Characterization of the Effects of Gabapentin and 3-Isobutyl-γ-Aminobutyric Acid on Substance P-induced Thermal Hyperalgesia 

1998 ◽  
Vol 88 (1) ◽  
pp. 196-205 ◽  
Author(s):  
Brett J. Partridge ◽  
Sandra R. Chaplan ◽  
Eiji Sakamoto ◽  
Tony L. Yaksh
Keyword(s):  
Substance P ◽  
Intrathecal Injection ◽  
Intraperitoneal Administration ◽  
Thermal Hyperalgesia ◽  
Radiant Heat ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Plantar Surface ◽  
Withdrawal Latency ◽  
Dose Dependent

Background The authors sought to characterize the pharmacologic characteristic and site of action of gabapentin (Neurontin) in a model of thermal hyperalgesia induced by intrathecal substance P administration. Methods Rats were prepared with long-term lumbar intrathecal catheters. Hind paw withdrawal latency was determined using a radiant heat stimulus focused through a glass surface onto the plantar surface of the paw. Results Within 5 min after intrathecal injection of substance P (30 nmol), hind paw withdrawal latency fell from 11 to 8 s. Gabapentin given intrathecally or intraperitoneally produced dose-dependent reversal of the thermal hyperalgesia, with complete reversal (ED100) occurring at 163 microg for intrathecal and 185 mg/kg for intraperitoneal administration. S(+)-3-isobutyl-gamma aminobutyric acid, but not R(-)-3-isobutyl-gamma aminobutyric acid, also produced dose-dependent reversal of the intrathecal substance P-induced thermal hyperalgesia (intrathecal ED100, 65 microg and intraperitonal ED100, 31 mg/kg). The effects of intraperitoneally administered gabapentin and 3-isobutyl-gamma aminobutyric acid were reversed by intrathecal pretreatment with D-serine (100 microg) but not by L-serine. All effects were observed at doses that had little effect on motor function or spontaneous activity. Intrathecal N-methyl-D-aspartate (2 nmol) induced thermal hyperalgesia, which was blocked by gabapentin (100 mg/kg intraperitoneally) and S(+)-3-isobutyl-gamma aminobutyric acid (30 mg/kg intraperitoneally). Conclusions The structure-activity relationship and the stereospecificity noted after intrathecal delivery suggest that gabapentin and S(+)-3-isobutyl-gamma aminobutyric acid act at a common spinal locus to modulate selectively a facilitated state of nociceptive processing.

Spinal Endogenous Acetylcholine Contributes to the Analgesic Effect of Systemic Morphine in Rats

2001 ◽  
Vol 95 (2) ◽  
pp. 525-530 ◽  
Author(s):  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Receptor Antagonist ◽  
Analgesic Effect ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Radiant Heat ◽  
Cholinergic Receptor ◽  
Inhibitory Effect ◽  
Withdrawal Latency ◽  
Aziridinium Ion

Background Systemic morphine is known to cause increased release of acetyicholine in the spinal cord. Intrathecal injection of the cholinergic receptor agonists or acetyicholinesterase inhibitors produces antinociception in both animals and humans. In the present study, we explored the functional importance of spinal endogenous acetylcholine in the analgesic action produced by intravenous morphine. Methods Rats were implanted with intravenous and intrathecal catheters. The antinociceptive effect of morphine was determined by the paw-withdrawal latency in response to a radiant heat stimulus after intrathecal treatment with atropine (a muscarinic receptor antagonist), mecamylamine (a nicotinic receptor antagonist), or cholinergic neurotoxins (ethylcholine mustard aziridinium ion [AF64A] and hemicholinium-3). Results Intravenous injection of 2.5 mg/kg morphine increased significantly the paw-withdrawal latency. Intrathecal pretreatment with 30 microg atropine (n = 7) or 50 microg mecamylamine (n = 6) both attenuated significantly the antinociceptive effect of morphine. The inhibitory effect of atropine on the effect of morphine was greater than that of mecamylanilne. Furthermore, the antinociceptive effect of morphine was significantly reduced in rats pretreated with intrathecal AF64A (n = 7) or hemicholinium-3 (n = 6) to inhibit the high-affinity choline transporter and acetylcholine synthesis. We found that intrathecal AF64A reduced significantly the [3H]hemicholinium-3 binding sites but did not affect its affinity in the dorsal spinal cord. Conclusions The data in the current study indicate that spinal endogenous acetylcholine plays an important role in mediating the analgesic effect of systemic morphine through both muscarinic and nicotinic receptors.

