Chemotherapy-induced Neuropathic Pain Model Research Articles

JWH-182: a safe and effective synthetic cannabinoid for chemotherapy-induced neuropathic pain in preclinical models

Chemotherapy-induced neuropathic pain (CINP), a condition with unmet treatment needs, affects over half of cancer patients treated with chemotherapeutics. Researchers have recently focused on the endocannabinoid system because of its critical role in regulating our bodies' most important functions, including pain. We used in vitro and in vivo methods to determine the toxicity profile of a synthetic cannabinoid, JWH-182, and whether it could be potentially effective for CINP alleviation. In vitro, we evaluated JWH-182 general toxicity, measuring fibroblast viability treated with various concentrations of compound, and its neuroprotection on dorsal root ganglion neurons treated with paclitaxel. In vivo, we performed an evaluation of acute and 28-day repeated dose toxicity in mice, with monitoring of health status and a complete histopathological examination. Finally, we evaluated the efficacy of JWH-182 on a CINP model in mice using specific pain assessment tests. JWH-182 has an acceptable toxicity profile, in both, in vitro and in vivo studies and it was able to significantly reduce pain perception in a CINP model in mice. However, the translation of these results to the clinic needs further investigation.

Characterization of Neural Plasticity in Monkey Models of Neuropathic Pain – A Secondary Publication

Neuropathic pain can occur as a result of injuries and diseases of the nervous system. Animal models using rodents have been developed and characterized to reveal plastic changes underlying neuropathic pain. However, structures and functions of some brain areas that are associated with pain perception differ between rodents and primates. Therefore, animal models using non-human primates, such as the macaque monkey, with brain structures and functions closer to those of humans are important for elucidating the mechanisms underlying pain in human patients. Recently, we measured brain activity using functional magnetic resonance imaging (fMRI) in a macaque model of chemotherapy-induced neuropathic pain and reported abnormal activation of pain-related brain regions including insular and secondary somatosensory cortices. In the monkey model of central post-stroke pain, moreover, the increased activation of pain-related areas as seen in the patients was confirmed by fMRI. These results indicate that fMRI measurement of brain activity combined with behavioral outcomes in macaque models could be used not only to understand the pathogenetic mechanisms but also to test therapeutic interventions for neuropathic pain.

METTL14-mediated m6A epitranscriptomic modification contributes to chemotherapy-induced neuropathic pain by stabilizing GluN2A expression via IGF2BP2.

Epigenetics is a biological process that modifies and regulates gene expression, affects neuronal function, and contributes to pain. However, the mechanism by which epigenetics facilitates and maintains chronic pain is poorly understood. We aimed to determine whether N6-methyladenosine (m6A) specifically modified by methyltransferase-like 14 (METTL14) alters neuronal activity and governs pain by sensitizing the GluN2A subunit of the N-methyl-d-aspartate receptor (NMDAR) in the dorsal root ganglion (DRG) neurons in a model of chemotherapy-induced neuropathic pain (CINP). Using dot blotting, immunofluorescence, gain/loss-of-function, and behavioral assays, we found that m6A levels were upregulated in L4-L6 DRG neurons in CINP in a DBP/METTL14-dependent manner, which was also confirmed in human DRGs. Blocking METTL14 reduced m6A methylation and attenuated pain hypersensitivity. Mechanistically, METTL14-mediated m6A modification facilitated the synaptic plasticity of DRG neurons by enhancing the GluN2A subunit of NMDAR, and inhibiting METTL14 blocked this effect. In contrast, overexpression of METTL14 upregulated m6A modifications, enhanced presynaptic NMDAR activity in DRG neurons, and facilitated pain sensation. Our findings reveal a previously unrecognized mechanism of METTL14-mediated m6A modification in DRG neurons to maintain neuropathic pain. Targeting these molecules may provide a new strategy for pain treatment.

