Sigma-1 Receptor Agonism Promotes Mechanical Allodynia After Priming the Nociceptive System with Capsaicin.

Sigma-1 receptor antagonists promote antinociception in several models of pain, but the effects of sigma-1 agonists on nociception (particularly when the nociceptive system is primed) are not so well characterized; therefore we evaluated the effects of sigma-1 agonists on pain under different experimental conditions. The systemic administration of the selective sigma-1 agonists (+)-pentazocine and PRE-084, as well as the nonselective sigma-1 agonist carbetapentane (used clinically as an antitussive drug), did not alter sensitivity to mechanical stimulation under baseline conditions. However, they greatly promoted secondary mechanical allodynia after priming the nociceptive system with capsaicin. These effects of sigma-1 agonists were consistent in terms potency with the affinities of these drugs for sigma-1 receptors, were reversed by sigma-1 antagonists, and were not observed in sigma-1 knockout mice, indicating that they are sigma-1-mediated. Repeated systemic treatment with PRE-084 induced proallodynic effects even 24 h after treatment completion, but only after the nociceptive system was primed. However, neither the presence of this drug in the organism nor changes in sigma-1 receptor expression in areas involved in pain processing explains its long-term effects, suggesting that sustained sigma-1 agonism induces plastic changes in the nociceptive system that promote nociception.

Sigma-1 receptor inhibition reverses acute inflammatory hyperalgesia in mice: role of peripheral sigma-1 receptors.

RATIONALE: Sigma-1 (σ1) receptor inhibition ameliorates neuropathic pain by inhibiting central sensitization. However, it is unknown whether σ1 receptor inhibition also decreases inflammatory hyperalgesia, or whether peripheral σ1 receptors are involved in this process. OBJECTIVE: The purpose of this study was to determine the role of σ1 receptors in carrageenan-induced inflammatory hyperalgesia, particularly at the inflammation site. RESULTS: The subcutaneous (s.c.) administration of the selective σ1 antagonists BD-1063 and S1RA to wild-type mice dose-dependently and fully reversed inflammatory mechanical (paw pressure) and thermal (radiant heat) hyperalgesia. These antihyperalgesic effects were abolished by the s.c. administration of the σ1 agonist PRE-084 and also by the intraplantar (i.pl.) administration of this compound in the inflamed paw, suggesting that blockade of peripheral σ1 receptors in the inflamed site is involved in the antihyperalgesic effects induced by σ1 antagonists. In fact, the i.pl. administration of σ1 antagonists in the inflamed paw (but not in the contralateral paw) was sufficient to completely reverse inflammatory hyperalgesia. σ1 knockout (σ1-KO) mice did not develop mechanical hyperalgesia but developed thermal hypersensitivity; however, the s.c. administration of BD-1063 or S1RA had no effect on thermal hyperalgesia in σ1-KO mice, supporting on-target mechanisms for the effects of both drugs. The antiedematous effects of σ1 inhibition do not account for the decreased hyperalgesia, since carrageenan-induced edema was unaffected by σ1 knockout or systemic σ1 pharmacological antagonism. CONCLUSIONS: σ1 receptors play a major role in inflammatory hyperalgesia. Targeting σ1 receptors in the inflamed tissue may be useful for the treatment of inflammatory pain.

Pharmacological properties of S1RA, a new sigma-1 receptor antagonist that inhibits neuropathic pain and activity-induced spinal sensitization.

