Rodent Models Of Chronic Pain Research Articles

Ketamine reduces aversion in rodent pain models by suppressing hyperactivity of the anterior cingulate cortex

Chronic pain is known to induce an amplified aversive reaction to peripheral nociceptive inputs. This enhanced affective response constitutes a key pathologic feature of chronic pain syndromes such as fibromyalgia. However, the neural mechanisms that underlie this important aspect of pain processing remain poorly understood, hindering the development of treatments. Here, we show that a single dose of ketamine can produce a persistent reduction in the aversive response to noxious stimuli in rodent chronic pain models, long after the termination of its anti-nociceptive effects. Furthermore, we demonstrated that this anti-aversive property is mediated by prolonged suppression of the hyperactivity of neurons in the anterior cingulate cortex (ACC), a brain region well known to regulate pain affect. Therefore, our results indicate that it is feasible to dissociate the affective from the sensory component of pain, and demonstrate the potential for low-dose ketamine to be an important therapy for chronic pain syndromes.

Inhibition of interleukin-6 function attenuates the central sensitization and pain behavior induced by osteoarthritis

Chronic pain is the most prominent and disabling symptom in the patients with osteoarthritis (OA), and the underlying mechanism largely remains unclear. Interleukin-6 (IL-6), a proinflammatory cytokine, is critically involved in the development and maintenance of central sensitization in several rodent models of chronic pain. The present study aims to elucidate the IL-6 mediated neurological adaptation in dorsal horn in the rat with monosodium iodoacetate (MIA) – induced OA. Significant upregulation of IL-6 expression was detected in the dorsal horn in the modeled rats. Blockade of IL-6 function by tocilizumab markedly suppressed the activation of astrocytes and microglia in the ipsilateral dorsal horn, reduced c-Fos immunoreactivity in dorsal horn neurons, and attenuated the upregulation of glutamate receptor subunits GluR1 and NR2B in dorsal horn in the rats with MIA-induced OA. It was further reported that administration of tocilizumab significantly improved the performance in weight-bearing test and mitigated the mechanical allodynia in the modeled rats. These data illustrated spinal IL-6 mediated mechanism underlying the chronic pain, and proposed the potential therapeutic effect of tocilizumab on the chronic pain in the setting of OA.

Functional MRI of the Reserpine-Induced Putative Rat Model of Fibromyalgia Reveals Discriminatory Patterns of Functional Augmentation to Acute Nociceptive Stimuli

Functional neuroimaging, applied to pre-clinical models of chronic pain, offers unique advantages in the drive to discover new treatments for this prevalent and oppressive condition. The high spatial and temporal resolution of fMRI affords detailed mapping of regional pharmacodynamics that underlie mechanisms of pain suppression by new analgesics. Despite evidence supporting the translational relevance of this approach, relatively few studies have investigated fMRI abnormalities in rodent models of chronic pain. In this study, we used fMRI to map the BOLD response in a recently developed putative rat model of fibromyalgia to innocuous and acute nociceptive stimuli by applying a step-wise graded electrical forepaw stimulation paradigm, with comparison to healthy controls. We observed discriminatory functional signatures (p < 0.001) to 2 mA electrical forepaw stimulation, found to be innocuous in the control group. As such, this translational approach provides sensitive and quantitative neural correlates of the underlying chronic disease. The regional patterns of functional augmentation were found to be concordant with previous studies of nociception in the anaesthetised rat brain, supporting the specificity of this approach in the study of altered central pain processing in reserpine induced myalgia. The methodology introduced in this work represents a novel platform for emerging treatment evaluation in highly experimentally controlled conditions.

Latent sensitization: a model for stress-sensitive chronic pain.

Latent sensitization is a rodent model of chronic pain that reproduces both its episodic nature and its sensitivity to stress. It is triggered by a wide variety of injuries ranging from injection of inflammatory agents to nerve damage. It follows a characteristic time course in which a hyperalgesic phase is followed by a phase of remission. The hyperalgesic phase lasts between a few days to several months, depending on the triggering injury. Injection of μ-opioid receptor inverse agonists (e.g., naloxone or naltrexone) during the remission phase induces reinstatement of hyperalgesia. This indicates that the remission phase does not represent a return to the normal state, but rather an altered state in which hyperalgesia is masked by constitutive activity of opioid receptors. Importantly, stress also triggers reinstatement. Here we describe in detail procedures for inducing and following latent sensitization in its different phases in rats and mice.

Involvement of Protein Kinase B/Akt in Analgesic Effect of Dexmedetomidine on Neuropathic Pain

Involvement of Protein Kinase B/Akt in Analgesic Effect of Dexmedetomidine on Neuropathic Pain

Predictive validity of behavioural animal models for chronic pain

Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature-based comparison between preclinical data and clinical trials will not reveal whether a particular model is generally predictive. Limited reports on negative outcomes prevents reliable estimate of specificity of any model. Animal models tend to be validated with standard analgesics and may be biased towards tractable pain mechanisms. But preclinical publications rarely contain drug exposure data, and drugs are usually given in high doses and as a single administration, which may lead to drug distribution and exposure deviating significantly from clinical conditions. The greatest challenge for predictive modelling is, however, the heterogeneity of the target patient populations, in terms of both symptoms and pharmacology, probably reflecting differences in pathophysiology. In well-controlled clinical trials, a majority of patients shows less than 50% reduction in pain. A model that responds well to current analgesics should therefore predict efficacy only in a subset of patients within a diagnostic group. It follows that successful translation requires several models for each indication, reflecting critical pathophysiological processes, combined with data linking exposure levels with effect on target.

