Mechanical Allodynia In Rats Research Articles

The interaction of morphine and selective serotonin reuptake inhibitors on mechanical allodynia in rats with a spinal nerve ligation

Nerve injury may produce a tactile allodynia. However, there are few reports regarding the interaction of morphine and selective serotonin reuptake inhibitors (SSRIs) during a neuropathic pain state. Therefore, we investigated the antiallodynic interaction between morphine and SSRIs in a rat model of neuropathic pain. Methods: Rats were prepared with a tight ligation of the left fifth and sixth lumbar spinal nerves and chronic intrathecal catheter implantation. Mechanical allodynia was then measured by application of von Frey filaments. Morphine, citalopram and paroxetine were administered intrathecally to obtain the dose-response curves. The 50% effective dose of morphine and citalopram or paroxetine were then coadministered to evaluate the drug interaction. In addition, naloxone and methysergide were administered to examine the reversal of the antiallodynic effect. Results: Intrathecal morphine produced a dose-dependent antagonism of the tactile allodynia, but intrathecal citalopram or paroxetine showed no antiallodynic effects. In addition, a morphine-citalopram or paroxetine combination produced an increase in the withdrawal threshold, but naloxone and methysergide reversed the antiallodynic effect. In addition, no interactions were observed between naloxone and citalopram or paroxetine, or morphine and methysergide. Conclusions: These results suggest that activation of both μ-opioid and serotonin receptors is required for the increased interaction to occur between morphine and SSRIs administered to reduce tactile allodynia. Thus, serotonin receptors take part in the antiallodynic action of morphine at the spinal level.

A Rat Model of Radicular Pain Induced by Chronic Compression of Lumbar Dorsal Root Ganglion with SURGIFLO ™

Radicular pain is a common and debilitating clinical pain condition. To date, the mechanisms of radicular pain remain unclear, partly because of the lack of suitable preclinical models. The authors report a modified rat model of radicular pain that could mimic a subset of clinical radicular pain conditions induced by the soft tissue compression on dorsal root ganglion. A rat model of radicular pain was produced by infiltrating the L5 intervertebral foramen with 60 microl of a hemostatic matrix (SURGIFLO; Johnson & Johnson, Somerville, NJ) resulting in chronic compression of lumbar dorsal root ganglion. Thermal hyperalgesia and mechanical allodynia were measured with or without epidural treatment with triamcinolone. Western blot was used to assess the expression of the NR1 subunit of the N-methyl-D-aspartate receptor and inhibitory factor kappabeta-alpha, an inflammatory marker, within the affected L5 dorsal root ganglion and spinal cord dorsal horn. Chronic compression of lumbar dorsal root ganglion resulted in: (1) persistent mechanical allodynia and thermal hyperalgesia up to 4 or 5 postoperative weeks and (2) up-regulation of the N-methyl-D-aspartate receptor and inhibitory factor kappabeta-alpha within the ipsilateral L5 dorsal root ganglion and spinal cord dorsal horn. Epidural administration of triamcinolone (6.25-100 microg) on postoperative day 3 dose-dependently attenuated both thermal hyperalgesia and mechanical allodynia in rats with chronic compression of lumbar dorsal root ganglion. The data suggest that this modified rat model of chronic compression of lumbar dorsal root ganglion may be a useful tool to explore the mechanisms as well as new therapeutic options of radicular pain.

The Interaction of Gabapentin and N6-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA) on Mechanical Allodynia in Rats with a Spinal Nerve Ligation