Peripheral mu-opioid receptor activation by dermorphin [D-Arg2, Lys4] (1–4) amide alleviates behavioral and neurobiological aberrations in rat model of chemotherapy-induced neuropathic pain

Paclitaxel, a frequently utilized chemotherapeutic agent, often gives rise to severe and distressing sensory neuropathy in patients undergoing chemotherapy. Unfortunately, current therapeutics for chemotherapy-induced neuropathic pain (CINP) demonstrate limited effectiveness and are burdened with the potential for central side effects such as sedation, respiratory depression, cognitive impairment, and addiction, posing substantial clinical challenges. In light of these limitations, present study is designed to investigate the therapeutic potential of Dermorphin [D-Arg2, Lys4] (1–4) amide (DALDA), a preferential peripherally acting mu-opioid receptor agonist, in rat model of CINP. The primary objective was to assess the analgesic properties of DALDA and elucidate the underlying mechanisms governing its therapeutic activity. Our findings revealed that DALDA treatment significantly ameliorated paclitaxel-induced evoked and spontaneous ongoing pain in rats without causing drug addiction and other central side effects. Molecular analyses further unveiled that paclitaxel administration resulted in increased expression of TRP channels, NR2B, voltage-gated sodium channels (VGSCs) and neuroinflammatory markers in both the dorsal root ganglion (DRG) and the spinal cord (L4-L5 region) of rats. DALDA treatment significantly downregulated ion channels (TRPs, VGSCs) and NR2B expressions, concomitant with the inhibition of microglial activation, resulting in the suppression of oxido-nitrosative stress and neuroinflammatory cascade. Findings from the current study suggests that peripheral mu-opioid receptors may offer a potential target for the treatment of patients suffering from CINP, offering new avenues for improved pain relief while minimizing central side effects.

Somatostatin Neurons from Periaqueductal Gray to Medulla Facilitate Neuropathic Pain in Male Mice

Projections from the periaqueductal gray (PAG) to the rostral ventromedial medulla (RVM) are known to engage in descending pain modulation, but how the neural substrates of the PAG-RVM projections contribute to neuropathic pain remains largely unknown. In this study, we showed somatostatin-expressing glutamatergic neurons in the lateral/ventrolateral PAG that facilitate mechanical and thermal hypersensitivity in a mouse model of chemotherapy-induced neuropathic pain. We found that these neurons form direct excitatory connections with neurons in the RVM region. Inhibition of this PAG-RVM projection alleviates mechanical and thermal hypersensitivity associated with neuropathy, whereas its activation enhances hypersensitivity in the mice. Thus, our findings revealed that somatostatin neurons within the PAG-RVM axial are crucial for descending pain facilitation and can potentially be exploited as a useful therapeutic target for neuropathic pain. PerspectiveWe report the profound contribution of somatostatin neurons within the PAG-RVM projections to descending pain facilitation underlying neuropathic pain. These results may help to develop central therapeutic strategies for neuropathic pain.

An NTS-CeA projection modulates depression-like behaviors in a mouse model of chronic pain

Depressive symptoms comorbid with chronic pain are a common health problem, but the underlying neural circuit mechanisms remain elusive. Here, we identify a glutamatergic projection from the nucleus of the solitary tract (NTS) to the central nucleus of the amygdala (CeA) that mediates depression-like behaviors in a chemotherapy-induced neuropathic pain model. Inhibition or ablation of the glutamatergic NTS neurons alleviates depressive but not hypersensitive behaviors in these mice. The projected neurons form excitatory synapses with somatostatin-expressing neurons in the CeA. Silencing the NTS-CeA projection alleviates depressive but not hypersensitive behaviors, whereas activating the proection promotes depressive behaviors. In addition, in naïve mice, activation of the NTS-CeA projection induces obvious depressive behaviors that can be blocked by silencing the CeA somatostatin-expressing neurons. Together, we reveal a modulatory role of the NTS and its glutamatergic projection to the CeA circuit in modulating depression-like behaviors comorbid to chronic pain.

Sex Differences in Kappa Opioid Receptor Agonist Mediated Attenuation of Chemotherapy-Induced Neuropathic Pain in Mice.

