Analgesic effects of centrally administered aminoglycoside antibiotics in mice

doi:10.1016/0304-3940(91)90373-2

Neuroscience Letters

Volume 126, Issue 1, 13 May 1991, Pages 67-70

https://doi.org/10.1016/0304-3940(91)90373-2 Get rights and content

Abstract

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 μg/mouse), gentamicin (40–160 μg/mouse) and kanamycin (80–320 μg/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 > gentamicin > 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.

References (33)

P. Adamson et al.
Presynaptic alpha₂ adrenoceptor and kappa-opiate receptor occupancy promotes closure of neuronal (N-type) calcium channels
Eur. J. Pharmacol.
(1989)
P.C. Contreras et al.
Dose-dependent effects of prolyl-leucyl-glycinamide on morphine-induced analgesia, tolerance and dependence
Eur. J. Pharmacol.
(1984)
E. Del Pozo et al.
Analgesic effects of calcium channel blockers in mice
Eur. J. Pharmacol.
(1987)
E. Del Pozo et al.
Analgesic effects of diltiazem and verapamil after central and peripheral administration in the hot plate test
Gen. Pharmacol.
(1990)
M.J. Millan
Kappa-opioid receptors and analgesia
Trends Pharmacol. Sci.
(1990)
M. Ocaña et al.
Antagonism by an ATP-dependent potassium channel blocker of morphine analgesia
Eur. J. Pharmacol.
(1990)
T. Ohnishi et al.
Decrease in analgesic effect of nifedipine following chronic morphine administration
Eur. J. Pharmacol.
(1988)
W.A. Prado et al.
Antinociception induced by intraperitoneal injection of gentamicin in rats and mice
Pain
(1990)
W.D. Atchinson et al.
Effects of antibiotics on uptake of calcium into nerve terminals
J. Pharmacol. Exp. Ther.
(1988)
J.M. Baeyens et al.
Interactions between calcium channel blockers and non-cardiovascular drugs: interactions with drugs acting at the neuromuscular or the CNS level
Pharmacol. Toxicol.
(1988)

F. Carta et al.

Effect of nifedipine on morphine-induced analgesia

Anesth. Analg.

(1990)

D.B. Chapman et al.

Metal ion interactions with opiates

Annu. Rev. Pharmacol. Toxicol.

(1980)

M. Dierssen et al.

Calcium channel modulation by dihydropyridines modifies sufentanil-induced antinociception in acute and tolerant conditions

Naunyn-Schmiedeberg's Arch. Pharmacol.

(1990)

H. Glossmann et al.

Structure and pharmacology of voltage-dependent calcium channels

ISI Atlas Sci. Pharmacol.

(1988)

R.A. Gross et al.

Dynorphin A selectively reduces a large transient (N-type) calcium current of mouse dorsal root ganglion neurons in cell culture

T.J. Haley et al.

Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse

Br. J. Pharmacol.

(1957)

Cited by (28)