We examined the antiallodynic interaction between gabapentin and adenosine A1 receptor agonist, N6-(2-phenylisopropyl)-adenosine R-(-)isomer (R-PIA), in a rat model of nerve ligation injury. Rats were prepared with ligation of left L5-6 spinal nerves and intrathecal catheter implantation for drug administration. Mechanical allodynia was measured by applying von Frey filaments. Gabapentin and R-PIA were administered to obtain the dose-response curve and the 50% effective dose (ED50). Fractions of ED50s were administered concurrently to establish the ED50 of the drug combination. The drug interaction between gabapentin and R-PIA was analyzed using the isobolographic method. Adenosine A1 receptor antagonist was administered intrathecally to examine the reversal of the antiallodynic effect. Locomotor function changes were evaluated by rotarod testing. Intrathecal gabapentin and R-PIA and their combination produced a dose-dependent antagonism against mechanical allodynia without severe side effects. Intrathecal gabapentin synergistically enhanced the antiallodynic effect of R-PIA when coadministered. There were no significant changes in rotarod performance time, except gabapentin 300 μg. In the combination group, the maximal antiallodynic effect was reversed by A1 adenosine receptor antagonist. These results suggest that activation of adenosine A1 receptors at the spinal level is required for the synergistic interaction on the mechanical allodynia.

Characterization of the antinociceptive and anti-inflammatory activities of doxycycline and minocycline in different experimental models

Tetracyclines induce anti-inflammatory effects unrelated to their antimicrobial activities. We investigated the effect induced by minocycline and doxycycline in models of nociceptive and inflammatory pain, edema, fever, cell migration and formation of fibrovascular tissue, as these effects have not been fully investigated. Tetracyclines were administered via intraperitoneal route 1 h before the tests. Minocycline and doxycycline (100 mg/kg) inhibited the second phase of the formalin-induced nociceptive response in mice. Doxycycline (100 mg/kg) also inhibited the first phase. The nociceptive response induced by phorbol 12,13-didecanoate (PDD) in mice was inhibited by doxycycline (100 mg/kg). Furthermore, carrageenan-induced mechanical allodynia in rats was inhibited by doxycycline and minocycline (50 or 100 mg/kg). However, they did not enhance the latency in the hot-plate test. It is unlikely that antinociception resulted from motor incoordination or muscle relaxing effect, as both tetracyclines (100 mg/kg) did not impair the motor activity of mice in the rota-rod test. Doxycycline (50 or 100 mg/kg) or minocycline (50 or 100 mg/kg) inhibited carrageenan-induced paw edema in rats. However, only minocycline (100 mg/kg) inhibited PDD-induced edema. Carrageenan-induced leukocyte migration into the peritoneal cavity of rats was inhibited by both tetracyclines (100 mg/kg). Endotoxin-induced fever in rats was also inhibited by doxycycline (50 or 100 mg/kg) or minocycline (100 mg/kg). Finally, formation of fibrovascular tissue induced by subcutaneous implant of a cotton pellet in mice was inhibited by a 6-day administration of both tetracyclines (50 or 100 mg/kg day). Concluding, this study clearly shows the antinociceptive and anti-inflammatory activities of these second-generation tetracyclines.

Activation of the nociceptin opioid system in rat sensory neurons produces antinociceptive effects in inflammatory pain: Involvement of inflammatory mediators

Despite a large body of literature on the nociceptin (NC) opioid system in pain modulation, the mechanism of action of NC remains largely unexplored. Here, we investigated the role and mode of action of the spinal NC system in inflammatory pain. Preemptive intrathecal administration of NC attenuated thermal hyperalgesia and mechanical allodynia in rats with intraplantar complete Freund's adjuvant (CFA) injection. By using immunohistochemistry in L4 dorsal root ganglion (DRG) neurons, a marked increase of NC and ORL1 receptor immunoreactivity was detected following CFA. Intrathecal administration of NC attenuated the CFA-induced increases of calcitonin gene-related peptide, transient receptor potential vanilloid-1, and tumor necrosis factor-alpha in DRG neurons. Real-time reverse transcription-polymerase chain reaction showed that NC reduced the up-regulation of inducible nitric oxide synthase mRNA but not that of neuronal nitric oxide synthase mRNA in spinal cord segments after CFA. Furthermore, [Nphe1]NC(1-13)NH2, a selective opioid receptor-like 1 (ORL1) receptor antagonist, significantly antagonized the effects of NC on pain modulation and on the expression of inflammatory mediators, indicating a specific NC action through the ORL1 receptor. Together, these findings reveal novel mechanisms by which the NC system produces analgesia.