BACKGROUND AND PURPOSE: The sigma-1 (σ(1) ) receptor is a ligand-regulated molecular chaperone that has been involved in pain, but there is limited understanding of the actions associated with its pharmacological modulation. Indeed, the selectivity and pharmacological properties of σ(1) receptor ligands used as pharmacological tools are unclear and the demonstration that σ(1) receptor antagonists have efficacy in reversing central sensitization-related pain sensitivity is still missing. EXPERIMENTAL APPROACH: The pharmacological properties of a novel σ(1) receptor antagonist (S1RA) were first characterized. S1RA was then used to investigate the effect of pharmacological antagonism of σ(1) receptors on in vivo nociception in sensitizing conditions and on in vitro spinal cord sensitization in mice. Drug levels and autoradiographic, ex vivo binding for σ(1) receptor occupancy were measured to substantiate behavioural data. KEY RESULTS: Formalin-induced nociception (both phases), capsaicin-induced mechanical hypersensitivity and sciatic nerve injury-induced mechanical and thermal hypersensitivity were dose-dependently inhibited by systemic administration of S1RA. Occupancy of σ(1) receptors in the CNS was significantly correlated with the antinociceptive effects. No pharmacodynamic tolerance to the antiallodynic and antihyperalgesic effect developed following repeated administration of S1RA to nerve-injured mice. As a mechanistic correlate, electrophysiological recordings demonstrated that pharmacological antagonism of σ(1) receptors attenuated the wind-up responses in spinal cords sensitized by repetitive nociceptive stimulation. CONCLUSIONS AND IMPLICATIONS: These findings contribute to evidence identifying the σ(1) receptor as a modulator of activity-induced spinal sensitization and pain hypersensitivity, and suggest σ(1) receptor antagonists as potential novel treatments for neuropathic pain.

Changes in [(3)H]glibenclamide binding to mouse forebrain membranes during morphine tolerance.

The characteristics of specific binding of the ATP-sensitive K(+) (K(ATP)) channel blocker [3H]glibenclamide to forebrain membranes (P(2) fraction, 4 degrees C) obtained from morphine-naive and -tolerant mice were evaluated. Morphine tolerance was induced by osmotic minipumps that released 45 mg/kg/day of morphine subcutaneously for 6 days. This treatment enhanced the antinociceptive ED(50) of morphine without changing its E(max). In morphine-naive animals, (1) both the association and the dissociation of [3H]glibenclamide were biphasic; (2) [3H]glibenclamide was displaced by other sulfonylureas (order of potency: glibenclamide>glipizide&z.Gt;tolbutamide) with pseudo-Hill coefficients lower than unity and biphasic Hofstee plots; and (3) Scatchard plots of saturation experiments were curvilinear, showed a Hill coefficient of 0.81+/-0.04 and suggested the presence of two binding sites with a K(D) of 0.13 and 3.17 nM and a B(max) of 12.30 and 84.47 fmol/mg protein, respectively. By contrast, in membranes obtained from morphine-tolerant animals, (1) the Scatchard plots showed only one population of binding sites with a K(D) of 0.87 nM and a B(max) of 77.99 fmol/mg protein, and the Hill coefficient was very close to unity (0.96+/-0.1); (2) competition experiments (using glibenclamide as displacer) showed a pseudo-Hill coefficient of 0.99+/-0.04; and (3) dissociation experiments showed only one phase of dissociation. These results suggest that [3H]glibenclamide binds to two different sites in membranes obtained from morphine-naive animals, but to only one site in morphine-tolerant animals. Consequently, it seems that morphine tolerance in mice involves adaptive changes in K(ATP) channels.

The NMDA receptor antagonist dizocilpine (MK-801) stereoselectively inhibits morphine-induced place preference conditioning in mice.

The effect of the non-competitive NMDA receptor antagonist dizocilpine (MK-801) on conditioned place preference induced by morphine was studied in mice. As expected, morphine (1-8 mg/kg, i.p.) elicited a significant preference for the drug-paired compartment. Pretreatment of mice with (+)-dizocilpine (0.1 and 0.2 mg/kg, i.p.), the more active dizocilpine enantiomer, dose-dependently reversed the conditioned place preference produced by morphine (4 mg/kg, i.p.), whereas (-)-dizocilpine (0.2 mg/kg, i.p.) did not modify morphine-induced effects. In contrast, both enantiomers of dizocilpine (at a dose of 0.2 mg/kg, i.p.) elicited a conditioned place preference. These data suggest that (1) NMDA receptors play a role in morphine-induced place preference, and (2) dizocilpine-reinforcing properties in the place preference paradigm do not seem to be dependent on NMDA receptor blockade.