Chemotherapy-induced neuropathic pain is a common side effect for cancer patients which has limited effective treatment options. Kappa opioid receptor (KOR) agonists are a promising alternative to currently available opioid drugs due to their low abuse potential. In the current study, we have investigated the effects of Salvinorin A (SalA) analogues, 16-Ethynyl SalA, 16-Bromo SalA and ethyoxymethyl ether (EOM) SalB, and in a preclinical model of paclitaxel-induced neuropathic pain in male and female C57BL/6J mice. Using an acute dose-response procedure, we showed that compared to morphine, 16-Ethynyl SalA was more potent at reducing mechanical allodynia; and SalA, 16-Ethynyl SalA, and EOM SalB were more potent at reducing cold allodynia. In the mechanical allodynia testing, U50,488 was more potent in males and SalA was more potent in females. There were no sex differences in the acute cold allodynia testing. In the chronic administration model, treatment with U50,488 (10 mg/kg) reduced the mechanical and cold allodynia responses to healthy levels over 23 days of treatment. Overall, we have shown that KOR agonists are effective in a model of chemotherapy-induced neuropathic pain, indicating that KOR agonists could be further developed to treat this debilitating condition.

Latent Pain Sensitization unmasks µ-δ opioid heteromer in neuropathic and inflammatory pain

Rodent models of latent pain sensitization can be used to study the episodic nature that chronic pain can exhibit. At pain remission, central sensitization is countered by the activity of endogenous opioid receptors. In animal models, latent pain sensitization can be unmasked by antagonizing opioid receptors resulting in pain relapse. Due to previous studies have focused predominantly on inflammatory pain, the presence of latent pain sensitization in animal model of chemotherapy-induced peripheral neuropathic pain and in female mice is unknown. This study investigates whether μ- and δ-OR suppress latent pain sensitization in model of chemotherapy-induced neuropathic pain in both sexes. We first targeted μ- and δ-OR separately in a model of chemotherapy induced neuropathy after remission to investigate whether antagonizing the receptors reinstated pain hypersensitivity. We then were able to specifically target the μ-δ OR heteromer using a novel peptide to prevent its heteromerization. We used this peptide to investigate whether disruption of the μ-δOR heteromer, after remission, reinstates pain hypersensitivity. At remission from cisplatin-induced neuropathic pain, antagonism of µOR and δOR reinstates pain hypersensitivity in both sexes. Disruption of the μ-δOR heteromer reinstates pain hypersensitivity in both sexes after remission from cisplatin-induced neuropathic and postsurgical pain. Taken together our findings suggest that the μ-δOR heteromer plays a crucial role in remission in various pain models and may represent a novel therapeutic target to prevent the relapse to pain and the transition to chronic pain. American Pain Society and the Rita Allen Foundation.

The µ-δ opioid heteromer masks latent pain sensitization in neuropathic and inflammatory pain in male and female mice

The episodic nature of chronic pain can be studied in the rodent model of latent pain sensitization. After remission, central sensitization is opposed by activation of opioid receptors. At the behavioral level, latent pain sensitization is unmasked when pain hypersensitivity is reinstated by opioid receptor (OR) antagonism. Previous studies have focused on inflammatory pain and male rodents. Whether latent pain sensitization occurs in models of chemotherapy-induced neuropathic pain in female and male mice is unknown. The first aim of this study was to investigate whether μ- and δ-OR suppress latent pain sensitization in our model of chemotherapy-induced neuropathic pain in both sexes.Mounting evidence suggests that μ-and δ-ORs form a heteromer and that the heteromer modulates pain sensitivity. Potential implications of the μ-δ OR heteromer in latent pain sensitization have not been fully explored due to a lack of tools to effectively modulate the heteromer. To specifically target the μ-δ OR heteromer, we used a specific interfering peptide blocking the heteromerization. The second aim of this study was to investigate whether disruption of the μ-δOR heteromer, after remission, reinstates pain hypersensitivity.After remission from cisplatin-induced neuropathic pain, antagonism of µ-OR and δOR reinstates pain hypersensitivity in both sexes. After remission from cisplatin-induced neuropathic pain and postoperative pain, disruption of the μ-δOR heteromer reinstates pain hypersensitivity in both sexes. Taken together our findings suggest that the μ-δOR heteromer plays a crucial role in remission in various pain models and may represent a novel therapeutic target to prevent the relapse to pain and the transition to chronic pain.