Analgesic effects of serotonergic, noradrenergic or dual reuptake inhibitors in the carrageenan test in rats: Evidence for synergism between serotonergic and noradrenergic reuptake inhibition

The efficacy of antidepressant drugs with serotonergic, noradrenergic, or dual reuptake inhibition was evaluated in reversing carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Duloxetine (1–30 mg/kg, i.p.), a balanced serotonergic–noradrenergic reuptake inhibitor (SNRI), was equiefficacious and more potent than the SNRI venlafaxine (3–100 mg/kg, i.p.) in reversing both thermal hyperalgesia and mechanical allodynia induced by carrageenan. In addition, the selective noradrenergic reuptake inhibitors (NRIs) thionisoxetine (0.03–10 mg/kg, i.p.) and desipramine (1–30 mg/kg, i.p.) also produced complete reversals of carrageenan-induced thermal hyperalgesia. However, only thionisoxetine exhibited a greater than 80% reversal of the carrageenan-induced mechanical allodynia. In contrast, the selective serotonergic reuptake inhibitors (SSRIs) paroxetine, sertraline, and fluoxetine (0.3–10 mg/kg i.p.) had little or no effect in the carrageenan model. In order to understand whether the observed enhanced effectiveness of the dual SNRIs was due to a possible synergism between serotonergic and noradrenergic reuptake inhibition, the effects of the NRI thionisoxetine alone and in combination with an inactive dose of the SSRI fluoxetine were determined. In the presence of fluoxetine, the potency of thionisoxetine in reversing carrageenan-induced hyperalgesia and allodynia was significantly increased by approximately 100-fold and brain concentrations of thionisoxetine were increased by 1.1- to 5-fold. The present data indicate fluoxetine pharmacodynamically potentiated the analgesic effects of thionisoxetine over and above a metabolic interaction between these two drugs. The present findings thus indicate that, in the carrageenan model, dual serotonergic–noradrenergic reuptake inhibition by dual SNRIs, or SSRI–NRI combinations, produces synergistic analgesic efficacy.

Inhibition of soluble epoxide hydrolase reduces LPS-induced thermal hyperalgesia and mechanical allodynia in a rat model of inflammatory pain

Soluble epoxide hydrolases catalyze the hydrolysis of epoxides in acyclic systems. In man this enzyme is the product of a single copy gene (EPXH-2) present on chromosome 8. The human sEH is of interest due to emerging roles of its endogenous substrates, epoxygenated fatty acids, in inflammation and hypertension. One of the consequences of inhibiting sEH in rodent inflammation models is a profound decrease in the production of pro-inflammatory and proalgesic lipid metabolites including prostaglandins. This prompted us to hypothesize that sEH inhibitors may have antinociceptive properties. Here we tested if sEH inhibitors can reduce inflammatory pain. Hyperalgesia was induced by intraplantar LPS injection and sEH inhibitors were delivered topically. We found that two structurally dissimilar but equally potent sEH inhibitors can be delivered through the transdermal route and that sEH inhibitors effectively attenuate thermal hyperalgesia and mechanical allodynia in rats treated with LPS. In addition we show that epoxydized arachidonic acid metabolites, EETs, are also effective in attenuating thermal hyperalgesia in this model. In parallel with the observed biological activity metabolic analysis of oxylipids showed that inhibition of sEH resulted with a decrease in PGD 2 levels and sEH generated degradation products of linoleic and arachidonic acid metabolites with a concomitant increase in epoxides of linoleic acid. These data show that inhibition of sEH may become a viable therapeutic strategy to attain analgesia.

The interaction of gabapentin and R-PIA on mechanical allodynia in rats with a spinal nerve ligation

The interaction of gabapentin and R-PIA on mechanical allodynia in rats with a spinal nerve ligation

Endothelin ET(B) receptor antagonist reduces mechanical allodynia in rats with trigeminal neuropathic pain.