Cromakalim differentially enhances antinociception induced by agonists of alpha(2)adrenoceptors, gamma-aminobutyric acid(B), mu and kappa opioid receptors.

The influence of the ATP-sensitive K+(KATP) channel opener cromakalim on the antinociception induced by agonists of several receptors coupled to pertussis toxin-sensitive G proteins, clonidine (alpha2 adrenoceptor), baclofen (gamma-aminobutyric acid(B) receptor), morphine (mu opioid receptor) and U50,488H (kappa opioid receptor), was evaluated with a tail-flick test in mice. The subcutaneous administration of clonidine (0.12-2 mg/kg), morphine (0.5-16 mg/kg), baclofen (2-16 mg/kg) and U50,488H (2-16 mg/kg) induced a dose-dependent antinociceptive effect. Cromakalim (8-64 microgram/mouse intracerebroventricularly [i.c.v.]) did not change tail-flick latency in control animals but produced a dose-dependent enhancement of the antinociception induced by clonidine and morphine, and shifted their dose-response curves to the left. These effects of cromakalim were antagonized dose dependently by the K(ATP) channel blocker gliquidone (0.1-8 microgram/mouse i.c.v.). On the other hand, cromakalim (16-64 microgram/mouse i.c.v.) did not significantly enhance the antinociception induced by baclofen and U50,488H and did not shift their dose-response curves. These results suggest that opening of the K(ATP) channels plays an important role in the antinociception mediated by alpha(2) adrenoceptors and mu opioid receptors, but not in that induced by gamma-aminobutyric acid(B) and kappa opioid receptors.

Effects of K+ channel blockers and openers on antinociception induced by agonists of 5-HT1A receptors.

The modulation by K+ channel-acting drugs of the antinociceptive effect of several 5-HT1A receptor agonists was examined with the hot plate test in mice. All the 5-HT1A receptor agonists tested induced dose-dependent antinociception, the order of potency being (+/-)-8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) > buspirone > or = lesopitron > or = tandospirone. The blockers of ATP-sensitive K+ channels (KATP) gliquidone and glipizide (1-4 and 16-64 micrograms/mouse i.c.v., respectively) reduced the antinociceptive effect of 8-OH-DPAT, whereas cromakalim (32-64 micrograms/mouse i.c.v.), an opener of KATP channels, enhanced the effect. In contrast, 4-aminopyridine (25-250 ng/mouse i.c.v.) and tetraethylammonium (10-20 micrograms/mouse i.c.v.), which antagonize several non-ATP-dependent K+ conductances, were inactive. The same results were found with other agonists of 5-HT1A receptors (lesopitron, buspirone and tandospirone): gliquidone inhibited whereas cromakalim increased their antinociceptive effects. None of the K+ channel-acting drugs modified the binding of [3H]8-OH-DPAT to hippocampal membranes, whereas all the 5-HT1A receptor agonists displaced the ligand. These results suggest that ATP-sensitive K+ conductances are involved in the antinociception induced by agonists of 5-HT1A receptors.

Subgroups among mu-opioid receptor agonists distinguished by ATP-sensitive K+ channel-acting drugs.