The cannabinoid CB2 receptor agonist LY2828360 synergizes with morphine to suppress neuropathic nociception and attenuates morphine reward and physical dependence

The opioid crisis has underscored the urgent need to identify safe and effective therapeutic strategies to overcome opioid-induced liabilities. We recently reported that LY2828360, a slowly signaling G protein-biased cannabinoid CB2 receptor agonist, suppresses neuropathic nociception and attenuates the development of tolerance to the opioid analgesic morphine in paclitaxel-treated mice. Whether beneficial effects of LY2828360 are dependent upon the presence of a pathological pain state are unknown and its impact on unwanted opioid-induced side-effects have never been investigated. Here, we asked whether LY2828360 would produce synergistic anti-allodynic effects with morphine in a paclitaxel model of chemotherapy-induced neuropathic pain and characterized its impact on opioid-induced reward and other unwanted side-effects associated with chronic opioid administration. Isobolographic analysis revealed that combinations of LY2828360 and morphine produced synergistic anti-allodynic effects in suppressing paclitaxel-induced mechanical allodynia. In wildtype (WT) mice, LY2828360 blocked morphine-induced reward in a conditioned place preference assay without producing reward or aversion when administered alone. The LY2828360-induced attenuation of morphine-induced reward was absent in CB2 knockout (CB2KO) mice. In the absence of a neuropathic pain state, LY2828360 partially attenuated naloxone-precipitated opioid withdrawal in morphine-dependent WT mice, and this withdrawal was itself markedly exacerbated in CB2KO mice. Moreover, LY2828360 did not reliably alter morphine-induced slowing of colonic transit or attenuate tolerance to morphine antinociceptive efficacy in the hot plate test of acute nociception. Our results suggest that cannabinoid CB2 receptor activation enhances the therapeutic properties of opioids while attenuating unwanted side-effects such as reward and dependence that occur with sustained opioid treatment.

Interleukin-10 resolves pain hypersensitivity induced by cisplatin by reversing sensory neuron hyperexcitability.

Understanding the mechanisms that drive transition from acute to chronic pain is essential to identify new therapeutic targets. The importance of endogenous resolution pathways acting as a "brake" to prevent development of chronic pain has been largely ignored. We examined the role of interleukin-10 (IL-10) in resolution of neuropathic pain induced by cisplatin. In search of an underlying mechanism, we studied the effect of cisplatin and IL-10 on spontaneous activity (SA) in dorsal root ganglia neurons. Cisplatin (2 mg/kg daily for 3 days) induced mechanical hypersensitivity that resolved within 3 weeks. In both sexes, resolution of mechanical hypersensitivity was delayed in Il10 mice, in WT mice treated intrathecally with neutralizing anti-IL-10 antibody, and in mice with cell-targeted deletion of IL-10R1 on advillin-positive sensory neurons. Electrophysiologically, small- to medium-sized dorsal root ganglia neurons from cisplatin-treated mice displayed an increase in the incidence of SA. Cisplatin treatment also depolarized the resting membrane potential, and decreased action potential voltage threshold and rheobase, while increasing ongoing activity at -45 mV and the amplitude of depolarizing spontaneous fluctuations. In vitro addition of IL-10 (10 ng/mL) reversed the effect of cisplatin on SA and on the depolarizing spontaneous fluctuation amplitudes, but unexpectedly had little effect on the other electrophysiological parameters affected by cisplatin. Collectively, our findings challenge the prevailing concept that IL-10 resolves pain solely by dampening neuroinflammation and demonstrate in a model of chemotherapy-induced neuropathic pain that endogenous IL-10 prevents transition to chronic pain by binding to IL-10 receptors on sensory neurons to regulate their activity.