Trigeminal neuropathic pain, which is associated with marked orofacial mechanical allodynia, is frequently refractory to currently available drugs. Because endothelins (ETs) can contribute to nociceptive changes in animal models of inflammatory, cancer, and diabetic neuropathic pain, the present study evaluated the influence of ET(A) and ET(B) receptor antagonists on orofacial mechanical allodynia in a rat model of trigeminal neuropathic pain. Unilateral constriction (C) of the infraorbital nerve (ION) caused pronounced and sustained bilateral mechanical allodynia, evaluated by application of von Frey hairs to the vibrissal pad. Mechanical allodynia on postoperative days 12-15 after nerve injury was abolished for up to 90 mins by subcutaneous administration of 2.5 mg/kg morphine, but was fully refractory to intravenous (iv) administration of 10 mg/kg of the dual ET(A) plus ET(B) or selective ET(A) receptor antagonists, bosentan and atrasentan, respectively. In sharp contrast, iv administration of 20 mg/kg of the selective ET(B) receptor antagonist, A-192621, caused a net 61 +/- 15% reduction of mechanical threshold, lasting 2 hrs. Co-injection of atrasentan plus A-192621 did not modify ION injury-induced mechanical allodynia. Injection of 10 pmol ET-1 into the upper lip of naive rats caused ipsilateral mechanical allodynia lasting up to 5 hrs. Thus, ET(B) receptor-mediated mechanisms contribute to orofacial mechanical allodynia induced by CION injury, but, some-how, functional ET(A) receptors are required for expression of the antiallodynic effect of ET(B) receptor blockade.

Attenuation of capsaicin-evoked mechanical allodynia by peripheral neuropeptide Y Y 1 receptors

Neuropeptide Y (NPY) and its cognate receptors are important modulators of nociception and their expression is significantly altered following injury. In particular, previous studies have demonstrated that the Y 1 subtype of NPY receptors inhibits nociceptive transmission from capsaicin-sensitive terminals in the dorsal horn of the spinal cord. The present study evaluated the function of the Y 1 receptor on peripheral terminals of primary afferent neurons by testing whether peripherally administered Y 1 agonists and antagonists alter capsaicin-evoked mechanical allodynia in rats and capsaicin-evoked immunoreactive calcitonin gene-related peptide (iCGRP) release from isolated superfused rat skin. Treatment with the Y 1 agonist [Leu 31,Pro 34]-NPY (0.5, 1, or 10 nmol) significantly inhibited capsaicin-evoked mechanical allodynia in a dose-dependent manner. This effect was reversible by pretreatment with the Y 1 antagonist BIBO3304 (10 nmol). The anti-allodynia produced by the Y 1 agonist occurred at a peripheral site of action, because injection into the paw contralateral to the site of the capsaicin injection had no effect on paw withdrawal latencies. In isolated skin, application of [Leu 31,Pro 34]-NPY (300 nM) significantly inhibited capsaicin-evoked CGRP release. BIBO3304 reversed this inhibition, having itself no effect on capsaicin-evoked iCGRP release. These studies indicate that the activation of peripheral Y 1 receptors produces anti-allodynia, possibly via the direct inhibition of capsaicin-sensitive fibers.

Involvement of the TTX-resistant sodium channel Nav 1.8 in inflammatory and neuropathic, but not post-operative, pain states

Antisense (AS) oligodeoxynucleotides (ODNs) targeting the Nav 1.8 sodium channel have been reported to decrease inflammatory hyperalgesia and L5/L6 spinal nerve ligation-induced mechanical allodynia in rats. The present studies were conducted to further characterize Nav 1.8 AS antinociceptive profile in rats to better understand the role of Nav 1.8 in different pain states. Consistent with earlier reports, chronic intrathecal Nav 1.8 AS, but not mismatch (MM), ODN decreased TTX-resistant sodium current density (by 60.5 ± 10.2% relative to MM; p < 0.05) in neurons from L4 to L5 dorsal root ganglia and significantly attenuated mechanical allodynia following intraplantar complete Freund’s adjuvant. In addition, 10 days following chronic constriction injury of the sciatic nerve, Nav 1.8 AS, but not MM, ODN also attenuated mechanical allodynia (54.3 ± 8.2% effect, p < 0.05 vs. MM) 2 days after initiation of ODN treatment. The anti-allodynic effects remained for the duration of the AS treatment, and CCI rats returned to an allodynic state 4 days after discontinuing AS. In contrast, Nav 1.8 AS ODN failed to reduce mechanical allodynia in the vincristine chemotherapy-induced neuropathic pain model or a skin-incision model of post-operative pain. Finally, Nav 1.8 AS, but not MM, ODN treatment produced a small but significant attenuation of acute noxious mechanical sensitivity in naïve animals (17.6 ± 6.2% effect, p < 0.05 vs. MM). These data demonstrate a greater involvement of Nav 1.8 in frank nerve injury and inflammatory pain as compared to acute, post-operative or chemotherapy-induced neuropathic pain states.

