Increased Withdrawal Threshold Research Articles

Spinal dopaminergic D1-and D2-like receptors have a sex-dependent effect in an experimental model of fibromyalgia

There is evidence about the importance of sex in pain. The purpose of this study was to investigate the effect of sex in the antiallodynic activity of spinal dopamine D1-and D2-like receptors in a model of fibromyalgia-type pain in rats. Reserpine induced the same extent of tactile allodynia in female and male rats. Intrathecal injection of SCH-23390 (3–30 nmol, D1-like receptor antagonist), pramipexole (0.15–15 nmol) or quinpirole (1–10 nmol D2-like receptor agonists) increased withdrawal threshold in reserpine-treated female rats. Those drugs induced a greater antiallodynic effect in female rats. Sex-difference was also observed in a nerve injury model. Ovariectomy abated the antiallodynic effect of SCH-23390 (30 nmol) in reserpine-treated rats, while systemic reconstitution of 17β-estradiol levels or intrathecal injection of estrogen receptor-α agonist protopanaxatriol in ovariectomized reserpine-treated females restored the antiallodynic effect of SCH-23390. Intrathecal administration of ICI-182,780 (estrogen receptor-α/β antagonist) or methyl-piperidino-pyrazole hydrate (estrogen receptor-α antagonist) abated 17β-estradiol-restored antiallodynic effect of SCH-23390 in rats. In contrast, ovariectomy slightly reduced the effect of pramipexole (15 nmol) or quinpirole (10 nmol) in reserpine-treated rats, whereas systemic reconstitution of 17β-estradiol levels did not modify the antiallodynic effect of both drugs. Combination 17β-estradiol/progesterone, but not 17β-estradiol nor progesterone alone, restored the antiallodynic effect of pramipexole and quinpirole in the rats. Mifepristone (progesterone receptor antagonist) abated 17β-estradiol + progesterone restoration of the antiallodynic effect of pramipexole and quinpirole. These data suggest that the antiallodynic effect of dopamine D1-and D2-like receptors in fibromyalgia-type pain depends on spinal 17β-estradiol/estrogen receptor-α and progesterone receptors, respectively.

Frozen vein wrapping for chronic nerve constriction injury reduces sciatic nerve allodynia in a rat model

BackgroundAutologous vein wrapping (VW) is used in the treatment of recurrent chronic constriction neuropathy and traumatic peripheral nerve injury. However, use of autologous veins is limited by the inability to obtain longer veins of sufficient length for larger sites. Frozen allograft tissue has several advantages, including its availability for large grafts, avoidance of donor-site morbidity, and shorter operation time. Here, we investigated the effect of frozen vein wrapping (FVW) in Wistar rats as a model of sciatic nerve injury.ResultsThe rats were grouped by treatment as (i) untreated after chronic constriction injury surgery (CCI; control group), (ii) treated with vein wrapping using freshly isolated vein (VW), and (iii) treated with vein wrapping using frozen vein (FVW). Mechanical allodynia was assessed with von Frey filaments on postoperative days (PODs) 1, 3, 5, 7, and 14. Gene expression of HO-1 was evaluated by quantitative polymerase chain reaction (qPCR). The response of heme oxygenase-1 gene, Hmox-1, expression to VW and FVW was assessed by RT-PCR. Both VW and FVW significantly increased withdrawal threshold levels compared to the untreated control group on POD 1, 3, and 5. Both VW and FVW also showed increased HO-1 expression compared to the CCI group.ConclusionsFVW increased the withdrawal threshold similar to VW in a rat CCI model for short periods. Frozen vein wrapping using vein allograft without donor site morbidity may be an alternative therapeutic option.

Measurement of mechanical withdrawal threshold on full-thickness cutaneous wounds in rats using the von Frey test.

