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Pain Jul 2022Diabetic neuropathy, often associated with diabetes mellitus, is a painful condition with no known effective treatment except glycemic control. Studies with neuropathic...
Diabetic neuropathy, often associated with diabetes mellitus, is a painful condition with no known effective treatment except glycemic control. Studies with neuropathic pain models report alterations in cannabinoid and opioid receptor expression levels; receptors whose activation induces analgesia. We examined whether interactions between CB1R and opioid receptors could be targeted for the treatment of diabetic neuropathy. For this, we generated antibodies that selectively recognize native CB1R-MOR and CB1R-DOR heteromers using a subtractive immunization strategy. We assessed the levels of CB1R, MOR, DOR, and interacting complexes using a model of streptozotocin-induced diabetic neuropathy and detected increased levels of CB1R, MOR, DOR, and CB1R-MOR complexes compared with those in controls. An examination of G-protein signaling revealed that activity induced by the MOR, but not the DOR agonist, was potentiated by low nanomolar doses of CB1R ligands, including antagonists, suggesting an allosteric modulation of MOR signaling by CB1R ligands within CB1R-MOR complexes. Because the peptide endocannabinoid, hemopressin, caused a significant potentiation of MOR activity, we examined its effect on mechanical allodynia and found that it blocked allodynia in wild-type mice and mice with diabetic neuropathy lacking DOR (but have CB1R-MOR complexes). However, hemopressin does not alter the levels of CB1R-MOR complexes in diabetic mice lacking DOR but increases the levels of CB1R-DOR complexes in diabetic mice lacking MOR. Together, these results suggest the involvement of CB1R-MOR and CB1R-DOR complexes in diabetic neuropathy and that hemopressin could be developed as a potential therapeutic for the treatment of this painful condition.
Topics: Animals; Cannabinoids; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Disease Models, Animal; Hyperalgesia; Ligands; Mice; Neuralgia; Receptors, Opioid; Receptors, Opioid, mu
PubMed: 34724682
DOI: 10.1097/j.pain.0000000000002527 -
International Journal of Molecular... Aug 2021Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb...
Oxaliplatin, a well-known chemotherapeutic agent, can induce severe neuropathic pain, which can seriously decrease the quality of life of patients. JI017 is an herb mixture composed of , , and . Its anti-tumor effect has been reported; however, the efficacy of JI017 against oxaliplatin-induced allodynia has never been explored. Single oxaliplatin injection [6 mg/kg, intraperitoneal, (i.p.)] induced both cold and mechanical allodynia, and oral administration of JI017 (500 mg/kg) alleviated cold but not mechanical allodynia in mice. Real-time polymerase chain reaction (PCR) analysis demonstrated that the upregulation of mRNA of spinal transient receptor potential vanilloid 1 (TRPV1) and astrocytes following oxaliplatin injection was downregulated after JI017 treatment. Moreover, TRPV1 expression and the activation of astrocytes were intensely increased in the superficial area of the spinal dorsal horn after oxaliplatin treatment, whereas JI017 suppressed both. The administration of TRPV1 antagonist [capsazepine, intrathecal (i.t.), 10 μg] attenuated the activation of astrocytes in the dorsal horn, demonstrating that the functions of spinal TRPV1 and astrocytes are closely related in oxaliplatin-induced neuropathic pain. Altogether, these results suggest that JI017 may be a potent candidate for the management of oxaliplatin-induced neuropathy as it decreases pain, spinal TRPV1, and astrocyte activation.
Topics: Aconitum; Administration, Oral; Angelica; Animals; Astrocytes; Cold Temperature; Disease Models, Animal; Down-Regulation; Zingiber officinale; Hyperalgesia; Mice; Oxaliplatin; Phytochemicals; Spine; TRPV Cation Channels
PubMed: 34445514
DOI: 10.3390/ijms22168811 -
Turkish Journal of Medical Sciences Dec 2021Cisplatin (CIS) is an effective antineoplastic agent used in the treatment of several cancer types. Peripheral neuropathy is a major dose-limiting side-effect in CIS...