scholarly journals The effect of baclofen on spontaneous and evoked behavioural expression of experimental neuropathic chronic pain

1999 ◽  
Vol 57 (3B) ◽  
pp. 753-760 ◽  
Author(s):  
TEREZINHA DE JESUS T. SANTOS ◽  
CARLOS M. DE CASTRO-COSTA ◽  
SÍLVIO D. A. GIFFONI ◽  
FRANKLIN J. C. SANTOS ◽  
RODRIGO S. N. RAMOS ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Aminobutyric Acid ◽  
Thermal Stimulus ◽  
Dependent Manner ◽  
Gamma Aminobutyric Acid ◽  
Analgesic Effects ◽  
Nociceptive Stimulus ◽  
Dose Dependent

Baclofen (beta-p-chlorophenyl-GABA) has been used in humans to treat spasticity, as well as trigeminal neuralgia. Since GABA (gamma-aminobutyric acid) has been implicated in inhibitory and analgesic effects in the nervous system, it was of interest to study the effect of baclofen in experimental neuropathic pain. With this purpose, experiments were carried out in 17 neuropathic rats with constrictive sciatic injury, as described by Bennet and Xie (1988), taking as pain parameters scratching behaviour and the latency to the thermal nociceptive stimulus. The results showed that baclofen induces, in a dose-dependent manner, significant decrease (p < 0.05) of scratching behaviour and significant increase (p < 0.05) of the latency to the nociceptive thermal stimulus. The absence of antagonism of naloxone suggested a non-participation of an opioid-mediated mechanism in this analgesic effect of baclofen on experimental neuropathic pain.

Preliminary results from a phase I study of substance P-saporin in terminal cancer patients with intractable pain.

2014 ◽  
Vol 32 (31_suppl) ◽  
pp. 191-191 ◽  
Author(s):  
Arthur E. Frankel ◽  
Hugh Nymeyer ◽  
Douglas A. Lappi ◽  
Denise Higgins ◽  
Chul Ahn ◽  
...  
Keyword(s):  
Substance P ◽  
Phase I ◽  
Cancer Patients ◽  
Phase I Study ◽  
Intrathecal Injection ◽  
Thermal Hyperalgesia ◽  
Single Subject ◽  
Intractable Pain ◽  
Lumbar Region ◽  
Cardiac Abnormalities

191 Background: For 10-15% of cancer patients, pain cannot be controlled using existing therapies (Zech et al., Pain, 63, 65-76, 1995). SP-SAP is the first targeted toxin to undergo phase I testing for pain. SP-SAP (Wiley and Lappi, Neurosci Lett, 230, 97-100, 1997) covalently linkes substance P (SP), a neuromodulator that binds to NK1 receptors on laminae I and X of the dorsal horn, and saporin (SAP), a ribosomal toxin that ablates cells that express NK1 and endocytose the toxin. Intrathecal injections of SP-SAP in rats reduce chemically or thermally induced pain, thermal hyperalgesia, and mechanical allodynia, with no signs of motor, sensory, or behavioral dysfunction (Mantyh et al., Science, 278, 275-9, 1997; Nichols et al., Science, 286, 1558-61, 1999; Suzuki et al., Nature Neurosci, 5, 139-26, 2002; Vierck et al., Neurosci, 199, 223-32, 2003). In canines, intrathecal injections into the lumbar region – 45 mcg for 10-15 kg (Allen et al., Toxicol Sci, 91, 286-98, 2006) or 15 mcg for 8-12 kg (Wiese et al., Anesthesiol, 119, 1163-77, 2013) – produce no neurological, behavioral, or histological deficits. A double-blinded RCT of SP-SAP for the treatment of bone pain in canines (Brown and Agnello, Anesthesiol, 199, 1178-85, 2013) showed that a single injection of 60 mcg (above 30 kg) or 40 mcg (below 30 kg) significantly reduced pain as measured by time to owner unblinding (p=0.002) or number of canines unblended (p=0.001). Methods: A single intrathecal injection of SP-SAP is made at the L5-S1 interspace of cancer patients with intractable sub-umbilical pain. Single subject cohorts are at doses of 1, 2, 4, 8, 16, 32, 64, and 90 mcg. Primary outcomes are assessed by pain survey (VAS “bothersome pain”, VAS “pain intensity”, ODI, EQ-5D, and BDI) and medication use log. Patients are monitored for toxicity, neurological and cardiac abnormalities, and SP-SAP antibodies for 6 months. Results: This report presents the results from the first three subjects of the phase I study. No evidence of toxicity or neurological or cardiac abnormalities were found. No clear evidence for pain reduction was observed. Conclusions: At existing doses (< 4 mcg), SP-SAP appears safe for human use. The study is continuing with dose escalation. Clinical trial information: NCT02036281.