A method for measuring mechanical withdrawal threshold of full-thickness cutaneous wound pain in animal models is lacking. This study aimed to confirm the validity and reactivity of the von Frey test in full-thickness cutaneous wounds in rats. A 1.5cm-diameter wound was established on the dorsal areas of male Sprague-Dawley rats and subcutaneously injected with either morphine hydrochloride (5.0mg/kg) or indomethacin (2.5mg/kg) with a 27-gauge needle on day three post-wounding. On day five post-wounding, an injection of morphine hydrochloride, indomethacin or lambda-carrageenan (1.0%) into the granulation tissue was also administered. The withdrawal threshold of mechanical stimulation of the wound edge was compared in each group before treatment with injection and at two, four, eight and 24 hours after injection. A total of 40 rats were used in the study. Since more severe inflammation in and around the wound was induced on day three post-wounding than that of day five, the withdrawal threshold measured on day three post-wounding was significantly lower than that of day five. The decrease of the withdrawal threshold was depressed by morphine hydrochloride and indomethacin treatment on day three post-wounding. While there was no significant difference between the changes in the withdrawal threshold after indomethacin treatment on day five post-wounding, we observed an increased withdrawal threshold after morphine hydrochloride treatment and decreased withdrawal threshold after lambda-carrageenan treatment on day five post-wounding. The results suggest that the von Frey test can be applied to measure the mechanical withdrawal threshold of full-thickness dorsal wounds in rats.

The Impact of Riluzole on Neurobehavioral Outcomes in Preclinical Models of Traumatic and Nontraumatic Spinal Cord Injury: Results From a Systematic Review of the Literature.

Study Design:Systematic review.Objective:To evaluate the impact of riluzole on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic spinal cord injury (SCI).Methods:An extensive search of the literature was conducted in Medline, EMBASE, and Medline in Process. Studies were included if they evaluated the impact of riluzole on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic SCI. Extensive data were extracted from relevant studies, including sample characteristics, injury model, outcomes assessed, timing of evaluation, and main results. The SYRCLE checklist was used to assess various sources of bias.Results:The search yielded a total of 3180 unique citations. A total of 16 studies were deemed relevant and were summarized in this review. Sample sizes ranged from 14 to 90, and injury models included traumatic SCI (n = 9), degenerative cervical myelopathy (n = 2), and spinal cord-ischemia (n = 5). The most commonly assessed outcome measures were BBB (Basso, Beattie, Besnahan) locomotor score and von Frey filament testing. In general, rats treated with riluzole exhibited significantly higher BBB locomotor scores than controls. Furthermore, riluzole significantly increased withdrawal thresholds to innocuous stimuli and tail flick latency following application of radiant heat stimuli. Finally, rats treated with riluzole achieved superior results on many components of gait assessment.Conclusion:In preclinical models of traumatic and nontraumatic SCI, riluzole significantly improves locomotor scores, gait function, and neuropathic pain. This review provides the background information necessary to interpret the results of clinical trials on the impact of riluzole in traumatic and nontraumatic SCI.

Blockade of α2-adrenergic or metabotropic glutamate receptors induces glutamate release in the locus coeruleus to activate descending inhibition in rats with chronic neuropathic hypersensitivity

Locus coeruleus (LC)-spinal noradrenergic projections are important to endogenous analgesic mechanisms and can be activated by local glutamate signaling in the LC. The current study examined the local glutamatergic, GABAergic, and noradrenergic influences on glutamate release in the LC and noradrenergic descending inhibition in rats 6 weeks after spinal nerve ligation (SNL). Intra-LC injection of the α2 adrenoceptor antagonist idazoxan or the group 2 metabotropic glutamate receptor (mGluR) antagonist (RS)-α-Methyl-4-tetrazolylphenylglycine (MTPG) increased withdrawal thresholds in SNL animals and this was reversed by the blockade of α-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors in the LC or α2-adrenoceptors in the spinal cord, but not in normal animals. Neither blockade of GABA-A nor GABA-B receptors in the LC affected withdrawal thresholds in normal and SNL animals. Intra-LC perfusion of idazoxan increased extracellular glutamate in the LC in SNL animals but not in normal animals. Intra-LC perfusion of MTPG increased extracellular glutamate in the LC in both normal and SNL animals. These results suggest that local noradrenaline and glutamate tonically inhibit glutamate release in the LC after peripheral nerve injury and this may contribute to reduced descending inhibition in response to noxious input during chronic neuropathic pain.