Synergistic interactions between the dual serotonergic, noradrenergic reuptake inhibitor duloxetine and the non-steroidal anti-inflammatory drug ibuprofen in inflammatory pain in rodents

Objectives The present study was undertaken to characterize whether the pharmacologic interaction between duloxetine, a balanced serotonergic and noradrenergic reuptake inhibitor, and the non-steroidal anti-inflammatory drug ibuprofen was simply additive, less than additive, or greater than additive (i.e., synergistic) in preclinical models of visceral and inflammatory pain, specifically acetic acid-induced writhing in mice and carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats. Methods In the writhing test, male CF-1 mice were injected intraperitoneally with 0.55% acetic acid and 5 min later the number of writhes was counted over a 5-min period. In the carrageenan models, male Sprague-Dawley rats were injected with a 1.5% carrageenan solution into the ventral surface of the hind paw; hypersensitivity to thermal and mechanical stimuli was subsequently evaluated 2 h post-carrageenan. Results Vehicle or a dose of duloxetine alone (1–100 mg/kg), ibuprofen alone (10–300 mg/kg), or duloxetine and ibuprofen in combination in a dose-ratio of 1:10 duloxetine:ibuprofen were orally administered 30 or 60 min before testing. Isobolographic analysis of the effects of duloxetine in combination with ibuprofen revealed a significant synergistic (greater than additive) interaction between duloxetine and ibuprofen both for reducing acetic acid-induced writhing and carrageenan-induced thermal hyperalgesia, but were additive for reversing mechanical allodynia. Conclusions Our data indicate that duloxetine and ibuprofen have synergistic efficacy in a visceral and an inflammatory pain model in rodents, and suggest that duloxetine and ibuprofen in combination may provide a useful approach to the clinical treatment of persistent pain, particularly inflammation-related pain.

Involvement of spinal glia in tetanically sciatic stimulation-induced bilateral mechanical allodynia in rats

The previous study showed involvement of spinal glia in tetanically sciatic stimulation-induced long-term potentiation (LTP) of C-fiber-evoked field potentials in the spinal dorsal horn. In the present study, the electrophysiological recording and paw withdrawal threshold (PWT) to von Frey stimulation were assessed following unilaterally tetanically sciatic stimulation in rats. Tetanic stimuli elicited LTP of both A- and C-fiber-evoked field potentials. After stimulation with the same parameter, bilateral PWTs to mechanical stimuli decreased. Intrathecal administration of fluorocitrate (1 nmol/10 μl), an astrocyte inhibitor, partially inhibited tetanic stimulation-induced reduction of bilateral PWTs. A similar effect also occurred at the contralateral side. And this bilateral inhibition of mechanical threshold lasted 8 days. Similarly, intrathecal administration of d-amino acid oxygenase (50 μg/μl, 10 μl), d-serine inhibitor, partially inhibited tetanic sciatic stimulation-induced reduction of bilateral PWTs for 24 h. The results showed that spinal glia plays an important role in bilaterally mechanical allodynia by tetanic sciatic stimulation of the sciatic nerve.