BACKGROUND/AIM
Cisplatin (CIS) is an effective antineoplastic agent used in the treatment of several cancer types. Peripheral neuropathy is a major dose-limiting side-effect in CIS therapy. Cannabinoids may alleviate this painful side effect. This study investigated the analgesic effects of anandamide (AN) on CIS-induced peripheral neuropathy, in vitro effects of AN in CIS neurotoxicity, and the contribution of nitric oxide (NO) in this effect.
MATERIALS AND METHODS
This is an experimental animal study. Primary dorsal root ganglion (DRG) cultures were prepared from one-day-old rats for in vitro investigations. DRG cells were incubated with CIS (100–300 M), and AN (10, 50, 100, and 500 μM) was administered with the submaximal concentration of CIS. Female Sprague Dawley rats were divided into control, CIS, CIS+AN, CIS+AN+L-NG-nitro arginine methyl ester (LNAME). CIS was administered 3 mg/kg i.p once weekly for 5 weeks. AN (1 mg/kg i.p) or in combination with 10 mg/kg i.p LNAME was administrated 30 min before CIS injection. Mechanical allodynia, thermal hyperalgesia, and tail clip tests were performed. After intracardiac perfusion, sciatic nerves (SN), and DRGs were isolated and semi-thin sections were stained with toluidine blue and investigated histologically. SPSS v. 21.0 and Sigma STAT 3.5 were used for statistical analysis. One/two way ANOVA, Kruskal–Wallis, and Wilcoxon signed ranks tests were used. A p-value of 0.05 was accepted as significant.
RESULTS
CIS caused significant mechanical allodynia. AN and AN+LNAME significantly increased hind paw withdrawal latency in mechanical allodynia test. The degenerated axons significantly increased in CIS group, while decreased in AN group. The frequency of larger neurons seemed to be higher in CIS+AN group.
CONCLUSION
AN may be a therapeutic alternative for the treatment of CIS-induced peripheral neuropathy. However, its central adverse effects must be considered.
Topics: Animals; Arachidonic Acids; Cisplatin; Endocannabinoids; Female; Hyperalgesia; NG-Nitroarginine Methyl Ester; Peripheral Nervous System Diseases; Polyunsaturated Alkamides; Rats; Rats, Sprague-Dawley
PubMed: 34118805
DOI: 10.3906/sag-2101-224 -
Toxins Sep 2020Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a...
Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may achieve more beneficial effects than monotherapy. Thus, we investigated the analgesic efficacies and spinal mechanisms of the combination strategy, including bee venom acupuncture (BVA) and venlafaxine (VLX) against paclitaxel-induced allodynia in mice. Four intraperitoneal infusions of paclitaxel on alternating days (2 mg/kg/day) induced cold and mechanical allodynia for at least 1 week as assessed using acetone and the von Frey hair test, respectively. Co-treatment of BVA (1.0 mg/kg, s.c., ST36) with VLX (40 mg/kg, i.p.) at the medium dose produced a longer-lasting and additive effect than each monotherapy at the highest dose (BVA, 2.5 mg/kg; VLX, 60 mg/kg). Spinal pre-administration of idazoxan (α-adrenergic receptor antagonist, 10 μg), methysergide (mixed 5-HT/5-HT receptor antagonist, 10 μg), or MDL-72222 (5-HT receptor antagonist, 10 μg) abolished this analgesia. These results suggest that the combination therapy with BVA and VLX produces long-lasting and additive analgesic effects on paclitaxel-induced allodynia, via the spinal noradrenergic and serotonergic mechanism, providing a promising clinical strategy.