(111) - Investigating the influence of exercise and diet on early life stress-induced pain and obesity in mice

Individuals who experience adverse childhood events show a susceptibility to developing chronic pain disorders. These disorders frequently present co-morbidly and with both mood and obesity-related metabolic disorders. Although the underlying mechanisms of these syndromes are yet to be established, it is recognized that the hypothalamic-pituitary-adrenal (HPA) axis plays a role in the regulation of the stress, nociceptive, and metabolic systems. Therefore, it is hypothesized that HPA axis dysfunction influences their pathogenesis. The present study is investigating the effect of exercise and diet interventions in a mouse model of early life stress that displays molecular evidence of altered HPA axis regulation as well as behavioral evidence of urogenital pain disorders. Neonatal maternal separation (NMS) was performed by separating entire litters from the dam for 3h/day starting on postnatal day 1 (P1) to P21. Naive pups remained undisturbed and all pups were weaned on P22. At 4 weeks of age NMS and naive mice either received free access to a running wheel in their home cage (exercised [-Ex]) or remained in sedentary housing (-Sed). Body composition analysis was assessed in adult mice using EchoMRI. Both male and female NMS-Sed mice weighed significantly more and had greater percent body fat compared to naive or Ex mice. At 16 weeks of age, male mice were placed on a high-fat/sucrose diet for one week. All groups displayed a significant increase in weight and percent body fat. Interestingly, a diet-induced increase in perigenital mechanical sensitivity was observed in all mice except for NMS-Sed, which had an increased withdrawal threshold compared to their baseline measurements. Our findings suggest that exercise can attenuate early life stress-induced development of obesity and potential metabolic syndrome. Future work will investigate the efficacy of an anti-inflammatory diet and long-term consequences of high-fat/sucrose diet consumption. Supported by NIH grants DK099611, DK103872, and HD057850.

Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a noneuphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine whether CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. Osteoarthritis was induced in male Wistar rats (150-175 g) by intra-articular injection of sodium monoiodoacetate (MIA; 3 mg). On day 14 (end-stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology, whereas pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 after MIA. Joint nerve myelination was calculated by G-ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100-300 μg) were assessed. In end-stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (P < 0.0001; n = 8). Acute, transient joint inflammation was reduced by local CBD treatment (P < 0.0001; n = 6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (P < 0.0001; n = 8), and was also found to be neuroprotective (P < 0.05; n = 6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.

Lack of Analgesic Synergy of the Cholecystokinin Receptor Antagonist Proglumide and Spinal Cord Stimulation for the Treatment of Neuropathic Pain in Rats

Neuropathic pain is difficult to manage and treat. Spinal cord stimulation (SCS) has become an established procedure for treating chronic neuropathic pain that is refractory to pharmacological therapy. In order to achieve better analgesia, a number of studies have evaluated the effectiveness of combining drug therapy with SCS. Cholecystokinin antagonists, such as proglumide, enhance the analgesic efficacy of endogenous opioids in animal models of pain. We previously reported that both systemic and spinal administration of proglumide enhances analgesia produced by both low- and high-frequency transcutaneous electrical nerve stimulation (TENS). Since SCS produces analgesia through endogenous opioids, we hypothesized that the analgesic effect of SCS would be enhanced through co-administration with proglumide in animals with neuropathic pain. Male Sprague-Dawley rats (n = 40) with spared nerve injury were given proglumide (20 mg/kg, i.p.) or saline prior to treatment with SCS (sham, 4 Hz, and 60 Hz). Mechanical withdrawal thresholds of the paw were measured before and after induction of nerve injury, and after SCS. Physical activity levels were measured after SCS. Both proglumide and SCS when given independently significantly increased withdrawal thresholds two weeks after nerve injury. However, there was no additional effect of combining proglumide and SCS on mechanical withdrawal thresholds or activity levels in animals with nerve injury. Proglumide may be a candidate for achieving analgesia for patients with refractory neuropathic pain conditions, but does not enhance analgesia produced by SCS.