Positive Allosteric Modulation of CB1 Cannabinoid Receptor Signaling Enhances Morphine Antinociception and Attenuates Morphine Tolerance Without Enhancing Morphine- Induced Dependence or Reward.

Opioid analgesics represent a critical treatment for chronic pain in the analgesic ladder of the World Health Organization. However, their use can result in a number of unwanted side-effects including incomplete efficacy, constipation, physical dependence, and overdose liability. Cannabinoids enhance the pain-relieving effects of opioids in preclinical studies and dampen unwanted side-effects resulting from excessive opioid intake. We recently reported that a CB1 positive allosteric modulator (PAM) exhibits antinociceptive efficacy in models of pathological pain and lacks the adverse side effects of direct CB1 receptor activation. In the present study, we evaluated whether a CB1 PAM would enhance morphine’s therapeutic efficacy in an animal model of chemotherapy-induced neuropathic pain and characterized its impact on unwanted side-effects associated with chronic opioid administration. In paclitaxel-treated mice, both the CB1 PAM GAT211 and the opioid analgesic morphine reduced paclitaxel-induced behavioral hypersensitivities to mechanical and cold stimulation in a dose-dependent manner. Isobolographic analysis revealed that combinations of GAT211 and morphine resulted in anti-allodynic synergism. In paclitaxel-treated mice, a sub-threshold dose of GAT211 prevented the development of tolerance to the anti-allodynic effects of morphine over 20 days of once daily dosing. However, GAT211 did not reliably alter somatic withdrawal signs (i.e., jumps, paw tremors) in morphine-dependent neuropathic mice challenged with naloxone. In otherwise naïve mice, GAT211 also prolonged antinociceptive efficacy of morphine in the tail-flick test and reduced the overall right-ward shift in the ED50 for morphine to produce antinociception in the tail-flick test, consistent with attenuation of morphine tolerance. Pretreatment with GAT211 did not alter somatic signs of μ opioid receptor dependence in mice rendered dependent upon morphine via subcutaneous implantation of a morphine pellet. Moreover, GAT211 did not reliably alter μ-opioid receptor-mediated reward as measured by conditioned place preference to morphine. Our results suggest that a CB1 PAM may be beneficial in enhancing and prolonging the therapeutic properties of opioids while potentially sparing unwanted side-effects (e.g., tolerance) that occur with repeated opioid treatment.

GABAergic cell transplants in the anterior cingulate cortex reduce neuropathic pain aversiveness.

Dysfunction of inhibitory circuits in the rostral anterior cingulate cortex underlies the affective (aversive), but not the sensory-discriminative features (hypersensitivity) of the pain experience. To restore inhibitory controls, we transplanted inhibitory interneuron progenitor cells into the rostral anterior cingulate cortex in a chemotherapy-induced neuropathic pain model. The transplants integrated, exerted a GABA-A mediated inhibition of host pyramidal cells and blocked gabapentin preference (i.e. relieved ongoing pain) in a conditioned place preference paradigm. Surprisingly, pain aversiveness persisted when the transplants populated both the rostral and posterior anterior cingulate cortex. We conclude that selective and long lasting inhibition of the rostral anterior cingulate cortex, in the mouse, has a profound pain relieving effect against nerve injury-induced neuropathic pain. However, the interplay between the rostral and posterior anterior cingulate cortices must be considered when examining circuits that influence ongoing pain and pain aversiveness.

Losartan, an Angiotensin II Type 1 Receptor Antagonist, Alleviates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain by Inhibiting Inflammatory Cytokines in the Dorsal Root Ganglia.

