or U50,488H. Antinociceptive synergy (i.e. a more than additive antinociceptive effect) was demonstrated with all of the combinations tested except for supraspinal DPDPE co-administered with spinal DAMGO. The results of this study provide support for the suggestion that supraspinal and spinal antinociceptive mechanisms share, in part, common neural circuits. Marked differences in the overall magnitude of the antinociceptive effects produced by the various combinations of opioid agonists were demonstrated through a secondary analysis of the data. When sequentially increasing i.c.v. doses of DAMGO were administered, significantly larger increases in nociceptive thresholds were observed with co-administration of intrathecal injections of low antinociceptive doses of either DAMGO or U50,488H compared to DPDPE. In contrast, when DPDPE was administered supraspinally, the largest increases in nociceptive thresholds were demonstrated with co-administration of DPDPE at the spinal site. The results of the secondary analysis provide support for the hypothesis that descending antinociceptive control systems activated by supraspinal administration of selective μ- and δ-opioid agonists interact, differently, with spinal μ-, δ, and κ-opioidergic mechanisms.

Antinociceptive and motor effects of delta/mu and kappa/mu combinations of intrathecal opioid agonists

Interactions between selective opioid agonists acting at spinal μ-, δ-, and κ-opioid receptors were evaluated by co-administering a low-antinociceptive dose of the selective δ-agonist, DPDPE, or the selective κ-agonist, U50,488H, with sequentially increasing doses of the selective β-agonist, DAMGO, intrathecally. Antinociceptive synergy (i.e., a more than additive antinociceptive effect) was observed with both combinations of opioid agonists tested. The demonstration of antinociceptive synergy suggests that the subtypes of spinal opioid receptors can act, at least in part, through a common neural circuit. Since our measure of antinociception, the Randall-Selitto paw-withdrawal test, is dependent on a normally functioning motor system, we also evaluated the effects of these same combinations of opioid peptides on motor coordination using a rotarod treadmill. A low-antinociceptive dose of DPDPE or U50,488H co-administered intrathecally, with sequentially increasing doses of DAMGO, did not worsen the decrement in rotarod performance observed with the same doses of DAMGO administered as a single agent. In fact, the low-antinociceptive dose of DPDPE significantly attenuated the decrease in rotarod performance produced when the same dose of DAMGO was administered as a single agent. The results of this study suggest that intrathecal combinations of selective μ- with both δ- or κ-selective opioid agonists can produce antinociceptive synergy without producing an increase in motor side effects. In addition, the results of a secondary analysis, that compared the antinociceptive data from this study with data from our previous studies of intrathecal combinations of sequentially increasing doses of U50,488H with low doses of DPDPE or DAMGO and sequentially increasing doses of DPDPE with low doses of DAMGO or U50,488H, demonstrate distinct differences in the magnitude of the antinociceptive interactions. The most prominent finding from the secondary analysis was that administration of the μ-opioid agonist, DAMGO, as a component of any combination regimen, resulted in the largest enhancement in antinociceptive effects.

Contribution of supraspinal μ- and δ-opioid receptors to antinociception in the rat

This study evaluated the contribution of supraspinal opioid receptors to the production of antinociception, in the rat. I.c.v. administration of a selective μ-(DAMGO) and a selective δ-(DPDPE), but not a selective κ- (U50,488H) opioid receptor agonist, produced significant dose-dependent increases in mechanical nociceptive thresholds. ICI 174,864, a δ-opioid receptor antagonist, completely blocked the antinociceptive effects produced by DPDPE ([D-Pen 2,D-Pen 5]enkephalin) at a dose that had no effect on the increases in nociceptive thresholds produced by DAMGO ([D-Ala 2,N-MePhe 4,Gly 5-ol]enkephalin). The simultaneous i.c.v. administration of a low-antinociceptive dose of DAMGO or DPDPE given in combination with sequentially increasing doses of the other cpioid agonist, produced synergy (i.e., a more than additive antinociceptive effect), at the lower doses tested. The results of these experiments provide evidence to support the suggestion that both supraspinal μ- and δ-opioid receptors contribute to the production of antinociception, in the rat.

Interactions between noradrenergic and cholinergic mechanisms involved in spinal nociceptive processing

Antinociceptive effects have been demonstrated after systemic and spinal administration of the adrenoceptor agonist clonidine and cholinomimetic drugs in animals and human. The present investigation was undertaken in rats to study the possible interactions between spinal noradrenergic and cholinergic mechanisms in modulating the reaction to nociceptive stimuli. Using the tail immersion test, an additive antinociceptive effect was found between intrathecal (IT) clonidine (10 micrograms) and physostigmine (15 micrograms, IT). The effect of clonidine was attenuated by atropine (15 micrograms, IT). Physostigmine (15 micrograms, IT) antinociception, which was of short duration was abolished by atropine (15 micrograms, IT) and attenuated by phentolamine (20 micrograms, IT). Neostigmine (5 micrograms, IT) produced a prolonged antinociceptive response. In animals pretreated with 6-hydroxydopamine IT, leading to a selective depletion of spinal cord noradrenaline, physostigmine (15 micrograms, IT) was ineffective in altering the nociceptive test response. Neither clonidine, nor physostigmine produced changes in latency times in the hot plate test (58 degrees C) in the doses employed. In conclusion, a clear-cut interaction exists between spinal noradrenergic and cholinergic systems for antinociception. To explain the interactions, several possible mechanisms may be considered, including cholinomimetic effects produced by clonidine, and the presence of muscarinic receptors in the dorsal horn of the spinal cord.