Impaired diffuse noxious inhibitory controls in specific alternation of rhythm in temperature-stressed rats

Fibromyalgia is characterized by chronic widespread musculoskeletal pain. A hypofunction in descending pain inhibitory systems is considered to be involved in the chronic pain of fibromyalgia. We examined functional changes in descending pain inhibitory systems in rats with specific alternation of rhythm in temperature (SART) stress, by measuring the strength of diffuse noxious inhibitory controls (DNIC). Hindpaw withdrawal thresholds to mechanical von Frey filament or fiber-specific electrical stimuli by the Neurometer system were used to measure the pain response. To induce DNIC, capsaicin was injected into the intraplantar of the forepaw. SART-stressed rats were established by exposure to repeated cold stress for 4 days. In the control rats, heterotopic intraplantar capsaicin injection increased withdrawal threshold, indicative of analgesia by DNIC. The strength of DNIC was reduced by naloxone (μ-opioid receptor antagonist, intraperitoneally and intracerebroventricularly), yohimbine (α2-adrenoceptor antagonist, intrathecally), and WAY-100635 (5-HT1A receptor antagonist, intrathecally) in the von Frey test. In SART-stressed rats, capsaicin injection did not increase withdrawal threshold in the von Frey test, indicating deficits in DNIC. In the Neurometer test, deficient DNIC in SART-stressed rats were observed only for Aδ- and C-fibers, but not Aβ-fibers stimulation. Analgesic effect of intracerebroventricular morphine was markedly reduced in SART-stressed rats compared with the control rats. Taken together, in SART-stressed rats, capsaicin-induced DNIC were deficient, and a hypofunction of opioid-mediated central pain modulation system may cause the DNIC deficit.

O efeito analgésico de tramadol não é mediado por receptores opioides na dor de ratos no pós‐operatório imediato

Background and objectivesTramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic‐like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. MethodsYoung male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone‐intraplantar tramadol, intraplantar naloxone‐intraplantar tramadol, intravenous naloxone‐intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5mg, naloxone 200μg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60min after incision. ResultsPlantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone‐intraplantar tramadol group and intravenous naloxone‐intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45min) was observed, the intravenous naloxone‐intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. ConclusionsTramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors.

Evaluation of anxiety-like behaviour in a rat model of acute postoperative pain.

Unrelieved acute postoperative pain can lead to a wide range of adverse effects, such as anxiety, depression, restlessness and sleep deprivation. To investigate anxiety-like behaviour in a postoperative pain model. Mechanical hypersensitivity was assessed with an electronic von Frey device, whereas anxiety-like behaviour was measured with light/dark testing and elevated plus maze testing. Rats developed significant mechanical hyperalgesia on 1, 3 and 8 days postsurgery compared with sham-operated rats. There was no reduction in motility between preincision and postincision when animals were allowed to move freely in an open field locomotion test. In light-dark tests, incised animals spent significantly less time than sham rats in the light compartment on the 1st and 3rd postoperative days. However, in an elevated plus maze test, differences between sham and incised rats were only observed on the 8th postoperative day as they spent significantly more time in the open arms. Pretreatment with morphine significantly increased withdrawal thresholds compared with treatment with saline (0.9% NaCl), but had no effect on light or open arm avoidance behaviour. We report that a rat model of acute postoperative pain is associated with anxiety-like increased light and open arm avoidance behaviour.

El efecto analgésico del tramadol no está mediado por receptores opiáceos en el dolor en ratones en el postoperatorio inmediato

Background and objectivesTramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic-like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. MethodsYoung male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone-intraplantar tramadol, intraplantar naloxone-intraplantar tramadol, intravenous naloxone-intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5mg, naloxone 200μg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60min after incision. ResultsPlantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone-intraplantar tramadol group and intravenous naloxone-intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45min) was observed, the intravenous naloxone-intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. ConclusionsTramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors.

Expression of Pain Receptors by Arthritis Treatment in Collagen Induced Murine Model of Rheumatoid Arthritis