Chemotherapy-induced peripheral neuropathy (CIPN) adversely impacts quality of life and a challenge to treat with existing drugs used for neuropathic pain. Losartan, an angiotensin II type 1 receptor (AT1R) antagonist widely used to treat hypertension, has been reported to have analgesic effects in several pain models. In this study, we assessed losartan's analgesic effect on paclitaxel-induced neuropathic pain (PINP) in rats and its mechanism of action in dorsal root ganglion (DRG). Rats received intraperitoneal injections of 2mg/kg paclitaxel on days 0, 2, 4, and 6 and received single or multiple intraperitoneal injections of losartan potassium dissolved in phosphate-buffered saline at various times. The mechanical thresholds, protein levels of inflammatory cytokines, and cellular location of AT1R and interleukin 1β (IL-1β) in the DRG were assessed with behavioral testing, Western blotting, and immunohistochemistry, respectively. Data were analyzed by two-way repeated-measures analysis of variance for the behavioral test or the Mann-Whitney U test for the Western blot analysis and immunohistochemistry. Single and multiple injections of losartan ameliorated PINP, and losartan delayed the development of PINP. Paclitaxel significantly increased, and losartan subsequently decreased, the expression levels of inflammatory cytokines, including IL-1β and tumor necrosis factor α (TNF-α), in the lumbar DRG. AT1R and IL-1β were expressed in both neurons and satellite cells and losartan decreased the intensity of IL-1β in the DRG. Losartan ameliorates PINP by decreasing inflammatory cytokines including IL-1β and TNF-α in the DRG. Our findings provide a new or add-on therapy for CIPN patients.

Forebrain medial septum sustains experimental neuropathic pain

The present study explored the role of the medial septal region (MS) in experimental neuropathic pain. For the first time, we found that the MS sustains nociceptive behaviors in rodent models of neuropathic pain, especially in the chronic constriction injury (CCI) model and the paclitaxel model of chemotherapy-induced neuropathic pain. For example, inactivation of the MS with intraseptal muscimol (2 μg/μl, 0.5 μl), a GABA mimetic, reversed peripheral hypersensitivity (PH) in the CCI model and induced place preference in a conditioned place preference task, a surrogate measure of spontaneous nociception. The effect of intraseptal muscimol on PH was comparable to that seen with microinjection of the local anesthetic, lidocaine, into rostral ventromedial medulla which is implicated in facilitating experimental chronic nociception. Cellular analysis in the CCI model showed that the MS region sustains nociceptive gain with CCI by facilitating basal nociceptive processing and the amplification of stimulus-evoked neural processing. Indeed, consistent with the idea that excitatory transmission through MS facilitates chronic experimental pain, intraseptal microinjection of antagonists acting at AMPA and NMDA glutamate receptors attenuated CCI-induced PH. We propose that the MS is a central monitor of bodily nociception which sustains molecular plasticity triggered by persistent noxious insult.

(258) - Changes in the estrous cycle following cannabinoid agonists chronic administration in an optimized chemotherapy-induced neuropathic pain model

Cannabis-like compounds have demonstrated antinociceptive properties in various chronic pain models. Synthetic cannabinoid such as CB1 (ACEA) and CB1/CB2 (CP55,940) agonists can modulate chronic pain perception. Indeed, they have previously been shown to alleviate chemotherapy-induced neuropathic pain. However, the impact of chronic administration of these compounds on the estrous cycle needs to be investigated. The goal of this study is to evaluate the role of these different (ACEA and CP55,940) cannabinoid agonists on the estrous cycle following chronic administration in a chemotherapy-induced neuropathic pain model in C57BL/6J mice. We evaluated the effects on the estrous cycle following chronic systemic administration of these different cannabinoid agonists (ACEA and CP55,940) in an optimized chemotherapy-induced neuropathic pain (cisplatin 5 mg/kg intraperitoneal and 4 % sodium bicarbonate subcutaneously weekly) mouse model. We tested the estrous cycle by daily vaginal lavage prior to daily injection with the different synthetic cannabinoids. Further staining of the slides with crystal violet and identification of the estrous cycle under the microscope following cell type identification enable the identification of the stage of the estrus cycle (proestrus, estrus, metestrus and diestrus). Our results suggest compound-specific effects, which may be influenced by hormonal changes and could be mediated by receptor selectivity. The nonselective CB1/2 agonist CP55,940 shifts the cycle towards metestrus—the infertile stage of the cycle. The CB1 selective agonist ACEA is also changing the estrus cycle towards metestrus. Further studies investigating the mechanism behind these compound- or receptor-specific influences on cycle progression is needed to fully appreciate the impact of physiological differences on hormonal responses and potential influence on pain perception. A better understanding of the cannabinoid-specific mechanisms responsible for changes in the estrous cycle and possible hormonal role in pain perception are mandatory to advance the development of long lasting, highly efficacious, and personalized pain therapies.

