INFORMAZIONI PERSONALI ISTRUZIONE E FORMAZIONE Università degli Studi di Torino, Facoltà di Psicologia, indirizzo di Psicologia Clinica e di Psicologia e Psicopatologia del ’età evolutiva Psicologia Clinica, Psicologia Cognitiva, Psicologia di Comunità, Psicologia Generale, Neuropsicologia Clinica, Psicologia Dinamica. • Eventuale qualifica/titolo conseguito Laurea in Psi
Test.paulchristomd.comCurr Pain Headache RepDOI 10.1007/s11916-010-0093-y The Effect of Morphine on Glial Cells as a PotentialTherapeutic Target for Pharmacological Developmentof Analgesic Drugs Haroon Hameed & Mariam Hameed & Paul J. Christo # Springer Science+Business Media, LLC 2010 Abstract Opioids have played a critical role in achieving pain relief in both modern and ancient medicine. Yet, theirclinical use can be limited secondary to unwanted side effects Opioids have been used in the treatment of pain for such as tolerance, dependence, reward, and behavioral thousands of years. Some date the use of opium poppy changes. Identification of glial-mediated mechanisms induc- extracts for analgesia as far back as 3000 BC ••].
ing opioid side effects include cytokine receptors, κ-opioid Unfortunately, use of opioids for the treatment of pain has receptors, N-methyl-D-aspartate receptors, and the recently been associated with potential disadvantages, including elucidated Toll-like receptors. Newer agents targeting these development of tolerance, dependence, and undue side receptors such as AV411, MK-801, AV333, and SLC022, effects such as constipation, urinary retention, and mood and older agents used outside the United States or for other and behavioral changes. Despite their side effects, opioids disease conditions, such as minocycline, pentoxifylline, and such as morphine, hydromorphone, oxycodone, and UV50488H, all show varied but promising profiles for fentanyl continue to be widely prescribed due to their providing significant relief from opioid side effects, while simultaneously potentiating opioid analgesia.
The personal and social consequences of opioid use, such as addiction, have not only led doctors and patients Keywords Toll-like receptor . Opioid receptor . Morphine .
to strive to limit opioid treatment, but there has also been Dependence . Reward . Tolerance . NMDA . Ibudilast .
an increasing trend toward tighter federal regulation of Dizocilpine . Minocycline . Pentoxifylline . Propentofylline .
opioid prescriptions. For example, there currently is a US Glial cell . Chronic pain . Analgesia . Pain relief Food and Drug Administration motion to increaseregulation of prescription of many opioids in the formof Risk Evaluation and Mitigation Strategies. Medica- tions that soon may be included are generic and trade Department of Physical Medicine and Rehabilitation,Johns Hopkins University School of Medicine, name versions of oral extended-release morphine and oxycodone, as well as extended-release transdermal In addition to an increased interest in responsible opioid use, the current climate makes it more important to find methods to mitigate the unwanted side effects of opioids while preserving their qualities of highly effec-tive pain relief. Many different mechanisms have been P. J. Christo (*)Division of Pain Medicine, Department of Anesthesiology implicated in the genesis of opioid tolerance and dependence. This article reviews some of the different Johns Hopkins University School of Medicine, mechanisms involved, as well as specific glial-modifying agents that enhance opioid analgesia and mitigate Baltimore, MD 21205, USAe-mail: email@example.com Glial Mechanisms of Pain, Opioid Tolerance, neuropathic pain. This is evidenced by research showing that intrathecal IL-1β injection can induce allodynia andhyperalgesia [, Also, experiments have shown Glial cells appear to have a prominent role in the that IL-1β induces apoptosis by phosphorylation of p38 of development of neuropathic pain syndromes such as MAPK, leading to the apoptotic caspace cascade by complex regional pain syndrome, herpes zoster, diabetic activation of caspace-3 . p38 MAPK has also been neuropathy, AIDS, and tumors [These cells linked to morphine tolerance in spinal microglia by a (astrocytes and microglia) make up 70% of cells found mechanism of upregulation of p38 MAPK positive cells within the central nervous system (CNS). They act as after chronic morphine administration ••]. The mecha- neuronal support cells and immune cells in the CNS and nisms in which IL-1β induces sensory neuronal sensitiza- have many important functions including maintaining tion to pain through IL-1 receptor type-1 activation is neuronal homeostasis, impulse propagation, immune re- thought to involve tyrosine kinases as well as protein kinase sponse, waste removal, and neuronal repair ]. They C ••]. On the contrary, intrathecal IL-1α administration surround synapses and lie in apposition to neuronal cell has been shown to dose dependently relieve neuropathic bodies . Further, glia appear to play a central role in pain symptoms ••]. IL-1—related cascades are well neuropathic pain perception development and mainte- studied and appear to be of high importance, especially in nance by modulating neuronal signal transmission and conjunction with other receptors in activating the processes excitability [as well as development of opioid that lead to negative glia-mediated opioid sequelae as tolerance and dependence. These cells become upregu- lated in chronic pain states, as evidenced by an increase of IL-6 has also been linked to the etiology of many their markers, glial fibrillary acid protein (GFAP), and cell neurological disorders as mentioned above. Studies have surface receptors (OX-42 and CD11b) Glial cells shown increased ipsilateral expression of IL-6 in the can be activated by noxious stimuli–like trauma, hypoxia, dorsal root ganglion after nociceptive stimulation [••].