Objective. Rheumatoid arthritis, the most common form of arthritis, is typically characterized by induced inflammatory pain in joints. Recent studies have reported on the expression of pain receptors such as transient receptor potential vanilloid 1 (TRPV1) and acid sensing ion channel 3 (ASIC3), which are related to pain induction and regulation. This study was conducted to investigate the expression of TRPV1 and ASIC3 in response to the analgesic effect of an arthritis treatment in a collagen-induced arthritis (CIA). Methods. Mice were divided into 3 groups: Control, CIA, and CIA with arthritis treatment. Mice received intraperitoneal injection with 10 mg/kg infliximab and 10 mg/kg meloxicam five times per week for 3 weeks. Mechanical hyperalgesia, histologic examination of the feet, serum levels of inflammatory cytokine such as interleukin-6 (IL-6), and interleukin-17 (IL-17), TRPV1 and ASIC3 expression were investigated. Results. The serum levels of IL-6 and IL-17 were lower in the treatment group (73.77±10.11 pg/mL and 26.75±7.17 pg/mL, respectively) compared to the CIA group (p<0.001). Histological analysis showed decreased synovial cell proliferation, leukocyte infiltration, and cartilage destruction in the treatment group compared with the CIA group. The CIA group that underwent arthritis treatment showed a significantly increased withdrawal threshold of mechanical nociception on the hind paw and increased expression of TRPV1 and ASIC3 compared to the CIA group. Conclusion. Arthritis treatment resulted in an anti-inflammatory and analgesic effect through upregulation of the activity of TRPV1 and ASIC3 in CIA mice. (J Rheum Dis 2015;22:85-92)

Local analgesic effect of tramadol is not mediated by opioid receptors in early postoperative pain in rats

Background and objectivesTramadol is known as a central acting analgesic drug, used for the treatment of moderate to severe pain. Local analgesic effect has been demonstrated, in part due to local anesthetic-like effect, but other mechanisms remain unclear. The role of peripheral opioid receptors in the local analgesic effect is not known. In this study, we examined role of peripheral opioid receptors in the local analgesic effect of tramadol in the plantar incision model. MethodsYoung male Wistar rats were divided into seven groups: control, intraplantar tramadol, intravenous tramadol, intravenous naloxone-intraplantar tramadol, intraplantar naloxone-intraplantar tramadol, intravenous naloxone-intravenous tramadol, and intravenous naloxone. After receiving the assigned drugs (tramadol 5mg, naloxone 200μg or 0.9% NaCl), rats were submitted to plantar incision, and withdrawal thresholds after mechanical stimuli with von Frey filaments were assessed at baseline, 10, 15, 30, 45 and 60min after incision. ResultsPlantar incision led to marked mechanical hyperalgesia during the whole period of observation in the control group, no mechanical hyperalgesia were observed in intraplantar tramadol group, intraplantar naloxone-intraplantar tramadol group and intravenous naloxone-intraplantar tramadol. In the intravenous tramadol group a late increase in withdrawal thresholds (after 45min) was observed, the intravenous naloxone-intravenous tramadol group and intravenous naloxone remained hyperalgesic during the whole period. ConclusionsTramadol presented an early local analgesic effect decreasing mechanical hyperalgesia induced by plantar incision. This analgesic effect was not mediated by peripheral opioid receptors.

Rufinamide Attenuates Mechanical Allodynia in a Model of Neuropathic Pain in the Mouse and Stabilizes Voltage-gated Sodium Channel Inactivated State

Voltage-gated sodium channels dysregulation is important for hyperexcitability leading to pain persistence. Sodium channel blockers currently used to treat neuropathic pain are poorly tolerated. Getting new molecules to clinical use is laborious. We here propose a drug already marketed as anticonvulsant, rufinamide. We compared the behavioral effect of rufinamide to amitriptyline using the Spared Nerve Injury neuropathic pain model in mice. We compared the effect of rufinamide on sodium currents using in vitro patch clamp in cells expressing the voltage-gated sodium channel Nav1.7 isoform and on dissociated dorsal root ganglion neurons to amitriptyline and mexiletine. In naive mice, amitriptyline (20 mg/kg) increased withdrawal threshold to mechanical stimulation from 1.3 (0.6-1.9) (median [95% CI]) to 2.3 g (2.2-2.5) and latency of withdrawal to heat stimulation from 13.1 (10.4-15.5) to 30.0 s (21.8-31.9), whereas rufinamide had no effect. Rufinamide and amitriptyline alleviated injury-induced mechanical allodynia for 4 h (maximal effect: 0.10 ± 0.03 g (mean ± SD) to 1.99 ± 0.26 g for rufinamide and 0.25 ± 0.22 g to 1.92 ± 0.85 g for amitriptyline). All drugs reduced peak current and stabilized the inactivated state of voltage-gated sodium channel Nav1.7, with similar effects in dorsal root ganglion neurons. At doses alleviating neuropathic pain, amitriptyline showed alteration of behavioral response possibly related to either alteration of basal pain sensitivity or sedative effect or both. Side-effects and drug tolerance/compliance are major problems with drugs such as amitriptyline. Rufinamide seems to have a better tolerability profile and could be a new alternative to explore for the treatment of neuropathic pain.