1. We evaluated the effects of the i.c.v. administration of different K+ channel blockers (gliquidone, 4-aminopyridine and tetraethylammonium) and an opener of K+ channels (cromakalim) on the antinociception induced by several mu-opioid receptor agonists in a tail flick test in mice. 2. The s.c. administration of all agonists of mu-opioid receptors tested (morphine, 1-16 mg kg-1; metadone, 1-6 mg kg-1; buprenorphine, 0.04-0.64 mg kg-1; fentanyl, 0.02-0.32 mg kg-1 and levorphanol, 0.2-3.2 mg kg-1) elicited a dose-dependent antinociceptive effect. 3. The ATP-sensitive K+ channel blocker, gliquidone (0.06-16 micrograms per mouse, i.c.v.) antagonized the antinociception induced by buprenorphine, morphine and metadone. In contrast, gliquidone (0.25-160 micrograms per mouse) did not modify the antinociceptive effects of fentanyl and levorphanol. 4. Cromakalim (4-64 micrograms per mouse, i.c.v.), an opener of ATP-sensitive K+ channels, enhanced the antinociception produced by buprenorphine, morphine, and methadone, and did not significantly modify the antinociceptive effects of fentanyl and levorphanol. 5. The i.c.v. administration of the K+ channel blockers tetraethylammonium (10 micrograms per mouse) or 4-aminopyridine (25 ng per mouse) did not significantly modify the antinociception induced by any mu-opioid receptor agonist tested. 6. These results suggest that the opening of ATP-sensitive K+ channels is involved in the antinociceptive effect of morphine, buprenorphine and methadone, but not in that of fentanyl or levorphanol. Consequently, we suggest that at least two subgroups can be distinguished among mu-opioid receptor agonists, each inducing antinociception through different effector mechanisms.

Role of ATP-sensitive K+ channels in antinociception induced by R-PIA, an adenosine A1 receptor agonist.

The influence of several K+ channel-acting drugs on antinociception induced by the adenosine A1 receptor agonist (-)-N6-(2-phenylisopropyl)-adenosine (R-PIA) was evaluated with a tail flick test in mice. The subcutaneous administration of R-PIA (0.5-8 mg/kg) induced a dose-dependent antinociceptive effect. The ATP-sensitive K+ (KATP) channel blocker gliquidone (2-8 micrograms/mouse, i.c.v.) produced a dose-dependent displacement to the right of the R-PIA dose-response line, whereas the KATP channel opener cromakalim (32 micrograms/mouse, i.c.v.) shifted it to the left. Several KATP channel blockers dose-dependently antagonized the antinociceptive effect of R-PIA, the order of potency being gliquidone > glipizide > glibenclamide (i.e., the same order of potency shown by these drugs in blocking KATP channels in neurons). In contrast, the K+ channel blockers 4-aminopyridine and tetraethylammonium did not antagonize the effect of R-PIA. These data suggest that antinociception produced by adenosine A1 receptor agonists is mediated by the opening of ATP-sensitive K+ channels. The present results, together with those of previous studies, further support a role for K+ channel opening in the antinociceptive effect of agonists of receptors coupled to Gi/Go proteins.

Electron probe microanalysis of gentamicin-induced changes on ionic composition of the vestibular gelatinous membrane.

Gentamicin-induced changes in ionic composition in the otolithic membrane of adult OF1 mice were evaluated in the gelatinous layers of the saccule and utricle by quantitative electron probe X-ray microanalysis. The otolithic membranes were plunge-frozen and freeze-dried to prevent the redistribution of elements. Quantitative analysis was carried out with an energy dispersive detector using the peak-to-background (P/B) ratio method and different salts dissolved in dextran as standards to calibrate the P/B ratio against the concentration of the elements P, S and K in the microprobe. Gentamicin selectively decreased the concentrations of P (P < 0.001) and S (P < 0.01) in the gelatinous membrane of the saccule, and had no effect in the utricle. The concentration of K also increased in the utricular gelatinous membrane (P < 0.05). The mechanism of ototoxicity in the gelatinous membrane is unknown, but the ability of aminoglycosides to block calcium channels may induce disturbances in the ionic equilibrium of the endolymphatic fluid, and thus affect the biochemical composition of the gelatinous membrane. This technique can be useful to evaluate the distribution of ions in the process of drug-induced ototoxicity.

Gentamicin ototoxicity in otoconia: quantitative electron probe X-ray microanalysis.