Anti-allodynic efficacy of the χ-conopeptide, Xen2174, in rats with neuropathic pain

Xen2174 is a structural analogue of Mr1A, a χ-conopeptide recently isolated from the venom of the marine cone snail, Conus marmoreus. Although both χ-conopeptides are highly selective inhibitors of the norepinephrine transporter (NET), Xen2174 has superior chemical stability relative to Mr1A. It is well-known that tricyclic antidepressants (TCAs) are also potent NET inhibitors, but their poor selectivity relative to other monoamine transporters and various G-protein-coupled receptors, results in dose-limiting side-effects in vivo. As TCAs and the α 2-adrenoceptor agonist, clonidine, have established efficacy for the relief of neuropathic pain, this study examined whether intrathecal (i.t.) Xen2174 alleviated mechanical allodynia in rats with either a chronic constriction injury of the sciatic nerve (CCI-rats) or an L5/L6 spinal-nerve injury. The anti-allodynic responses of i.t. Mr1A and i.t. morphine were also investigated in CCI-rats. Paw withdrawal thresholds were assessed using calibrated von Frey filaments. Bolus doses of i.t. Xen2174 produced dose-dependent relief of mechanical allodynia in CCI-rats and in spinal nerve-ligated rats. Dose-dependent anti-allodynic effects were also produced by i.t. bolus doses of Mr1A and morphine in CCI-rats, but a pronounced ‘ceiling’ effect was observed for i.t. morphine. The side-effect profiles were mild for both χ-conopeptides with an absence of sedation. Confirming the noradrenergic mechanism of action, i.t. co-administration of yohimbine (100 nmol) with Xen2174 (10 nmol) abolished Xen2174 s anti-allodynic actions. Xen2174 appears to be a promising candidate for development as a novel therapeutic for i.t. administration to patients with persistent neuropathic pain.

Involvement of an increased spinal TRPV1 sensitization through its up-regulation in mechanical allodynia of CCI rats

Vanilloid receptor 1 (TRPV1) antagonists are known to attenuate the neuropathic pain symptoms in peripheral nerve injury models, but the mechanism(s) of their effect remains unclear. At the same time, the role of spinal TRPV1 in pain transduction system has not been fully understood. In this study, the role of spinal TRPV1 in mechanical allodynia in rat chronic constriction injury (CCI) model was investigated. Intrathecal administration of a selective TRPV1 antagonist, N-(4-tertiarybutylphenyl)-4-(3-cholorphyridin-2-yl)tetrahydropryazine-1(2H)-carbox-amide (BCTC) significantly attenuated mechanical allodynia in CCI rats at 100 and 300 nmol. In vitro, BCTC inhibited capsaicin (300 nM)-induced releases of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) and substance P-like immunoreactivity (SP-LI) from the rat spinal cord slice preparations with IC 50s of 37.0 and 36.0 nM, respectively, confirming that BCTC potently inhibits TRPV1 function in the rat spinal cord. TRPV1 expression levels in the spinal cord following CCI were quantified in by Western blot analysis. TRPV1 protein levels were significantly increased in the ipsilateral side of the lumbar spinal cord at 7 and 14 days following CCI surgery, but not in the contralateral side. Furthermore, capsaicin (300 nM)-evoked release of CGRP-LI was significantly higher in the ipsilateral spinal cord of CCI rats (14 days after surgery) than that of sham-operated rats. These findings suggest that an increased sensitization of the spinal TRPV1 through its up-regulation is involved in the development and/or maintenance of mechanical allodynia in rat CCI model.

Analgesic effects of the selective group II (mGlu2/3) metabotropic glutamate receptor agonists LY379268 and LY389795 in persistent and inflammatory pain models after acute and repeated dosing