Rolipram, a Selective Phosphodiesterase 4 Inhibitor, Ameliorates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain through Inhibition of Inflammatory Cytokines in the Dorsal Root Ganglion.

Chemotherapy-induced neuropathic pain is a significant side effect of chemotherapeutic agents and is the most common reason for stopping chemotherapy. The aim of the present study was to find the major site and mechanisms of action by which rolipram, a selective phosphodiesterase-4 inhibitor, alleviates paclitaxel-induced neuropathic pain. Chemotherapy-induced neuropathic pain was induced in adult male Sprague-Dawley rats by intraperitoneal injection of paclitaxel on four alternate days. Rolipram was administered systemically or locally into the lumbar spinal cord, L5 dorsal root ganglion, sciatic nerve, or skin nerve terminal. The mechanical threshold, the protein level of several inflammatory cytokines, and the cellular locations of phosphodiesterase-4 and interleukin-1β in the dorsal root ganglion were measured by using behavioral testing, Western blotting, and immunohistochemistry, respectively. The local administration (0.03-mg) of rolipram in the L5 dorsal root ganglion ameliorated paclitaxel-induced pain behavior more effectively than did local administration in the other sites. Paclitaxel significantly increased the expression of inflammatory cytokines including tumor necrosis factor-α (2.2 times) and interleukin-1β (2.7 times) in the lumbar dorsal root ganglion, and rolipram significantly decreased it. In addition, phosphodiesterase-4 and interleukin-1β were expressed in the dorsal root ganglion neurons and satellite cells and paclitaxel significantly increased the intensity of interleukin-1β (2 times) and rolipram significantly decreased it. These results suggest that the major site of action of rolipram on paclitaxel-induced neuropathic pain in rats was the dorsal root ganglion. Rolipram decreased the expression of inflammatory cytokines in the dorsal root ganglion. Thus, phosphodiesterase-4 inhibitors may ameliorate chemotherapy-induced neuropathic pain by decreasing expression of inflammatory cytokines in the dorsal root ganglion.

Modulating the endocannabinoid pathway as treatment for peripheral neuropathic pain: a selected review of preclinical studies.

Chemotherapy-induced neuropathic pain is a distressing and commonly occurring side effect of many commonly used chemotherapeutic agents, which in some cases may prevent cancer patients from being able to complete their treatment. Cannabinoid based therapies have the potential to manage or even prevent pain associated with this syndrome. Pre-clinical animal studies that investigate the modulation of the endocannabinoid system (endogenous cannabinoid pathway) are being conducted to better understand the mechanisms behind this phenomenon. Five recent pre-clinical studies identified from Medline published between 2013 and 2016 were selected for review. All studies evaluated the effect of small-molecule agonists or antagonists on components of the endocannabinoid system in rats or mice, using cisplatin or paclitax-el-induced allodynia as a model of chemotherapy-induced neuropathic pain. Activation of the cannabinoid receptor-2 (CB-2) receptor by AM1710 blocked paclitaxel-induced mechanical and cold allodynia in one study. Four studies investigating the activation of both cannabinoid receptor-1 (CB-1) and CB-2 receptors by dual-agonists (WIN55,21 and CP55,940), or by the introduction of inhibitors of endocannabinoid metabolisers (URB597, URB937, JZL184, and SA-57) showed reduction of chemotherapy-induced al-lodynia. In addition, their results suggest that anti-allodynic effects may also be mediated by additional receptors, including TRPV1 and 5-hydroxytryptamine (5-HT1A). Pre-clinical studies demon-strate that the activation of endocannabinoid CB-1 or CB-2 receptors produces physiological effects in animal models, namely the reduction of chemotherapy-induced allodynia. These studies also provide in-sight into the biological mechanism behind the therapeutic utility of cannabis compounds in managing chemotherapy-induced neuropathic pain, and provide a basis for the conduct of future clinical studies in patients of this population.