Mechanisms of the antinociceptive action of gabapentin
2006, Journal of Pharmacological Sciences
Gabapentin, a γ-aminobutyric acid (GABA) analogue anticonvulsant, is also an effective analgesic agent in neuropathic and inflammatory, but not acute, pain systemically and intrathecally. Other clinical indications such as anxiety, bipolar disorder, and hot flashes have also been proposed. Since gabapentin was developed, several hypotheses had been proposed for its action mechanisms. They include selectively activating the heterodimeric GABAB receptors consisting of GABA_B1a and GABA_B2 subunits, selectively enhancing the NMDA current at GABAergic interneurons, or blocking AMPA-receptor-mediated transmission in the spinal cord, binding to the L-α-amino acid transporter, activating ATP-sensitive K⁺ channels, activating hyperpolarization-activated cation channels, and modulating Ca²⁺ current by selectively binding to the specific binding site of [³H]gabapentin, the α2δ subunit of voltage-dependent Ca²⁺ channels. Different mechanisms might be involved in different therapeutic actions of gabapentin. In this review, we summarized the recent progress in the findings proposed for the antinociceptive action mechanisms of gabapentin and suggest that the α2δ subunit of spinal N-type Ca²⁺ channels is very likely the analgesic action target of gabapentin.
Effects of neomycin on high-threshold Ca<sup>2+</sup> currents and tetrodotoxin-resistant Na<sup>+</sup> currents in rat dorsal root ganglion neuron
2002, European Journal of Pharmacology
High-threshold Ca²⁺ channels and tetrodotoxin-resistant Na⁺ channels are highly expressed in small dorsal root ganglion neurons. In acutely isolated rat dorsal root ganglion neurons, the effects of neomycin, one of the aminoglycoside antibiotics, on high-threshold Ca²⁺ currents and tetrodotoxin-resistant Na⁺ currents were examined using whole-cell patch recording. We showed for the first time that neomycin dose-dependently inhibited peak high-threshold Ca²⁺ currents and peak tetrodotoxin-resistant Na⁺ currents with half-maximal inhibitory concentrations at 3.69 μM (n=20) and 1213.44 μM (n=25), respectively. Inactivation properties of high-threshold Ca²⁺ currents and activation properties of tetrodotoxin-resistant Na⁺ currents were also affected by neomycin with reduction of excitability of small dorsal root ganglion neurons. Half-maximal inactivation voltage of high-threshold Ca²⁺ currents was −45.56 mV before and −50.46 mV after application of neomycin (n=10). Half-maximal activation voltage of tetrodotoxin-resistant Na⁺ currents was −19.93 mV before and −11.19 mV after administration of neomycin (n=15). These results suggest that neomycin can inhibit high-threshold Ca²⁺ currents and tetrodotoxin-resistant Na⁺ currents in small dorsal root ganglion neurons, which may contribute to neomycin-induced peripheral and central analgesia.
Neomycin blocks capsaicin-evoked responses in rat dorsal root ganglion neurons
2001, Neuroscience Letters
Small dorsal root ganglion (DRG) neurons are characterized by sensitivity to capsaicin. In acutely isolated rat DRG neurons, the effect of neomycin, one of the aminoglycoside antibiotics, on capsaicin-evoked current and voltage responses was examined using whole-cell patch-clamp recording. We showed for the first time that neomycin dose-dependently inhibited capsaicin-evoked currents with half-maximal inhibitory concentration at 130.60 μM (n=70). Under current-clamp condition, depolarization and firing rate evoked by capsaicin became weakened when neomycin was perfused to the neurons (n=10). Neomycin had no significant effect on the resting potentials of DRG neurons. These results suggest that neomycin could inhibit capsaicin-sensitive responses in small DRG neurons, which may contribute to neomycin-induced peripheral analgesia.
Antinociceptive effect of amikacin and its interaction with morphine and naloxone
2000, Pharmacological Research
Amikacin sulphate (30 mg kg⁻¹) administered either intraperitoneally (i.p.) or subcutaneously (s.c.) produced antinociceptive effect in BALB/c mice in the acetic acid writhing test which is employed as an inflammatory pain model. The lack of difference between two routes with regard to antinociceptive potency was taken as evidence for the absence of a local effect. Amikacin sulphate-induced antinociception seems unlikely to be due to non-specific behaviour alteration, since this drug, at a dose range of 15–100 mg kg⁻¹did not affect motor coordination of mice in rot-a-rod test. Morphine (1 mg kg⁻¹) also caused antinociception when administered i.p. or s.c. but the effect was greater with the latter route. At the i.p. site; the concurrent use of amikacin and morphine produced more remarkable antinociception compared to their individual usages. Besides, naloxone (2 mg kg⁻¹) significantly decreased antinociceptive effect of amikacin but itself also exerted antinociception. At present, we have no plausible explanation for these findings at the i.p. site.
Effects of intrathecally administered aminoglycoside antibiotics, calcium-channel blockers, nickel and calcium on acetic acid-induced writhing test in mice
1998, General Pharmacology
- 1.
  Antinociceptive effects of intrathecally administered aminoglycoside antibiotics, calcium-channel blockers, nickel and calcium ions on the acetic acid–induced writhing test in mice were examined.
- 2.
  Neomycin (0.5–20.0 μg/mouse) gentamicin (5–40 μg/mouse), nicardipine, diltiazem and verapamil (0.5–80.0 μg/mouse) and calcium ions (0.02–1.0 μmol/mouse) exerted a dose-dependent antinociceptive activity on the acetic acid–induced writhing test. Nickel ions ( 2.5, 5.0 and 10.0 μmol/mouse) were found ineffective in this test.
- 3.
  These results suggest that N- and L-type, but not T-type, voltage-dependent calcium channels are implicated in the spinal processing of nociceptive information.
Polyamine deprivation provokes an antalgic effect
1996, Life Sciences
It is well established that inhibition of putrescine formation using D,L-2-(ctifluoromethyl)ornithine and feeding a polyamine-deficient diet together with non-absorbable antibiotics (neomycin and metronidazole), prevent almost completely the growth of tumors in rats. A similar regimen given to patients with prostate cancer not only reduced the titer of prostate specific antigen in serum, but surprisingly provoked at the same time an antalgic effect. This observation led us to study the potentiation effect of polyamine deprivation on pain threshold in healthy rats. Animals were fed for 2 weeks with an artificial diet of known polyamine content, in combination with antibiotics and 2-(difluoromethyl)ornithine, and were then submitted to pain stimuli using two models, the Randall-Selitto test and the Tail-Flick test Polyamine deprivation produced in these models an increase in the latency of the response, even under conditions which did not produce significant changes of the polyamine concentrations in blood and brain. From these observations, we may conclude that the polyamines play a role in the perception of nociceptive stimuli under physiological conditions.

View all citing articles on Scopus

View full text

Analgesic effects of centrally administered aminoglycoside antibiotics in mice

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Gen. Pharmacol.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pain

Effects of antibiotics on uptake of calcium into nerve terminals

J. Pharmacol. Exp. Ther.

Interactions between calcium channel blockers and non-cardiovascular drugs: interactions with drugs acting at the neuromuscular or the CNS level

Pharmacol. Toxicol.

Effect of nifedipine on morphine-induced analgesia

Anesth. Analg.

Metal ion interactions with opiates

Annu. Rev. Pharmacol. Toxicol.

Calcium channel modulation by dihydropyridines modifies sufentanil-induced antinociception in acute and tolerant conditions

Naunyn-Schmiedeberg's Arch. Pharmacol.

Structure and pharmacology of voltage-dependent calcium channels

ISI Atlas Sci. Pharmacol.

Dynorphin A selectively reduces a large transient (N-type) calcium current of mouse dorsal root ganglion neurons in cell culture

Pharmacological effects produced by intracerebral injection of drugs in the conscious mouse

Br. J. Pharmacol.