Chronic gentamicin ototoxicity was evaluated in the otolithic membrane of adult OF1 mice at the otoconial layer of the saccule and utricle by quantitative electron probe X-ray microanalysis of Ca and K. The otolithic membranes were plunge-frozen and freeze-dried. The analysis was carried out with an energy dispersive detector using the peak-to-back-ground ratio method and different inorganic salts of Ca and K as standards to calibrate the microprobe. Ca and K in the otoconia are related via a linear function in both the saccule and the utricle. This association is not maintained after exposure to gentamicin, which suggests that this aminoglycoside antibiotic interferes with the Ca-K equilibrium in the otoconia. A dose of 200 mg/kg gentamicin twice a day for 5 days did not affect Ca in the mineral phase of the otoconia, but did increase K in both saccular (p < 0.05) and utricular (p < 0.01) otoconia. These increases in K may reflect a modification in the composition of the endolymph, resulting from cellular damage at the plasma membrane.

ATP-sensitive K+ channel openers inhibit morphine withdrawal.

We studied the effects of two different ATP-sensitive K+ channel openers on naloxone-precipitated withdrawal in morphine-dependent mice. The i.c.v. administration of cromakalim and diazoxide (both at 5-40 micrograms/mouse) dose-dependently inhibited several signs of morphine withdrawal (number of jumps and episodes of forepaw tremors, and body weight loss). At present it is impossible to specify the exact mechanism(s) involved in this effect. However, considering that morphine opens K+ channels in neurons, it is tempting to suggest that K+ channel openers can mimic the effects of morphine on neuronal K+ currents, and as a consequence can act as substitutes for this drug during morphine withdrawal.

Role of L-type calcium channels on yohimbine-precipitated clonidine withdrawal in vivo and in vitro.

This study was designed to elucidate the possible participation of L-type calcium channels in the expression of clonidine-withdrawal precipitated by yohimbine in clonidine-dependent animals. Mice implanted for 5 days with osmotic minipumps containing the alpha 2-adrenoceptor agonist clonidine showed symptoms of a withdrawal syndrome (jerks, headshakes, defecations and weight loss) when yohimbine, an alpha 2-adrenoceptor antagonist, was injected. Similarly, isolated rat ilea incubated with clonidine in vitro showed a withdrawal contracture when yohimbine was added to the organ bath. The effects of L-type calcium channel blockers (verapamil and diltiazem) and the stimulant Bay K 8644 on these two different types of withdrawal responses were evaluated. A dose-dependent decrease in yohimbine-precipitated clonidine withdrawal in vivo was observed when verapamil (10-40 mg/kg, s.c. and 120 micrograms/mouse, i.c.v.) or diltiazem (5-20 mg/kg, s.c. and 160 micrograms/mouse, i.c.v.) were administered to mice dependent on clonidine. No effect was found after Bay K 8644 (0.5-5 mg/kg, s.c. and 1-5 micrograms/mouse) was injected under these conditions. In vitro, both verapamil (0.1-5 microM) and D-cis-diltiazem (1-50 microM) concentration-dependently reduced the height of the yohimbine-precipitated withdrawal contracture in rat ileum incubated with clonidine. Furthermore, the effect of diltiazem was stereospecific, as D-cis-diltiazem 10 microM markedly inhibited clonidine withdrawal, whereas the same concentration of L-cis-diltiazem had no effect. In contrast, the calcium channel stimulant Bay K 8644 (0.1-1 microM) increased the height of the ileum withdrawal contracture.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential effects of K+ channel blockers on antinociception induced by alpha 2-adrenoceptor, GABAB and kappa-opioid receptor agonists.