Topics: Acupuncture Therapy; Analgesics; Animals; Bee Venoms; Combined Modality Therapy; Disease Models, Animal; Hyperalgesia; Male; Mice, Inbred C57BL; Paclitaxel; Pain Threshold; Serotonin and Noradrenaline Reuptake Inhibitors; Spinal Cord; Venlafaxine Hydrochloride
PubMed: 32998357
DOI: 10.3390/toxins12100620 -
The Journal of Pain Jul 2021Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence... (Randomized Controlled Trial)
Randomized Controlled Trial
Nocebo hyperalgesia is a pervasive problem that significantly adds to the burden of pain. Conditioning is a key mechanism of nocebo hyperalgesia and recent evidence indicates that, once established, nocebo hyperalgesia is resistant to extinction. This means that preventive strategies are critical. We therefore tested whether two novel strategies - overshadowing (Experiment 1) and pre-exposure (Experiment 2) - could inhibit conditioned nocebo hyperalgesia. Overshadowing involves introducing additional cues during conditioning that should compete with and overshadow learning about the target nocebo cue. Pre-exposure involves pre-exposing the target nocebo cue in the absence of pain, which should diminish its ability to become associated with pain later. In both studies, healthy volunteers (N = 141) received exposure to a series of electrocutaneous pain stimuli with and without a sham electrode 'activated', which they were led to believe was a genuine hyperalgesic treatment. Nocebo conditioning was achieved by pairing sham activation with high pain prior to testing at equivalent pain intensity. In both studies, standard nocebo conditioning led to clear nocebo hyperalgesia relative to natural history controls. In Experiment 1, there was no evidence that overshadowing attenuated nocebo hyperalgesia. Importantly, however, Experiment 2 found that pre-exposure successfully attenuated nocebo hyperalgesia with post hoc analysis suggesting that this effect was dose-dependent. These findings provide novel evidence that pre-exposure, but not overshadowing, could be a cheap and effective way for mitigating the substantial harm caused by conditioned nocebo hyperalgesia in clinical settings. PERSPECTIVE: Nocebo hyperalgesia causes substantial patient burden with few preventive options available. Our study found novel evidence that pre-exposing treatment cues without pain, but not overshadowing them with other cues, has the capacity to inhibit conditioned nocebo hyperalgesia. Pre-exposure may therefore be an effective preventive strategy to combat nocebo hyperalgesia.
Topics: Adolescent; Adult; Conditioning, Psychological; Cues; Female; Humans; Hyperalgesia; Male; Nocebo Effect; Pain Measurement; Transcutaneous Electric Nerve Stimulation; Young Adult
PubMed: 33636369
DOI: 10.1016/j.jpain.2021.02.008 -
European Journal of Pain (London,... Apr 2018Current medical treatments for chemotherapy-induced pain (CIP) are either ineffective or have adverse side effects. Acupuncture may alleviate CIP, but its effectiveness...
BACKGROUND
Current medical treatments for chemotherapy-induced pain (CIP) are either ineffective or have adverse side effects. Acupuncture may alleviate CIP, but its effectiveness against this condition has not been studied. Paclitaxel causes neuropathic pain in cancer patients.
METHODS
We evaluated the effects of electroacupuncture (EA) on paclitaxel-induced CIP in a rat model. Paclitaxel (2 mg/kg) or vehicle was injected (i.p.) on alternate days of 0-6. The resulting pain was treated with 10 Hz/2 mA/0.4 ms pulse EA for 30 min at the equivalent of human acupoint GB30 (Huantiao) once every other day between days 14 and 26. For sham control, EA needles were inserted into GB30 without stimulation. Von Frey filaments with bending forces of 2-8 g and 15 g were used to assess mechanical allodynia and hyperalgesia, respectively, on day 13 and once every other day between 14-26 days and then for 2-3 weeks after EA treatment.
RESULTS
Compared to sham control, EA significantly alleviated paclitaxel-induced mechanical allodynia and hyperalgesia, as shown by less frequent withdrawal responses to the filaments. The alleviation of allodynia/hyperalgesia lasted up to 3 weeks after the EA treatment. EA significantly inhibited phosphorylation of Ca /calmodulin-dependent protein kinase II (CaMKII) in the spinal cord. KN-93, a selective inhibitor of p-CaMKII, inhibited mechanical allodynia/hyperalgesia and p-CaMKII. 5-HT1A receptor antagonist blocked EA inhibition of allodynia/hyperalgesia and p-CaMKII.