The role of spinal adrenergic receptors on the antinociception of ginsenosides in a rat postoperative pain model

BackgroundThe effect of spinal adrenergic and cholinergic receptors on the anti-nociceptive effect of intrathecal ginsenosides was determined in a rat postoperative pain model.MethodsCatheters were placed into the intrathecal space of male Sprague-Dawley rats. Postoperative pain was evoked by an incision to the plantar surface of a hind paw. Withdrawal thresholds was used as a nociceptive parameter and was measured with a von Frey filament. After observing the effect of intrathecal ginsenosides, an alpha-1 adrenergic receptor antagonist (prazosin), an alpha-2 adrenergic receptor antagonist (yohimbine), a muscarinic acetylcholine receptor antagonist (atropine), and a nicotinic acetylcholine receptor antagonist (mecamylamine) were given 10 min before administration of the ginsenosides to analyze the contribution of spinal adrenergic and cholinergic receptors on the antinociceptive effect of ginsenosides.ResultsPaw incision decreased withdrawal threshold in incised site of paw, but no change of withdrawal threshold was not seen in non-incised site. The intrathecal ginsenosides increased withdrawal threshold of the incised paw in a dose-dependent manner. Pre-treatment with both prazosin and intrathecal yohimbine antagonized the anti-nociceptive effect of the ginsenosides. However, pre-treatments with atropine or mecamylamine had any effect on the antinociceptive activity of ginsenosides.ConclusionsIntrathecal ginsenosides are effective in attenuation of postoperative pain induced in the rat model. Anti-nociceptive action of ginsenosides is partially mediated by spinal adrenergic receptors, but does not appear to be related to spinal cholinergic receptors.

Spinal cord stimulation reduces hypersensitivity through activation of opioid receptors in a frequency‐dependent manner

Spinal cord stimulation (SCS) is used for the management of chronic intractable neuropathic pain. While used clinically, it is unclear if SCS produces its effects by activation of opioid receptors. The current study aimed to determine if endogenous opioids mediate the analgesia produced by SCS at different frequencies of stimulation in rats with neuropathic pain [spared nerve injury (SNI) model]. Mechanical withdrawal thresholds of the paw were tested before and after 6 h of SCS at different frequencies (4 Hz, 60 Hz and sham) given daily for 4 days at 90% motor threshold 2 weeks after SNI. Rats were given naloxone (3-10 mg/kg/h), naltrindole (1 mg/kg/h) or were made tolerant to morphine (375 g pellets daily), and effects of SCS were tested. A dose of 3 mg/kg/h naloxone prevented the analgesia produced by 4-Hz, but not 60-Hz, SCS; 10 mg/kg/h prevented the analgesia produced by 60-Hz SCS. Naltrindole prevented the analgesia produced by 60-Hz, but not 4-Hz, SCS. In morphine-tolerant rats, 4-Hz SCS had no effect on withdrawal thresholds, but 60-Hz SCS remained effective as seen by increased withdrawal thresholds. These results suggest that both 4- and 60-Hz SCS, in part, work through opioid receptor mechanisms, with 4-Hz SCS activating μ-opioid receptors while 60-Hz SCS activated δ-opioid receptors.

Intrathecal endothelin-1 has antinociceptive effects in rat model of postoperative pain