1. The effects of several K+ channel blockers (sulphonylureas, 4-aminopyridine and tetraethylammonium) on the antinociception induced by clonidine, baclofen and U50,488H were evaluated by use of a tail flick test in mice. 2. Clonidine (0.125-2 mg kg-1, s.c.) induced a dose-dependent antinociceptive effect. The ATP-dependent K+ (KATP) channel blocker gliquidone (4-8 micrograms/mouse, i.c.v.) produced a dose-dependent displacement to the right of the clonidine dose-response line, but neither 4-aminopyridine (4-AP) (25-250 ng/mouse, i.c.v.) nor tetraethylammonium (TEA) (10-20 micrograms/mouse, i.c.v.) significantly modified clonidine-induced antinociception. 3. The order of potency of sulphonylureas in antagonizing clonidine-induced antinociception was gliquidone > glipizide > glibenclamide > tolbutamide, which is the same order of potency as these drugs block KATP channels in neurones of the CNS. 4. Baclofen (2-16 mg kg-1, s.c.) also induced a dose-dependent antinociceptive effect. Both 4-AP (2.5-25 ng/mouse, i.c.v.) and TEA (10-20 micrograms/mouse, i.c.v.) dose-dependently antagonized baclofen antinociception, producing a displacement to the right of the baclofen dose-response line. However, gliquidone (8-16 micrograms/mouse, i.c.v.) did not significantly modify the baclofen effect. 5. None of the K+ channel blockers tested (gliquidone, 8-16 micrograms/mouse; 4-AP, 25-250 ng/mouse and TEA, 10-20 micrograms/mouse, i.c.v.), significantly modified the antinociception induced by U50,488H (8 mg kg-1, s.c.). 6. These results suggest that the opening of K+ channels is involved in the antinociceptive effect of alpha 2 and GABAB, but not kappa-opioid, receptor agonists. The K+ channels opened by alpha2-adrenoceptor agonists seem to be ATP-dependent channels, whereas those opened by GABAB receptor agonists are not.

Gliquidone, an ATP-dependent K+ channel antagonist, antagonizes morphine-induced hypermotility.

The effect of gliquidone, an ATP-dependent K+ (KATP) channel blocker, on morphine-induced hypermotility in mice was studied. Morphine (5-40 mg/kg s.c.) dose dependently increased ambulatory activity. Gliquidone (10 micrograms/mouse i.c.v.) induced a parallel displacement to the right of the morphine dose-response curve. Moreover, gliquidone (10 and 40 micrograms/mouse i.c.v.) produced a dose-dependent antagonism of morphine (20 mg/kg s.c.)-induced hypermotility. These results suggest that KATP channels are involved in morphine-induced hypermotility. The present data, together with those of previous studies showing antagonism by KATP channel blockers of morphine-induced antinociception and hyperthermia, further indicate that the opening of KATP channels plays an important role in the mechanism of action of morphine.

ATP-dependent K+ channel blockers antagonize morphine- but not U-504,88H-induced antinociception.

The effects of four ATP-dependent K+ channel blockers (hypoglycemic sulfonylureas) against morphine- and U50488H-induced antinociception were evaluated using the tail flick test in mice. None of the sulfonylureas tested significantly modified tail flick latency in control animals. However, i.c.v. pretreatment with gliquidone (0.4-1.6 micrograms/mouse), glipizide (2.5-10 micrograms/mouse), glibenclamide (10-40 micrograms/mouse) or tolbutamide (20-80 micrograms/mouse) dose dependently antagonized morphine-induced antinociception approximately equieffectively, the only difference being in potency: gliquidone > glipizide > glibenclamide > tolbutamide. This effect of sulfonylureas was very specific, since none antagonized the antinociception elicited by U50488H even at doses twice as great as the dose that induced maximum antagonism of morphine antinociception. Because morphine, but not U50488H, opens K+ channels in neurons and because the order of potency of the different sulfonylureas for blocking ATP-dependent K+ channels in neurons and for antagonizing morphine antinociception is the same, we suggest that morphine antinociception is mediated by the opening of ATP-dependent K+ channels.

Centrally administered aminoglycoside antibiotics antagonize naloxone-precipitated withdrawal in mice acutely dependent on morphine.

The effects of i.c.v. administration of several aminoglycoside antibiotics on naloxone-precipitated morphine withdrawal symptoms were evaluated in mice acutely dependent on morphine. Neomycin (10-40 micrograms/mouse), gentamicin (40-160 micrograms/mouse) and kanamycin (80-320 micrograms/mouse) produced a dose-dependent reduction of the number of precipitated jumps, forepaw tremors and head shakes. The order of potency of the aminoglycoside antibiotics on all withdrawal symptoms was neomycin > gentamicin > kanamycin, which is the same order that these drugs show as N-type calcium channel blockers. The capacity of several drugs that decrease neuronal calcium availability (such as lanthanum and L-type calcium channel blockers) to antagonize opiate withdrawal is well known. In the light of these findings, our results suggest that the mechanism of aminoglycoside-induced inhibition of morphine abstinence may be related to the capacity of these antibiotics to block N-type calcium channels, and to decrease neuronal calcium availability.

