Weak Antinociceptive Effect Research Articles

The Anti-Nociceptive Effects of Nicotine in Humans: A Systematic Review and Meta-Analysis.

Pain can have a serious impact on a patient's physical, mental, and social health, often causing their quality of life to decline. Various nicotine dosage forms, such as nicotine patches and nasal spray, have been developed and used as analgesics in clinical settings. However, there is controversy over the anti-nociceptive effects of nicotine among different clinical trials. The purpose of this meta-analysis is to quantify the analgesic effect of nicotine patches, nicotine nasal spray, and tobacco smoking on pain in humans. Relevant articles published in English prior to July 2023 were identified using the PubMed, Cochrane Library, and Embase online databases in accordance with PRISMA (2020) guidelines. Two reviewers independently screened and selected studies, extracted data, and assessed the quality of the included studies using version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). RStudio was used for data synthesis, heterogeneity assessment, sensitivity analysis, publication bias assessment, trim-and-fill analyses, and generating forest plots. Sixteen eligible articles, including k = 5 studies of pain tolerance (n = 210), k = 5 studies of pain threshold (n = 210), and k = 12 studies of pain scores (N = 1249), were included for meta-analysis. Meta-analytic integration for pain threshold (Hedges' g = 0.28, 95% CI = 0-0.55, Z = 1.99, p = 0.05) and pain tolerance (Hedges' g = 0.32, 95% CI = 0.05-0.59, Z = 2.30, p = 0.02) revealed that nicotine administered via tobacco smoke generated acute analgesic effects to thermal stimuli. Meta-analytic integration for pain scores revealed that nicotine had a weak anti-nociceptive effect on postoperative pain of -0.37 (95% CI = -0.77 to 0.03, Z = -1.80) but with no statistical significance (p = 0.07). In addition, a limited number of included studies revealed that long-term smoking produced hyperalgesia that may be characterized as small to medium in magnitude (Hedges' g = 0.37, 95% CI = 0.29-0.64, Z = 5.33, p < 0.01). These results help to clarify the mixed outcomes of trials and may ultimately inform the treatment of pain. We observed that acute nicotine administration prolonged the laboratory-induced pain threshold and tolerance time and may mildly relieve postoperative pain. In addition, long-term tobacco smoking may have a nociceptive effect on different types of chronic pain. More research is needed to determine the anti-nociceptive effects of nicotine in humans, and to understand the optimal timing, dose, and method of delivery of nicotine.

Treatment-Resistant Depression (TRD): Is the Opioid System Involved?

About 30% of major depression disorder patients fail to achieve remission, hence being diagnosed with treatment-resistant major depression (TRD). Opium had been largely used effectively to treat depression for centuries, but when other medications were introduced, its use was discounted due to addiction and other hazards. In a series of previous studies, we evaluated the antinociceptive effects of eight antidepressant medications and their interaction with the opioid system. Mice were tested with a hotplate or tail-flick after being injected with different doses of mianserin, mirtazapine, trazodone, venlafaxine, reboxetine, moclobemide, fluoxetine, or fluvoxamine to determine the effect of each drug in eliciting antinociception. When naloxone inhibited the antinociceptive effect, we further examined the effect of the specific opioid antagonists of each antidepressant drug. Mianserin and mirtazapine (separately) induced dose-dependent antinociception, each one yielding a biphasic dose-response curve, and they were antagonized by naloxone. Trazodone and venlafaxine (separately) induced a dose-dependent antinociceptive effect, antagonized by naloxone. Reboxetine induced a weak antinociceptive effect with no significant opioid involvement, while moclobemide, fluoxetine, and fluvoxamine had no opioid-involved antinociceptive effects. Controlled clinical studies are needed to establish the efficacy of the augmentation of opiate antidepressants in persons with treatment-resistant depression and the optimal dosage of drugs prescribed.