ischemia, inflammation, infection, or neuronal degenera- Interestingly, in contrast to the pain promoting effects of tion. More specifically, activation occurs through the IL-1, intrathecal IL-6 injection has been shown to have an binding of various neurotransmitter receptors, such as inhibitory effect on neuropathic pain .
substance P, glutamate, N-methyl-D-aspartate (NMDA), Among the studied cytokines, IL-10 has been shown and purinergic receptors. Continuous nociceptive input to possess the most potent anti-inflammatory action, and results in high levels of glutamate within synapses leading its release downregulates the expression of other cyto- to dysregulation of glutamate transporters (GLT1 and kines, namely IL-1β, IL-6, and TNF-α . IL-10 has GLAST), which are critical for removal of this excitatory also been shown in experimental animals to reduce neurotransmitter, further enhancing prolonged glial acti- chronic pain over 2 months duration after administration vation. After astrocytic receptor activation, the mitogen- of a single dose It acts by downregulating proin- activated protein kinase (MAPK) intracellular signaling flammatory genes, which leads to decreased expression of pathways become activated. The MAPK family has three the above mentioned cytokines and their receptors and main members: the extracellular signal-regulated kinase, upregulation of their functional antagonists [, ]. IL-10 c-Jun N-terminal kinase (JNK), and p38 , each of which upregulation is currently a promising new target for glia- can activate the transcription factor, nuclear factor-κB modifying medications, and we expect much research (NF-κB), ultimately resulting in increased production of regarding such Il-10—modifying agents in the coming many substances such as proinflammatory cytokines and chemokines, neurotrophic factors, prostaglandins, nitric TNF-α is another potent cytokine associated with the oxide, complement proteins, free radicals, neurotoxins, induction of inflammation in the CNS as well as in and excitatory amino acids [, Important cytokines peripheral tissues. In the CNS, it is also produced by in the generation of pain include interleukin (IL)-1α, IL- microglial cells and has been shown to be released after 1β, IL-6, tumor necrosis factor (TNF)-α, and IL-10 and injury [It appears to have dual action. Although its are discussed below. These spinal cytokines have also proinflammatory destructive effects are mediated through been shown to oppose acute and chronic opioid analgesia the p55 TNF-α receptor-1 [interestingly, TNF-α also plays a neuroprotective role. This is demonstrated by itsability to encourage expression of antiapoptotic and anti- oxidative proteins via the p75 TNF-α receptor-2 ]. Bothof these effects through different receptor mechanisms may IL-1α and IL-1β, the IL-1 type-1 receptor and its accessory provide targets for future glia-modifying medications protein, appear to be important in the generation of to be associated with neuropathic pain, glial activation, andopioid side effects; they provide a convincing platform of evidence in favor of the central role of the TLRs. Further, various knockout and knockdown studies of TLR2 and TLR4 that show suppression of nerve injury—induced allodynia strengthen this viewpoint [, ].
TLRs offer a convincing body of evidence of their role in neuropathic pain. Among these, TLR4 appears to be the most significant, with TLR2 and TLR3 playing minor roles.