CONCLUSIONS
Electroacupuncture activates 5-HT 1A receptors in the spinal cord and inhibits p-CaMKII to alleviate both allodynia and hyperalgesia. The data support acupuncture/EA as a complementary therapy for CIP.
SIGNIFICANCE
Electroacupuncture (EA) activates spinal 5-HT1A receptors to inhibit p-CaMKII to alleviate paclitaxel-induced pain. Acupuncture/EA may be used as a complementary therapy for CIP.
Topics: Acupuncture Points; Animals; Antineoplastic Agents, Phytogenic; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Electroacupuncture; Hyperalgesia; Male; Neuralgia; Paclitaxel; Phosphorylation; Rats; Rats, Sprague-Dawley; Spinal Cord
PubMed: 29034548
DOI: 10.1002/ejp.1132 -
ENeuro Feb 2023Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold...
Oxaliplatin is a platinum-based chemotherapeutic agent that causes cold and mechanical allodynia in up to 90% of patients. Silent Nav1.8-positive nociceptive cold sensors have been shown to be unmasked by oxaliplatin, and this event has been causally linked to the development of cold allodynia. We examined the effects of pregabalin on oxaliplatin-evoked unmasking of cold sensitive neurons using mice expressing GCaMP-3 in all sensory neurons. Intravenous injection of pregabalin significantly ameliorates cold allodynia, while decreasing the number of cold sensitive neurons by altering their excitability and temperature thresholds. The silenced neurons are predominantly medium/large mechano-cold sensitive neurons, corresponding to the "silent" cold sensors activated during neuropathy. Deletion of α2δ1 subunits abolished the effects of pregabalin on both cold allodynia and the silencing of sensory neurons. Thus, these results define a novel, peripheral inhibitory effect of pregabalin on the excitability of "silent" cold-sensing neurons in a model of oxaliplatin-dependent cold allodynia.
Topics: Mice; Animals; Oxaliplatin; Hyperalgesia; Pregabalin; Sensory Receptor Cells; Cold Temperature
PubMed: 36720644
DOI: 10.1523/ENEURO.0395-22.2022 -
The Journal of Pain Dec 2007In certain patients with neuropathic pain, the pain is dependent on activity in the sympathetic nervous system. To investigate whether the spared nerve injury model...
UNLABELLED
In certain patients with neuropathic pain, the pain is dependent on activity in the sympathetic nervous system. To investigate whether the spared nerve injury model (SNI) produced by injury to the tibial and common peroneal nerves and leaving the sural nerve intact is a model for sympathetically maintained pain, we measured the effects of surgical sympathectomy on the resulting mechanical allodynia, mechanical hyperalgesia, and cold allodynia. Decreases of paw withdrawal thresholds to von Frey filament stimuli and increases in duration of paw withdrawal to pinprick or acetone stimuli were observed in the ipsilateral paw after SNI, compared with their pre-SNI baselines. Compared with sham surgery, surgical lumbar sympathectomy had no effect on the mechanical allodynia and mechanical hyperalgesia induced by SNI. However, the sympathectomy significantly attenuated the cold allodynia induced by SNI. These results suggest that the allodynia and hyperalgesia to mechanical stimuli in the SNI model is not sympathetically maintained. However, the sympathetic nervous system may be involved, in part, in the mechanisms of cold allodynia in the SNI model.
PERSPECTIVE
The results of our study suggest that the SNI model is not an appropriate model of sympathetically maintained mechanical allodynia and hyperalgesia but may be useful to study the mechanisms of cold allodynia associated with sympathetically maintained pain states.