Endothelin-1 is known to be a potent vasoconstrictor. Administration of endothelin-1 to the central nervous system (CNS) induces antinociceptive effects. Nociceptive stimuli affect dorsal root ganglion (DRG) neurons and neurons/astrocytes/microglia in the dorsal horn of the spinal cord. Surgical incision in the plantar aspect of the rat hindpaw is a model for postoperative pain, and withdrawal thresholds reportedly decrease around the incision. We hypothesized that intrathecal endothelin-1 would have antinociceptive effects in this model, and affect DRG neurons and microglia/neurons in the dorsal horn. Intrathecal endothelin-1 partially restored the withdrawal threshold (which was decreased by plantar incision). BQ-123, and BQ-788 (specific endothelin ETA- and ETB-receptor antagonists, respectively) attenuated the increase in withdrawal threshold induced by endothelin-1. Phosphorylation of extracellular signal-regulated kinase (ERK) in DRG neurons and microglial activation/ERK phosphorylation in the dorsal horn were observed following the incision. Endothelin-1 decreased the incision-induced increase in the numbers of phosphorylated ERK-positive neurons in DRG and activated microglia in the dorsal horn, without affecting the numbers of phosphorylated ERK-positive neurons in the dorsal horn. BQ-123 or BQ-788 partially suppressed these endothelin-1-induced alterations. Our results show that the pain threshold, which is decreased by surgical stimuli, is partially restored by intrathecal endothelin-1 through both endothelin ETA- and ETB- receptors in DRG neurons and microglia in the spinal cord. Endothelin-1 administration to the CNS may be worth considering as a new candidate for the treatment of postoperative pain and to mitigate prolonged periods of pain.

Neuropathic pain as a process: reversal of chronification in an animal model

Peripheral neuropathic pain arises from trauma to sensory nerves. Other types of acute neurotrauma such as stroke and spinal cord injury are treated immediately, largely to prevent secondary damage. To pursue the possibility that neuropathic pain may also be amenable to early treatment, a rat model of neuropathic pain was induced using a 2-mm polyethylene cuff implanted around one sciatic nerve. Within 24 hours, hypersensitivity to von Frey hair stimulation appeared, as indicated by decreased paw withdrawal thresholds. When the cuff was removed 24 hours after implantation, readings returned to pre-implantation levels starting as early as day 18. When the cuff was removed after 4 days, there was a period of initial hypersensitivity, and then an increase toward baseline at two time points near the end of the study; therefore, only a partial recovery toward pre-implantation values occurred. Having established that a temporal reversal can occur, the next step examined possible pharmacological reversal. The tachykinin NK1 receptor antagonist, CP-96,345, produced a minor increase in withdrawal thresholds in animals with the cuff left permanently implanted. To determine the effect of early and repeated administration of CP-96,345, it was given daily on days 1–4. The cuff was removed on day 4. Six days later, readings showed reversal of tactile hypersensitivity. We suggest that persistent neuropathic pain occurs from processes that develop over several hours and days, and that some of these processes may be prevented by early medical intervention. Thus, nerve injury in the context of chronic neuropathic pain should be treated in a similar manner to nerve injury resulting from stroke, spinal cord injury, and other types of neurotrauma. We suggest that effective medical intervention within the first few hours after nerve injury may spare a patient from a chronic debilitating pain that may be refractory to later therapies.

Activation of spinal and supraspinal cannabinoid-1 receptors leads to antinociception in a rat model of neuropathic spinal cord injury pain

Activation of CNS cannabinoid subtype-1 (CB1) receptors has been shown to mediate the antinociceptive and other effects of systemically administered CB receptor agonists. The endogenous peptide CB receptor ligand hemopressin (HE) has previously demonstrated an antinociceptive effect in rats with a hind paw inflammation, without exhibiting characteristic CB1 receptor-mediated side-effects. The current study evaluated the effect of intrathecal (i.t.) and intracerebroventricular (i.c.v.) injection of HE in a rat model of neuropathic spinal cord injury (SCI) pain. The non-subtype selective CB receptor agonist WIN 55,212-2 was also centrally administered in SCI rats as a comparator. Four weeks following an acute compression of the mid-thoracic spinal cord, rats displayed markedly decreased hind paw withdrawal thresholds, indicative of below-level neuropathic pain. Central administration of WIN 55,212-2 significantly increased withdrawal thresholds, whereas HE did not. Hemopressin has been reported to block CB1 receptors in vitro, similar to the CB1 receptor antagonist rimonabant. Pretreatment with rimonabant completely blocked the antinociceptive effect of centrally administered WIN 55,212-2, but pretreatment with HE did not. While the data confirm that activation of either supraspinal or spinal CB1 receptors leads to significant antinociception in SCI rats, the current data do not support an antinociceptive effect from an acute blockade of central CB1 receptors, HE's putative antinociceptive mechanism, in neuropathic SCI rats. Although such a mechanism could be useful in other models of pain with a significant inflammatory component, the current data indicate that activation of CB1 receptors is needed to ameliorate neuropathic SCI pain.