TLR4 is normally expressed on microglia, but its expres-sion can also be induced on astrocytes in response to IL interleukin, TNF tumor necrosis factor inflammation [The CNS microglial response toinflammation includes activation of the TLR4-related path-ways, leading to increased IFN-γ, IL-1β, and TNF-α. This TLR4-related cascade has been explained using the well-defined effect of bacterial LPS on the CNS. After binding A very exciting discovery has been elaboration of the Toll-like the LPS-binding protein, LPS is delivered to cluster receptor (TLR) and how it relates to glial activation. TLRs are determinant 14 (CD14) on the microglial cell membrane, a group of pattern recognition receptors found on astrocytes causing activation of intracellular sphingomyelinase, which and mainly microglia that can be activated by exogenous cleaves to form ceramide. Ceramide causes production of a (pathogenic proteins) and endogenous (IL-1β, TNF-α) “lipid raft” containing the coreceptor myeloid differentia- molecules; when activated, they produce an immune response tion factor 2 (MyD2), TLR4, and heat shock proteins 70 resulting in the release of cytokines. TLR activation has been and 90, in addition to others. Further heterodimerization positively linked to the development of opioid tolerance and and homodimerization of MyD2-TLR4 pairs occurs after other side effects, decreased opioid efficacy, and the develop- LPS presentation by CD14 to MyD2. Finally, proinflam- ment and maintenance of neuropathic pain ••]. TLRs are matory cytokine production results from the NF-κB MAPK composed of 10 different transmembrane receptors that bind a wide variety of exogenous and endogenous substances, Prior studies have also shown direct links between TLR4 which are inherently immunoreactive. Exogenous TLR- and neuropathic pain models. One study showed TLR4 was activating substances, which have been well characterized, important in initiation of nerve injury-induced hypersensi- include lipopolysaccharides (LPS), such as gram-negative tivity, and correspondingly, TLR4 mRNA has been shown bacteria, and endogenous substances that include cell to be increased in spinal microglia post-L5 nerve transec- membrane components, DNA and RNA, plasma proteins, tion [••]. TLR4 knockout animals do not develop and heat shock proteins ]. TLRs that have received allodynia, which is likely due to reduction of glial the most attention with respect to mediating neuropathic pain activation and cytokine expression; TLR4 antisense nucle- otide therapy results in reduced spinal proinflammatory TLRs appear to activate very similar signaling pathways cytokine production and reduced microglial activation, with to IL-1, and some researchers now refer to this pathway as resultant decreased centrally mediated neuropathic pain the TLR-IL1 signaling pathway [That is, TLRs work ]. These effects may be mediated through decreased through activation of an adapter protein known as myeloid binding of TLRs to heat shock proteins (HSPs), especially differentiation factor 88 (MyD88). This factor leads to HSP70 and HSP90, with resultant decreased induction of activation of the IL-1 receptor—associated kinases (IRAKs) TNF-α and IL-6 release [Moreover, decreased activa- and TNF receptor—associated factor-6 (TRAF6), which tion of TLR4 results in decreased induction of its ligand finally culminates in activation of NF-κB . Other fibronectin, which has been shown to be upregulated in TLR-associated pathways include the JNK and interferon neuropathic pain, and is responsible for P2X4 ATP-receptor (IFN) pathways [Both TLR2 and TLR4 are important activation post nerve injury . This P2X4 down- in recognizing endogenous pain-mediating signals such as regulation is thought to be closely linked to a decrease in those mentioned above. These studies have shown a highly development of allodynia ]. P2X4 is also closely related interconnected web of pathways involving TLRs and other to microglial migration, which plays a role in the well-defined proinflammatory pathways previously known development and maintenance of neuropathic pain [ Toll-like Receptors and Inflammatory Pain previously proven effects showing that positive andnegative isomers of naloxone block TLR4 [••, Although direct evidence is lacking, tissue damage and Other studies have shown potentiation of analgesia subsequent release of endogenous proinflammatory prod- after morphine administration in TLR4 knockout mice, ucts and factors as well exogenous substances, such as although there was no difference in initial pain thresh- bacterial endotoxins, can lead to inflammatory pain.
olds between the TLR4 knockouts and wild-type mice.
Levels of inflammatory pain correlate with microglial This further supports the role of TLR4 in antagonizing activation. Secondary to this, some propose a concept morphine-induced analgesia. Moreover, naloxone admin- that microglial activation is necessary to states involving istered concomitantly with morphine potentiated analge- facilitated pain, which include inflammatory pain in sia in the wild-type mice but not in the TLR4 knockouts addition to neuropathic pain . This correlates with data reporting increased upregulation of microglial activa-tion markers following administration of LPS and poly- inosinic:polycytidylic acid, a viral infection simulator]. In addition, in a model of Freund’s adjuvant- NMDA-positive glutamate receptors have also been shown induced chronic inflammatory pain, increased expression to be important in the modulation of morphine tolerance. A of TLR4 and inflammatory cytokines has been described.
great deal of research has helped explain the details of These data contribute to the validity of a relationship enhancement of NMDA activity after morphine adminis- between inflammatory pain and TLR activation.
tration. This effort was inspired by studies showing thatMK-801, an NMDA-receptor antagonist, could attenuate Toll-like Receptors and Opioid Tolerance and Dependence morphine tolerance and dependence, whereas other studiesshow that ketamine and dextromethorphan could decrease For some time, researchers have postulated that an opioid requirements when administered with morphine independent mechanism is responsible for tolerance, hyper- ]. It was subsequently shown that after chronic opioid algesia, physical dependence, reward, and respiratory administration, there is downregulation of the glutamate depression than those effects mediated by classical opioid transporter (GLAST) in astrocytes, which likely causes an receptors such as µ, κ, and δ receptors.