Topics: Animals; Blood Vessels; Cold Temperature; Disease Models, Animal; Glyoxylates; Hyperalgesia; Male; Nerve Fibers; Pain; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy; Sympathectomy; Time Factors
PubMed: 17693138
DOI: 10.1016/j.jpain.2007.06.008 -
Biomedicine & Pharmacotherapy =... Mar 2019Chemotherapy-induced peripheral neuropathy (CIPN) is a pharmacoresistant neurological complication induced by some antitumor drugs. This study aimed to assess...
BACKGROUND AND PURPOSE
Chemotherapy-induced peripheral neuropathy (CIPN) is a pharmacoresistant neurological complication induced by some antitumor drugs. This study aimed to assess antiallodynic properties of aripiprazole and ceftriaxone used alone or in combination to attenuate neuropathic pain related to CIPN caused by oxaliplatin.
METHODS
Neuropathic pain was induced in mice by a single intraperitoneal dose of oxaliplatin (10 mg/kg). Aripiprazole and ceftriaxone were used in a single- or repeated dosing protocol. Their antiallodynic activity was assessed using von Frey and cold plate tests on the day of oxaliplatin injection and after 7 days. The influence of aripiprazole and ceftriaxone on animals' locomotor activity and motor coordination was also assessed.
RESULTS
Single-dose and repeated-dose aripiprazole 10 mg/kg and ceftriaxone 200 mg/kg used alone and in combination attenuated early-phase and late-phase tactile allodynia in oxaliplatin-treated mice. Repeated administrations of ceftriaxone 200 mg/kg prevented the development of late-phase tactile allodynia. Both drugs showed no antiallodynic properties in the cold plate test. Single-dose aripiprazole 1 and 10 mg/kg but not its repeated administration significantly decreased locomotor activity of oxaliplatin-treated mice. Single-dose aripiprazole 1 and 10 mg/kg, aripiprazole 1 mg/kg + ceftriaxone 50 mg/kg and aripiprazole 1 mg/kg + ceftriaxone 200 mg/kg impaired motor coordination in the rotarod test.
CONCLUSIONS
In mice, neither ceftriaxone nor aripiprazole attenuated cold allodynia. Ceftriaxone alone could attenuate tactile allodynia caused by oxaliplatin without inducing motor adverse effects. Although the administration of aripiprazole reduced tactile allodynia, this effect seems to be limited considering severe motor deficits induced by this drug.
Topics: Animals; Aripiprazole; Ceftriaxone; Drug Therapy, Combination; Hyperalgesia; Male; Mice; Neuralgia; Oxaliplatin; Pain Measurement; Pain Threshold
PubMed: 30841467
DOI: 10.1016/j.biopha.2019.01.008 -
Proceedings of the National Academy of... Jul 2024Spinal cord dorsal horn inhibition is critical to the processing of sensory inputs, and its impairment leads to mechanical allodynia. How this decreased inhibition...
Spinal cord dorsal horn inhibition is critical to the processing of sensory inputs, and its impairment leads to mechanical allodynia. How this decreased inhibition occurs and whether its restoration alleviates allodynic pain are poorly understood. Here, we show that a critical step in the loss of inhibitory tone is the change in the firing pattern of inhibitory parvalbumin (PV)-expressing neurons (PVNs). Our results show that PV, a calcium-binding protein, controls the firing activity of PVNs by enabling them to sustain high-frequency tonic firing patterns. Upon nerve injury, PVNs transition to adaptive firing and decrease their PV expression. Interestingly, decreased PV is necessary and sufficient for the development of mechanical allodynia and the transition of PVNs to adaptive firing. This transition of the firing pattern is due to the recruitment of calcium-activated potassium (SK) channels, and blocking them during chronic pain restores normal tonic firing and alleviates chronic pain. Our findings indicate that PV is essential for controlling the firing pattern of PVNs and for preventing allodynia. Developing approaches to manipulate these mechanisms may lead to different strategies for chronic pain relief.
Topics: Parvalbumins; Animals; Chronic Pain; Mice; Neurons; Hyperalgesia; Male; Action Potentials; Small-Conductance Calcium-Activated Potassium Channels
PubMed: 38916998
DOI: 10.1073/pnas.2403777121