Differential potentiation by calcium antagonists of neuromuscular blockade induced by pancuronium and succinylcholine in cats in vivo.

The effects of several calcium antagonists (verapamil, nicardipine and two diltiazem isomers, d-cis and l-cis diltiazem) alone and associated to non-depolarizing (pancuronium) and depolarizing (succinylcholine) neuromuscular blockers, were evaluated on sciatic nerve-tibialis anterior muscle preparations from cats in vivo. The calcium antagonists used (at 0.1 and 0.5 mg/kg iv) did not modify the height of muscular twitches elicited indirectly. However, these agents potentiated in a dose-dependent way the neuromuscular blockade induced by iv pancuronium (2-40 micrograms/kg) and succinylcholine (6-200 micrograms/kg). The order of potency in increasing the effects of pancuronium was nicardipine much greater than d-cis diltiazem greater than or equal to verapamil, whereas the order of potency in enhancing succinylcholine effects was d-cis diltiazem greater than or equal to verapamil much greater than nicardipine. The effects of diltiazem were stereoselective, thus the potentiation induced by d-cis diltiazem was significantly greater in all cases than that induced by l-cis diltiazem, which suggests that calcium channel blockade plays a role in these interactions. However, other mechanisms such as calcium antagonists-induced nicotinic receptor desensitization may also be involved.

Analgesic effects of centrally administered aminoglycoside antibiotics in mice.

The possible analgesic effects of i.c.v. administration of several aminoglycoside antibiotics were evaluated in mice using hot plate and tail flick tests. Neomycin (10-80 micrograms/mouse), gentamicin (40-160 micrograms/mouse) and kanamycin (80-320 micrograms/mouse) produced dose-dependent increases in the latencies to forepaw licking and jumping in hot plate test. These drugs also produced dose-dependent increases in the percentage of animals showing analgesia in tail flick test. The order of potency of these aminoglycoside antibiotics in both tests was neomycin greater than gentamicin greater than kanamycin, which is exactly the same order that these drugs show as N-type calcium channel blockers. Bearing in mind this fact and the well known analgesic activity of several drugs which decrease neuronal calcium availability, we suggest that the mechanism of aminoglycoside-induced antinociception may be related to the capacity of these antibiotics to block N-type calcium channels and decrease neuronal calcium availability.

Differential effects of L-type calcium channel blockers and stimulants on naloxone-precipitated withdrawal in mice acutely dependent on morphine.

The effects of L-type calcium channel blockers and stimulants on naloxone-precipitated withdrawal in mice acutely dependent on morphine were evaluated. Verapamil (10-80 mg/kg), diltiazem (20-120 mg/kg) and nicardipine (20-160 mg/kg), when administered subcutaneously, produced a dose-dependent reduction in forepaw tremor and weight loss during the abstinence reaction; jumping was also reduced by all three drugs, although the effect was not statistically significant in the case of nicardipine. By contrast, the calcium agonist Bay K 8644 (0.5-2 mg/kg, SC) increased forepaw tremor and weight loss, although this latter effect did not reach statistical significance. The effects of the calcium channel active drugs on the rotarod test were also explored, no correlation appearing with the results observed in abstinence (except for the jumping response), which suggests that the withdrawal results are not influenced by motor incoordination or unspecific CNS depression. These findings suggest that L-type calcium channels probably play an important role in withdrawal after acute morphine dependence. Taken together with other observations in chronic models, these results show that calcium channels are similarly involved in morphine abstinence after acute and chronic dependence, in contrast to the differences in the content and uptake of neuronal calcium induced by morphine under both conditions.