Analysis of the antinociceptive interactions in two-drug combinations of gabapentin, oxcarbazepine and amitriptyline in streptozotocin-induced diabetic mice

Antiepileptic and antidepressant drugs are the primary treatments for pain relief in diabetic neuropathy. Combination therapy is a valid approach in pain treatment, where a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of two-drug combinations of gabapentin, oxcarbazepine, and amitriptyline on nociception in diabetic mice and aimed to determine the type of interaction between components. The nociceptive responses in normal and diabetic mice were assessed by the tail-flick test. The testing was performed before and three weeks after the diabetes induction with streptozotocin (150 mg/kg; i.p.), when the antinociceptive effects of gabapentin, oxcarbazepine, amitriptyline and their two-drug combinations were examined. Gabapentin (10–40 mg/kg; p.o.) and oxcarbazepine (20–80 mg/kg; p.o.) produced a significant, dose-dependent antinociception in diabetic mice while amitriptyline (5–60 mg/kg; p.o.) produced weak antinociceptive effect. In normal mice, neither of the drugs produced antinociception. Gabapentin and oxcarbazepine, co-administered in fixed-dose fractions of the ED 50 to diabetic mice, induced significant, dose-dependent antinociception. Isobolographic analysis revealed synergistic interaction. Oxcarbazepine (10–60 mg/kg; p.o.) + amitriptyline (5 mg/kg; p.o.) and gabapentin (10–30 mg/kg; p.o.) + amitriptyline (5 mg/kg; p.o.) combinations significantly and dose-dependently reduced nociception in diabetic mice. Analysis of the log dose–response curves for oxcarbazepine or gabapentin in a presence of amitriptyline and oxcarbazepine or gabapentin applied alone, revealed a synergism in oxcarbazepine–amitriptyline and additivity in gabapentin–amitriptyline combination. These findings provide new information about the combination therapy of painful diabetic neuropathy and should be explored further in patients with diabetic neuropathy.

The antinociceptive properties of reboxetine in acute pain

The antinociceptive effects of the selective noradrenaline reuptake inhibitor antidepressant reboxetine and its interaction with various opioid and noradrenaline receptor subtypes were evaluated. Reboxetine (i.p.) induced a weak dose-dependent antinociceptive effect in acute pain, using the hotplate model. The reboxetine-induced antinociception was significantly inhibited by the opioid receptor antagonists naloxone, nor-BNI, naltrindole and b-FNA, implying a non-selective role for the opioid receptors in the reboxetine's antinociceptive effect. The adrenergic antagonists yohimbine and phentolamine attenuated to some extent the reboxetine-induced antinociception, implying a minor adrenergic mechanism of antinociception. The addition of opioid or alpha2 agonists, did not potentiate the antinociception effect of reboxetine. Thus, it seems that reboxetine possesses a weak antinociceptive effect, mediated by non-selective opioid receptors and influenced somewhat by noradrenaline alpha2 receptors. These results suggest that reboxetine as monotherapy does not have sufficient efficacy in the management of acute pain. However, further research is needed in order to establish its possible use alone or in combination with other antidepressants or analgesics in the amelioration of chronic pain disorders.

The Effect of Intrathecal Epigallocatechin Gallate on the Development of Antinociceptive Tolerance to Morphine

Background: A major ingredient of green tea is epigallocatechin-3-gallate (EGCG), and this is known to have many beneficial effects for cancer prevention and also on the cardiovascular system and neurodegenerative diseases through its anti-oxidant, anti-angiogenic, anti-inflammatory, lipid-lowering and neuroprotective properties. Its actions on nociception and the spinal nervous system have been examined in only a few studies, and in these studies EGCG showed an antinociceptive effect on inflammatory and neuropathic pain, and a neuroprotective effect in motor neuron disease. This study was performed to investigate the effect of EGCG on acute thermal pain and the development of morphine tolerance at the spinal level. Methods: The experimental subjects were male Sprague-Dawley rats and the Hot-Box test was employed. A single or double-lumen intrathecal catheter was implanted at the lumbar enlargement for drug administration. An osmotic pump was used to infuse morphine for 7 days for induction of morphine tolerance. EGCG was injected repeatedly for 7 days at twice a day through the intrathecal catheter. Results: Intrathecal EGCG increased the paw withdrawal latency (PWL) after repeated administration for 7 days at twice a day, but this did not happen with administering on single bolus injection of EGCG. In addition, the antinociceptive effect of intrathecal morphine was not affected by co-administration with EGCG. A continuous 7-day infusion of morphine caused a significant decrease of the PWL in the control group (M ＋ S, morphine plus saline). In contrast, intrathecal EGCG injection over 7 days blocked the decrease of the PWL in the experiment group (M ＋ E, morphine plus EGCG). Conclusions: Intrathecal ECGC produced a weak antinociceptive effect for acute thermal pain, but it did not change the morphine's analgesic effect. However, the development of antinociceptive tolerance to morphine was attenuated by administering intrathecal EGCG.