Group II (mGluR2/3) metabotropic glutamate receptors have been implicated in the mechanisms of persistent pain states. In the present study, the effects of the selective group II metabotropic glutamate receptor agonists LY379268 and LY389795 were evaluated in the formalin test, carrageenan-induced thermal hyperalgesia and mechanical allodynia, and capsaicin-induced mechanical allodynia in rats. The agonists LY379268 and LY389795 produced dose-dependent decreases in formalin-induced behaviors that were antagonized by the mGlu2/3 receptor antagonist LY341495. The group II antagonist LY341495 produced parallel shifts in the LY379268 dose–response curve, consistent with a competitive antagonism. LY379268 decreased formalin-induced behaviors after intracisternal but not intrathecal administration, suggesting primarily a supraspinal site of action. Both LY379268 and LY389795 produced a dose-related reversal of carrageenan-induced thermal hyperalgesia and capsaicin-induced mechanical allodynia, but had no effect on carrageenan-induced mechanical allodynia. Both agonists also increased response latencies in the hot plate test, but were without effect in the tail-flick test. However, both agonists produced motor impairment on the inverted screen at doses that were analgesic. Moreover, tolerance to the analgesic effects of LY379268 developed after 4 days of once-daily repeated administration in the formalin, carrageenan, capsaicin and hot plate tests. The present findings indicate that group II (mGluR2/3) metabotropic glutamate receptors may be involved in the mechanisms of hyperalgesia and allodynia, however tolerance rapidly develops to these effects.

Efficacy of Duloxetine, a Potent and Balanced Serotonergic and Noradrenergic Reuptake Inhibitor, in Inflammatory and Acute Pain Models in Rodents

Duloxetine, a selective but balanced serotonergic and noradrenergic reuptake inhibitor, was evaluated in the acute nociceptive pain models of tail flick and hot plate in mice and in the persistent and/or inflammatory pain models of acetic acid-induced writhing in mice, carrageenan-induced thermal hyperalgesia and mechanical allodynia in rats, and capsaicin-induced mechanical allodynia in rats. In acute pain models, duloxetine had no significant effect on response latency in the mouse tail-flick test but produced modest increases in response latencies in the mouse hot plate test. Morphine produced dose-related analgesic effects in both the mouse tail-flick and hot plate tests. In models of inflammatory and/or persistent pain, duloxetine, morphine, and ibuprofen produced dose-related decreases in acetic acid-induced writhing in mice. Duloxetine, ibuprofen, and gabapentin also produced dose-dependent reversals of both thermal hyperalgesia and mechanical allodynia produced by carrageenan in rats. In addition, both duloxetine and morphine produced a significant reduction of capsaicin-induced mechanical allodynia in rats. Duloxetine and gabapentin were without substantial effect on the Rotorod test in mice, whereas morphine and ibuprofen produced a significant impairment. Our data indicate that duloxetine may be efficacious in the treatment of persistent and/or inflammatory pain states at doses that have modest or no effect on acute nociception or motor performance.

Cancer pain: palliative care: Analgesic effect of the neuronal nicotinic receptor agonist, ABT-594, in a rat chemotherapy-induced neuropathic pain model

ABT-594 represents a novel class of broad-spectrum analgesics whose primary mechanism of action is activation of the neuronal nicotinic receptors (NNRs). In addition to its positive effects in rat models of acute and persistent pain, ABT-594 has been shown to be analgesic in the rat spinal nerve ligation model of neuropathic pain. The present study characterized the effects of ABT-594 in a rat model of chemotherapy-induced neuropathic pain in which male Sprague-Dawley rats were surgically implanted with 14-day mini-osmotic pumps set to deliver 30 μg kg-1 day-1 vincristine, i.v. ABT-594 was determined to attenuate mechanical allodynia with an ED50 = 40 nmol/kg, i.p.: therefore, it was approximately one half-log unit more potent in the current model than in the spinal nerve ligation model. The analgesic effect of ABT-594 in the vincristine model was completely blocked by systemic administration of mecamylamine (a non-selective NNR antagonist; 5 μmol/kg, i.p.) and by central administration of chlorisondamine (a non-selective NNR antagonist that does not readily cross the blood brain barrier; 10 μg, i.c.v.), but not at all by systemic administration of chlorisondamine (0.5 μmol/kg, i.p.) nor naloxone (a non-selective opiate receptor antagonist; 25 μmol/kg, i.p.). In summary, the NNR agonist, ABT-594, was demonstrated to attenuate mechanical allodynia in a rat chemotherapy-induced neuropathic pain model via a centrally-mediated, NNR-(and non-opioid-)related mechanism of action. The data are in accordance with previous findings on the effects an NNR agonist (A-85380) on thermal acute pain in rats; however, they are in contrast to A-85380's effects on mechanical allodynia in spinal nerve ligation rats, where it was found to have both centrally- and peripheral-mediated, NNR-related mechanisms of actions. The support of Abbott Laboratories for this project is gratefully acknowledged.