Characterization of the Antihyperalgesic Action of a Novel Peripheral Mu-opioid Receptor Agonist-Loperamide 

1999 ◽  
Vol 90 (1) ◽  
pp. 225-234 ◽  
Author(s):  
Natsuko Nozaki-Taguchi ◽  
Tony L. Yaksh
Keyword(s):  
Thermal Injury ◽  
Thermal Hyperalgesia ◽  
Radiant Heat ◽  
Opioid Agonist ◽  
Mu Opioid ◽  
Plantar Surface ◽  
Opioid Receptor Agonist ◽  
Elimination Half ◽  
Systemic Side Effects ◽  
Peripheral Opioid Receptors

Background Preclinical and clinical evidence indicates that locally administered opioid agonists produce an antihyperalgesic effect through peripheral opioid receptors in inflamed tissue. Loperamide, a mu opioid agonist, does not cross the blood-brain barrier and therefore lacks central effects after systemic administration. The authors defined the effects of topical loperamide on a thermal injury-induced hyperalgesia. Methods In halothane-anesthetized rats, thermal injury was induced by placing the plantar surface of a hindpaw on a hot plate (52.0+/-1 degrees C) for 45 s. Loperamide was prepared in a cream emulsion (ADL 2-1294B, 0.5%, 1.7%, and 5.0%). The drug was applied as follows: before or after injury on the injured paw and on a normal paw and after injury on the injured paw of morphine-tolerant rats. Paw withdrawal latency to a radiant heat source was measured to determine the nociceptive threshold. A pharmacokinetic study was performed with the use of 14C-labeled drug. Results Thermal injury yielded a significant thermal hyperalgesia. Loperamide, but not the vehicle, posttreatment on the injured paw resulted in a dose-dependent antihyperalgesic effect, which was reversible with naloxone (1 mg/kg given intraperitoneally). Treatment with loperamide on the normal paw produced short-lasting hypoalgesia, but the effect was not reversible with naloxone. Pretreatment at 1 and 2 but not 4 h with loperamide was effective. A rightward shift of the dose-response curve was observed in rats made tolerant to systemic morphine with subcutaneous morphine pellets. No rats with drug treatment displayed any evident behavior changes (eg., loss of corneal or pinna reflexes or change in ambulation). Drug activity in the tissue revealed an elimination half life of 2.3 h and negligible concentration in the blood. Conclusions Loperamide, a peripherally acting mu opioid agonist, applied topically at the site of inflammation possesses a significant antihyperalgesic action without any systemic side effects.

scholarly journals Adding Dexmedetomidine to Articaine Increases the Latency of Thermal Antinociception in Rats

2020 ◽  
Vol 67 (2) ◽  
pp. 72-78
Author(s):  
Yukako Tsutsui ◽  
Katsuhisa Sunada
Keyword(s):  
Local Anesthesia ◽  
Local Anesthetic ◽  
Pain Perception ◽  
Low Dose ◽  
Cardiovascular Effects ◽  
Radiant Heat ◽  
Plantar Surface ◽  
Withdrawal Latency ◽  
Male Wistar Rats ◽  
Low Toxicity