From selective to highly selective SSRIs: A comparison of the antinociceptive properties of fluoxetine, fluvoxamine, citalopram and escitalopram

Most Serotonin Selective Reuptake Inhibitors (SSRIs) have been found to possess secondary binding properties, while citalopram and its S-enantiomer (escitalopram) have been reconfirmed “purest SSRIs”. Using the mouse model of acute pain hotplate analgesia meter, we evaluated the antinociceptive properties of fluoxetine, fluvoxamine, citalopram and escitalopram, injected i.p. Fluvoxamine induced a dose-dependent clear antinociceptive effect (with an ED 50 value of 6.4 mg/kg). Both fluoxetine and citalopram induced (separately) only a weak antinociceptive effect with an inverse “U” shape curve. All three drug's effects were not abolished by naloxone. Escitalopram did not elicit any effect at quasi-equipotent doses. These findings show that fluoxetine, fluvoxamine and citalopram given i.p. are weak antinociceptors, (not mediated through opioid mechanisms), while escitalopram possesses no antinociceptive properties when injected i.p. This difference between citalopram and escitalopram calls for further studies in order to assess the various differences between the two enantiomers of citalopram, and between each enantiomer and the racemic mixture.

The antinociceptive effect of zolpidem and zopiclone in mice

Zolpidem and zopiclone are two of a newer hypno-sedative class of drugs, the “Z compounds”. Their use for the treatment of short-term insomnia has been expanding constantly during the last two decades. The “Z compounds” are considered to cause less significant rebound insomnia or tolerance than the conventional hypnotic benzodiazepines. Their possible antinociceptive effect and interaction with the opioid system has not been studied yet. Our results demonstrate a significant difference between the antinociceptive properties of zopiclone and zolpidem when injected s.c. in the hotplate analgesic assay in mice. Zopiclone induced a weak, dose-dependent antinociceptive effect, antagonized only by the α 2-adrenergic receptor antagonist yohimbine. Zolpidem induced a weak, biphasic dose-dependent antinociceptive effect, antagonized primarily by the non-selective opioid antagonist naloxone and by yohimbine. The weak antinociceptive effect of both drugs, evident only at very high doses (far beyond those used clinically to induce sleep), implies no clinical use for zopiclone or zolpidem in the management of pain. However, the possible interaction of zolpidem with the opioid system should be further investigated (in behavioral models, which do not overlap with the acute-pain antinociception model we used), both for possible side effects in special populations (i.e. elderly) and for possible drug–drug interactions, in order to minimize possible hazards and maximize clinical beneficial effects of its use for sleep.

The Atypical Neuroleptics Clozapine and Olanzapine Differ Regarding Their Antinociceptive Mechanisms and Potency

Using the mouse tail-flick assay, we evaluated the antinociceptive effect and the interaction with the opioid, adrenergic, and serotonergic systems of the two “atypical” neuroleptic agents clozapine and olanzapine. Clozapine induced a potent antinociceptive effect in a dose-dependent manner with ED 50 of 8.7 mg/kg. This effect was antagonized by the nonselective opioid antagonist naloxone ( p < 0.05), implying an opioid mechanism of action involved in clozapine-induced antinociception. Further evaluation demonstrated the involvement of μ 1-, μ 2-, κ 1- opioid receptor subtypes and of α 2-adrenoreceptors in clozapine antinociception but not the serotonin receptors. Olanzapine induced a weak antinociceptive effect. The highest effect found was a 50% antinociception following an injection of 10 mg/kg. As the olanzapine dose increased beyond 10 mg/kg, latencies declined almost back to baseline. Yohimbine (an α 2-adrenoreceptor antagonist) significantly reduced olanzapine's antinociceptive effect almost completely (to 10%; p < 0.05), while both naloxone and metergoline (a nonselective 5-HT receptor antagonist) reduced it only partially. These results indicate the possible involvement of the α 2-adrenoreceptors in olanzapine antinociception and to a less extent the involvement of opioid and serotonergic receptors. Although both clozapine and olanzapine are dibenzodiazepines with similar “atypical” antipsychotic properties, it seems that they differ notably not only regarding their hematological side effects, but regarding their interaction with the opioid system as well.

Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study.