The Effect of an Intraperitoneal Injection of Ketamine and Ketorolac on Mechanical Allodynia in Rats with Spinal Nerve Ligation

Background: It is difficult to manage the symptoms of neuropathic pain, especially alloynia. The mechanism of the induction and maintenance of mechanical allodynia has been extensively researched for several decades. N-methyl-D-aspartate (NMDA) receptor antagonists are known to reduce mechanical allodynia. Recently, the role of prostaglandins in spinal nociceptive processing has been the focus of attention. Therefore, the present study was designed to investigate the effect of a combination of ketamine, a non-competitive NMDA antagonist, and of ketorolac, non-selective cyclooxygenase (COX) inhibitor on mechanical allodynia. Methods: Male SD rats were prepared by tightly ligating the left L5 and L6 spinal nerves. All rats developed mechanical allodynia 7 days after surgery. N group (control, n = 6) received 5 ml of 0.9% normal saline intraperitoneally. K group (n = 6) received ketamine 1 mg/kg. T group received ketorolac 30 mg/kg, and KT group received ketamine 1 mg/kg and ketorolac 30 mg/kg simultaneously. Paw withdrawal thresholds to von Frey hairs were measured before and at 15 min, 30 min, 60 min and 120 min after drug administration. Results: Normal saline and ketamine 1 mg/kg did not increase the paw withdrawal threshold from baseline. Ketorolac 30 mg/kg increased the paw withdrawal threshold only at 120 min after intraperitoneal injection. However, the co-administration of ketamine 1 mg/kg and ketorolac 30 mg/kg increased the paw withdrawal threshold significantly from baseline for 120 min. Conclusions: Intraperitoneal injection of ketamine and ketorolac attenuated the mechanical allodynia developed by spinal nerve ligation. Therefore, we suggest that combination of ketamine and ketorolac might be useful for the management of neuropathic pain.

Effect of intrathecal octreotide on thermal hyperalgesia and evoked spinal c-Fos expression in rats with sciatic constriction injury.

This study was designed to determine whether intrathecal octreotide (sandostatin), a synthetic octapeptide derivative of somatostatin, relieved thermal hyperalgesia and reduced the evoked spinal c-Fos expression in rats with chronic constriction injury (CCI) of the sciatic nerve. Intrathecal catheters were implanted in rats 7 days before CCI of the sciatic nerve over the left hind limb. After confirmation of the development of thermal hyperalgesia by decreased paw withdrawal latencies (PWL) to heat stimulation 7 days after CCI, intrathecal sandostatin at 20, 40, and 80 microg was administered, respectively. Rats in the control group received saline injections intrathecally. PWLs were evaluated at 30, 60, 120, 180, and 240 min after drug administration. Detection of Fos-like immunoreactivity (Fos-LI) neurons in the dorsal horn of the spinal cord following drug administration was performed after mechanical stimulation (stroking of the hind paws) on the 14th day after CCI. The reduction of PWL was attenuated significantly in the groups that received intrathecal sandostatin at 20, 40, and 80 g when compared with the saline group. However, PWL did not return to pre-CCI values in all groups. In the 40 microg group, PWL returned up to 76% of pre-CCI values 120 min after drug administration. Stroking of the hind paw in CCI-treated (ipsilateral) limbs induced a significantly greater expression of spinal Fos-LI neurons than that of non-CCI treated (contralateral) limbs in each group. The number of Fos-LI neurons in animals receiving intrathecal sandostatin was dose-dependently reduced. Expression of Fos-LI neurons in the 80 microg group was nearly completely inhibited. These data suggest that intrathecal sandostatin significantly relieved thermal hyperalgesia behaviorally but with limited effects and dose-dependently reduced spinal Fos-LI neurons expression evoked by stroking stimulation, which may reflect mechanical allodynia in rats with sciatic constriction injury. This implies that intrathecal sandostatin was effective in the treatment of neuropathic pain.