Articaine is a low-toxicity local anesthetic that is widely used in dentistry. Typically, epinephrine is added to prolong the duration of articaine local anesthesia; however, epinephrine exhibits adverse effects. Low-dose dexmedetomidine (DEX), an α2-adrenoreceptor agonist, reportedly prolongs local anesthesia without notable adverse cardiovascular effects. The purpose of this study was to assess whether a combination of low-dose DEX and articaine would provide a low-toxicity local anesthetic option for dental procedures without adverse cardiovascular effects. Thus, this study investigated whether DEX could prolong the local anesthetic effect of articaine using a rat model of pain. Adult male Wistar rats (N = 44; 11 per group) received a 50-μL subcutaneous injection into the plantar surface of the hind paws; injections were composed of either normal saline, 4% articaine (2 mg articaine), combined 5 μg/kg DEX and 4% articaine (1.25 μg DEX + 2 mg articaine), or combined epinephrine (1:100,000) and 4% articaine (0.9 μg epinephrine + 2 mg articaine). Subsequent acute pain perception was determined by paw withdrawal movement in response to infrared radiant heat stimulation of the plantar region. Paw withdrawal latency was tested at 5-minute intervals. Paw withdrawal latency values at 35 and 40 minutes were 3.83 ± 1.76 and 3.29 ± 1.43 seconds for articaine alone, 7.89 ± 2.72 and 7.25 ± 3.37 seconds for DEX and articaine, and 8.95 ± 2.28 and 8.17 ± 3.01 seconds for epinephrine and articaine. DEX prolonged the paw withdrawal latency of articaine for up to 35 minutes (p = .015) but not 40 minutes after injection (p = .052) when compared to articaine alone. The combination of DEX and articaine can provide effective local anesthesia for up to 35 minutes after injection.

Nucleus accumbens to globus pallidus GABA projection subserving ambulatory activity

1980 ◽  
Vol 238 (1) ◽  
pp. R65-R69 ◽  
Author(s):  
D. L. Jones ◽  
G. J. Mogenson
Keyword(s):  
Nucleus Accumbens ◽  
Synergistic Effect ◽  
Globus Pallidus ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Ambulatory Activity ◽  
Gaba Antagonist ◽  
Dose Dependent

The present experiments investigated the hypothesis of a projection relating to the release of gamma-aminobutyric acid (GABA) from the nucleus accumbens to the globus pallidus subserving ambulatory activity in the rat. The GABA antagonist picrotoxin, microinjected into the globus pallidus, elicited dose-dependent increases in ambulatory activity. The administration of dopamine into the nucleus accumbens had a synergistic effect and further stimulated ambulatory activity. GABA injected into the ventral posterior globus pallidus significantly attenuated the ambulatory activity stimulated by injecting dopamine into the nucleus accumbens. These observations provide evidence of a GABAergic projection from the nucleus accumbens to the globus pallidus and implicate it in the initiation of ambulatory activity.

Acetazolamide and Amiloride Inhibit Pentobarbital-induced Facilitation of Nocifensive Reflexes 

1999 ◽  
Vol 90 (4) ◽  
pp. 1158-1164 ◽  
Author(s):  
David P. Archer ◽  
Sheldon Roth
Keyword(s):  
Radiant Heat ◽  
Postsynaptic Membrane ◽  
No Synthase ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Withdrawal Latency ◽  
Drug Concentrations ◽  
Nociceptive Reflexes ◽  
Channel Open Time ◽  
The Impact

Background Neuronal excitation may result from stimulation of gamma-aminobutyric acid A (GABA(A)) receptors that prolong the channel opening, depolarizing the postsynaptic membrane. Drugs such as acetazolamide or amiloride can block GABA depolarization. Barbiturates facilitate nociceptive reflexes and also prolong the GABA(A) channel open-time. To evaluate the possible mechanism, the authors studied the impact of acetazolamide and amiloride on pentobarbital-induced nocifensive reflex facilitation. Because nitric oxide (NO) is a mediator of reflex facilitation, the authors evaluated the effects of NO synthase inhibition. Methods Nocifensive reflex thresholds were quantified with the hind paw withdrawal latency from radiant heat (HPW latency) in the rat. Nocifensive reflexes were facilitated with intraperitoneal injection of pentobarbital (30 mg/kg). The authors tested the roles of GABA-mediated depolarization and NO in reflex facilitation by pretreatment with acetazolamide and amiloride and inhibition of NO synthase with L-NAME and 7-NI, respectively. Sedative effects of pentobarbital were evaluated with the righting reflex, the response to vibrissal stimulation, and plasma drug concentrations. Results Pentobarbital decreased the hind paw withdrawal latency from 11.2+/-1 to 8.3+/-1 s (P &lt; 0.001). Pretreatment with each of the four test drugs limited the reduction in reflex facilitation after pentobarbital to 1.3 s or less, similar to the reduction seen after saline injection, without altering sedation. L-NAME increased plasma pentobarbital concentrations by 10% without changing the concentration associated with return of responsiveness. Conclusions Pentobarbital-induced nocifensive reflex facilitation was inhibited by all four tested drugs without evidence of increased sedation. The results are consistent with a role for GABA(A) receptor-mediated depolarization in barbiturate-induced hyper-reflexia.

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