Single and combined effects of Δ9 -tetrahydrocannabinol and cannabidiol in a mouse model of chemotherapy-induced neuropathic pain.

The non-psychoactive phytocannabinoid cannabidiol (CBD) can affect the pharmacological effects of Δ9 -tetrahydrocannabinol (THC). We tested the possible synergy between CBD and THC in decreasing mechanical sensitivity in a mouse model of paclitaxel-induced neuropathic pain. We also tested the effects of CBD on oxaliplatin- and vincristine-induced mechanical sensitivity. Paclitaxel-treated mice (8.0mg·kg-1 i.p., days 1, 3, 5 and 7) were pretreated with CBD (0.625-20.0mg·kg-1 i.p.), THC (0.625-20.0mg·kg-1 i.p.) or CBD+THC (0.04+0.04-20.0+20.0mg·kg-1 i.p.), and mechanical sensitivity was assessed on days 9, 14 and 21. Oxaliplatin-treated (6.0mg·kg-1 i.p., day 1) or vincristine-treated mice (0.1mg·kg-1 i.p. days 1-7) were pretreated with CBD (1.25-10.0mg·kg-1 i.p.), THC (10.0mg·kg-1 i.p.) or THC+CBD (0.16mg·kg-1 THC+0.16mg·kg-1 CBD i.p.). Both CBD and THC alone attenuated mechanical allodynia in mice treated with paclitaxel. Very low ineffective doses of CBD and THC were synergistic when given in combination. CBD also attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity, while THC significantly attenuated vincristine- but not oxaliplatin-induced mechanical sensitivity. The low dose combination significantly attenuated oxaliplatin- but not vincristine-induced mechanical sensitivity. CBD may be potent and effective at preventing the development of chemotherapy-induced peripheral neuropathy, and its clinical use may be enhanced by co-administration of low doses of THC. These treatment strategies would increase the therapeutic window of cannabis-based pharmacotherapies.

Early life vincristine exposure evokes mechanical pain hypersensitivity in the developing rat.

Vincristine (VNC) is commonly used to treat pediatric cancers, including the most prevalent childhood malignancy, acute lymphoblastic leukemia. Although clinical evidence suggests that VNC causes peripheral neuropathy in children, the degree to which pediatric chemotherapeutic regimens influence pain sensitivity throughout life remains unclear, in part because of the lack of an established animal model of chemotherapy-induced neuropathic pain during early life. Therefore, this study investigated the effects of VNC exposure between postnatal days (P) 11 and 21 on mechanical and thermal pain sensitivity in the developing rat. Low doses of VNC (15 or 30 μg/kg) failed to alter nociceptive withdrawal reflexes at any age examined compared with vehicle-injected littermate controls. Meanwhile, high dose VNC (60 μg/kg) evoked mechanical hypersensitivity in both sexes beginning at P26 that persisted until adulthood and included both static and dynamic mechanical allodynia. Hind paw withdrawal latencies to noxious heat and cold were unaffected by high doses of VNC, suggesting a selective effect of neonatal VNC on mechanical pain sensitivity. Gross and fine motor function appeared normal after VNC treatment, although a small decrease in weight gain was observed. The VNC regimen also produced a significant decrease in intraepidermal nerve fiber density in the hind paw skin by P33. Overall, the present results demonstrate that high-dose administration of VNC during the early postnatal period selectively evokes a mechanical hypersensitivity that is slow to emerge during adolescence, providing further evidence that aberrant sensory input during early life can have prolonged consequences for pain processing.