Depression and Pain

Depression and Pain

Evidence for suppression of spinal glial activation by dexmedetomidine in a rat model of monoarthritis

1. Spinal glial cells play a key role in developing and maintaining allodynia and hyperalgesia following tissue inflammation. Dexmedetomidine, a highly selective α(2) -adrenoceptor (α(2) -AR) agonist, has exhibited a significant analgesic effect in various rodent models of chronic pain. However, whether spinal glial activation is involved in the analgesic effect of dexmedetomidine remains unknown. The present study investigated whether spinal administration of dexmedetomidine could antagonize glial activation in the spinal dorsal horn and attenuate thermal hyperalgesia in complete Freund's adjuvant (CFA)-induced ankle joint monoarthritic (MA) rats. 2. Unilateral intra-articular injection of CFA produced a robust activation of microglia and astrocytes in the spinal cord, which was associated with the development and maintenance of thermal hyperalgesia. Repeated lumbar puncture (LP) administration of dexmedetomidine (10 μg) significantly attenuated MA-induced thermal hyperalgesia in a cumulative manner. Monoarthritis-induced spinal glial activation was also suppressed following dexmedetomidine application. The α(2A) -AR, essential for the antinociceptive effects of α(2) -AR agonists, was detected in spinal neurons and glia, as well as in dorsal root ganglion primary afferent neurons, which may be implicated in dexmedetomidine-induced suppression of spinal glial activation and antihyperalgesic effects. 3. These data provide the first evidence that blocking spinal glial activation is involved in the analgesic action of dexmedetomidine.

Antinociceptive profile of a selective metabotropic glutamate receptor 1 antagonist YM-230888 in chronic pain rodent models

Metabotropic glutamate receptor 1 (mGlu 1 receptor) has been suggested to play an important role in pain transmission. In this study, the effects of a newly-synthesized mGlu 1 receptor antagonist, ( R)- N-cycloheptyl-6-({[(tetrahydro-2-furyl)methyl]amino}methyl)thieno[2,3- d]pyrimidin-4-ylamine (YM-230888), were examined in a variety of rodent chronic pain models in order to characterize the potential analgesic profile of mGlu 1 receptor blockade. YM-230888 bound an allosteric site of mGlu 1 receptor with a K i value of 13 ± 2.5 nM and inhibited mGlu 1-mediated inositol phosphate production in rat cerebellar granule cells with an IC 50 value of 13 ± 2.4 nM. It showed selectivity for mGlu 1 versus mGlu 2–mGlu 7 subtypes and ionotropic glutamate receptors. YM-230888 recovered mechanical allodynia with an ED 50 value of 8.4 mg/kg p.o. in L5/L6 spinal nerve ligation models. It also showed antinociceptive response at doses of 10 and 30 mg/kg p.o. in streptozotocin-induced hyperalgesia models. In addition, it significantly reduced pain parameters at a dose of 30 mg/kg p.o. in complete Freund's adjuvant-induced arthritic pain models. Although YM-230888 showed no significant effect on rotarod performance time at doses of 10 or 30 mg/kg p.o., it significantly decreased it at a dose of 100 mg/kg p.o. On the other hand, YM-230888 showed no significant sedative effect in locomotor activity measurement up to 100 mg/kg p.o. These results suggest that the blockade of mGlu 1 receptors is an attractive target for analgesics. YM-230888 has potential as a new analgesic agent for the treatment of various chronic pain conditions. In addition, YM-230888 may be a useful tool for the investigation of mGlu 1 receptors.

Effects of ReN1869, a CNS‐available antihistamine, on capsaicin‐ and histamine‐induced neurogenic inflammation in healthy subjects

AbstractReN1869 (elsewhere referred to as NNC 05‐1869) is a new tricyclic compound which is chemically related to amitriptyline, but is without any significant interaction with other receptors except for the histamine H1‐receptor, where it functions as an antagonist. The compound exhibits antinociceptive effects in rodent models of chronic pain and is effective against inflammation of neurogenic origin. The present trial was designed to assess the effect of a single dose of ReN1869 in humans on neurogenic inflammation induced by capsaicin and histamine and on the concomitant itch and pain sensation. Twenty‐four healthy male subjects were enrolled in this randomized, double‐blind, two‐period, crossover trial consisting of a single oral dose of 95 mg ReN1869 and matching placebo. Thirty minutes after dosing the participants received, in a randomized order, either histamine (on the skin of the palmar forearm, prick test) before capsaicin (on the skin of the back) in both trial periods and capsaicin before histamine in both periods. Several pharmacodynamic tests were performed after the capsaicin/histamine application: laser somatosensory‐evoked potentials (Laser‐SEP), sensory and pain threshold to laser stimuli of increasing intensity, planimetry of areas of wheal and flare, pinprick hyperalgesia, brush‐evoked pain, allodynia, skin reflection spectrometry (colorimetry), and visual analog scale of itch. ReN1869 had significant effects on the histamine‐induced phenomena. No wheal could be evoked in 14/21 evaluated subjects in contrast to all placebo‐treated subjects. The area of flare was reduced by 80% and itching by 65%. The flare induced by capsaicin was only slightly (not significantly) reduced by ReN1869. However, ReN1869 strongly influenced Laser‐SEP evoked by nociceptive stimuli from the capsaicin‐treated skin area by a 25% reduction of the amplitude of the P2 component, whereas the N1 component was not affected. This observation reflects a central analgesic effect without a peripheral component. The dosing was well tolerated and no particular adverse events were related to the trial drug. Conclusively, ReN1869 represents a new class of antihistamines that has antiinflammatory properties (related to antihistaminergic effects) as well as central analgesic effects (probably mediated centrally through histamine H1 receptors). Drug Dev. Res. 57:193–199, 2002. © 2003 Wiley‐Liss, Inc.