1. Although it is well known that morphine induces significant immunosuppression, the potential immunosuppressive activity of morphine derived drugs commonly used in the treatment of pain (codeine, hydromorphone, oxycodone) has never been evaluated. 2. We evaluated in the mouse the effect of the natural opiates (morphine and codeine) and synthetic derivatives (hydromorphone, oxycodone, nalorphine, naloxone and naltrexone) on antinociceptive thresholds and immune parameters (splenocyte proliferation, Natural Killer (NK) cell activity and interleukin-2 (IL-2) production). 3. Morphine displayed a potent immunosuppressive effect that was not dose-related to the antinociceptive effect, codeine possessed a weak antinociceptive effect and limited immunosuppressive activity; nalorphine, a mu-antagonist and kappa-agonist, exerted a potent immunosuppressive effect, but had very weak antinociceptive activity. The pure kappa-antagonist nor-BNI antagonized the antinociceptive, but not the immunosuppressive effect of nalorphine. 4. Hydromorphone and oxycodone, potent antinociceptive drugs, were devoid of immunosuppressive effects. 5. The pure antagonists naloxone and naltrexone potentiated immune responses. 6. Our data indicate that the C6 carbonyl substitution, together with the presence of a C7-8 single bond potentiates the antinociceptive effect, but abolishes immunosuppression (hydromorphone and oxycodone). 7. The single substitution of an allyl on the piperidinic ring resulted in a molecule that antagonized the antinociceptive effect but maintained the immunosuppressive effect. 8. Molecules that carry modifications of C6, the C7-8 bond and C14, together with an allyl or caboxymethyl group on the piperidinic ring antagonized both the antinociceptive and the immunosuppressive effect of opiates and were themselves immunostimulants.

Central B2 receptor involvement in the antinociceptive effect of bradykinin in rats.

1. The effect of intracerebroventricular (i.c.v.) injection of bradykinin (BK) and related peptides was tested on the dental pulp electrical stimulation threshold (DPEST) in rats. 2. BK (4, 8 and 16 nmol) induced a dose-dependent increase of DPEST, indicative of an antinociceptive effect. 3. I.c.v. injection of equimolar doses of BK-related peptides, Lys-BK and Met-Lys-BK, also induced an increase of DPEST, but the magnitude of the effect was not as intensive as that induced by BK, when the maximum increase of DPEST was considered. The peptide T-kinin induced a short lasting and weak antinociceptive effect. 4. The B1 agonist, des-Arg9-BK (8 nmol) induced a significant antinociceptive effect, but this was not as intensive as that induced by BK. 5. The B2 antagonist D-Arg0-Hyp3-Thi5,8-D-Phe7-BK (D-Arg0) competitively antagonized the BK-induced antinociception. Likewise, Hyp3-Thi5,8-D-Phe7-BK (Hyp) also antagonized BK effect. However, the compound Thi5,8-D-Phe7-BK (Thi), initially considered a pure BK antagonist, induced an antinociceptive effect, supporting previous observations that this peptide can also act as a partial agonist. 6. It is concluded that the dose-dependent antinociceptive effect induced by i.c.v. injection of BK is mediated by the stimulation of brain B2 receptors.

Autoradiographic studies concerning the supraspinal site of the antinociceptive action of morphine when inhibiting the hindleg flexor reflex in rabbits

Previous investigations in unrestrained, conscious rabbits showed that the site of action of morphine when it inhibits the hindleg flexor reflex is located in structures easily reached from the 4th ventricle. In the present investigation using 14C-morphine, the site of action of the drug was localized more precisely. The distribution pattern of morphine around the 4th ventricle after intraventricular and intracisternal injection was visualized by autoradiography and correlated with the pharmacological effect in the individual experiments. Thus, structures bordering the caudal parts of the 4th ventricle and the extraventricular cerebrospinal fluid space within this region could be excluded as sites of action. On the other hand, structures in the floor of the rostral part of the fossa rhomboidea are highly putative as sites of morphine action. The concentration of morphine along the permeation route from the ventricle to nearby structures was determined by combining the results of radioassay, autoradiography and optical scanning. The concentrations calculated for structures at different distances from the ventricular wall were compared with those concentrations obtained after systemic application of equieffective morphine dosages. It was concluded that the relevant receptors are located somewhat more than 1000 μm away from the ventricular wall. When a weak antinociceptive effect is observed, this region corresponds to the border zone of the autoradiographically-blackened area. The results are discussed with reference to the technical problems of this procedure as well as the anatomical structures and physiological mechanisms involved in supraspinal control of spinal nociceptive reflex activity.