increase in glutamate in the synaptic cleft, as well as an In a recent study, the induction of opioid-induced upregulation of D-serine, thereby potentiating NMDA- hyperalgesia in triple receptor knockout mice suggests receptor signaling. In addition, morphine has been shown that opioids also act through different mechanisms to upregulate brain-derived neurotrophic factor (BDNF) in separate from the classic opioid receptors on neurons. It cultured microglia. This, coupled with the finding that has been shown that opioids can bind to TLR-4 receptors BDNF upregulates the antiopioid subunit of the NMDA on glial cells leading to their activation and synthesis of receptor subtype known as GluRepsilon1 (NR2A), led nociceptive cytokines, thus enhancing neuropathic pain researchers to believe that the NR2A receptor may be the and counteracting opioid analgesic effects [Opioid site of morphine-induced NMDA receptor-dependent anti- receptor-independent opioid effects were corroborated by opioid activity ••]. This concept is further corroborated the development of opioid-induced hyperalgesia in triple by the enhancement of morphine analgesia in NR2A opioid receptor knockout animals that were administered morphine. Further experiments have shown that intrathecalmorphine analgesia can be prolonged when coadminis- tered with LPS variants, which are TLR4 competitivereceptor antagonists, and with TLR1/IL-1 receptor domain κ-Opioid receptors (KORs) are a type of opioid receptor adapter protein inhibitors. Interestingly, concomitant with a somewhat different mechanism of action from the intrathecal-intrathecal, systemic-systemic, and systemic- classic µ receptor. For example, they have been shown to intrathecal administration of morphine with naloxone, be activated by dynorphins after partial sciatic nerve respectively, have all been shown to prolong acute ligation. In turn, this has led to glial proliferation in contrast morphine analgesia. The simultaneous and continuous to µ receptors, which decrease glial proliferation [ administration of naloxone and morphine intrathecally Further, they have shown promise in the attenuation of has been shown to attenuate morphine-induced hyper- morphine tolerance ]. Unfortunately, it has been difficult algesia, which occurs after prolonged morphine adminis- to locate agents that possess these positive KOR agonist tration. Further, this dual administration significantly effects of diminishing tolerance while lacking the negative decreased withdrawal after opioid administration was KOR agonist effects such as dysphoria and psychomimetic terminated. All these effects are thought to be related to Specific Medications With Potential for Use as Opioid 801 is not able to decrease morphine tolerance once it has A recent study attributed a part of MK-801’s ability to reduce opioid tolerance to an inhibition of the NMDAreceptor-dependent activation of spinal JNK; this kinase has AV411 (Avigen, Inc., Alameda, CA) is a blood-brain been shown to be involved in the development of morphine permeable, nonspecific phosphodiesterase inhibitor that analgesic tolerance ]. Interestingly, MK-801 injection in acts centrally by way of attenuation of glial cell activation the ventral periaqueductal gray area increased the acute and reduction of proinflammatory activating factors, such analgesic action when coadministered with morphine but as cytokines (TNF-α, IL-1β), nitric oxide, and chemokines did not affect nociception when administered alone, such as monocyte chemo-attractant protein-1 and fractal- suggesting that different tolerance mechanisms occur in kines; it increases production of anti-inflammatory IL-10 the spinal cord compared with the periaqueductal gray area , •]. It was initially used to treat bronchial asthma and ]. It should be noted that despite having antinociceptive poststroke dizziness, which has been attributed to its ability effects in chronic pain models, MK-801 has been shown to to reduce inflammation and cause vasodilatation [In a have the opposite effect in acute pain models causing recent study, AV411 was shown to reduce mechanical allodynia caused by neuropathic pain as well as noxiousneuropathy induced by chemotherapeutic agents (paclitaxel and vincristine); it was also shown to reduce morphinetolerance.
SLC022 (Solace Pharmaceuticals, Canterbury, Kent, United When administered systemically, AV411 was shown to Kingdom) is an orally available, blood-brain permeable, be distributed to the spinal cord and to attenuate morphine- methylxanthine derivative that acts as a glial inhibitor and induced glial cell activation in certain brain regions. AV411 has been shown to attenuate neuropathic pain states as well has also been shown to inhibit peripheral inflammatory as chemotherapy-induced painful neuropathy [Studies cells , ], which has been suggested as a possible cause have shown that it decreases allodynia, possibly through of reduced pain perception peripherally. Other recent altering γ-aminobutyric acid (GABA)ergic tone through published data demonstrate that AV411 reduced spontane- modulation of glutamic acid decarboxylase in the spinal ous opioid withdrawal, protected naloxone-induced mor- cord after injury, as well as reducing an injury-induced phine withdrawal when given during the period of development of morphine dependence, and simultaneously Apart from its advantageous role in pain reduction, enhanced analgesic effects (three to five times increases in propentofylline has also been shown to modulate drug acute potency), even in situations in which opioid depen- reward. In vivo studies have shown that intraperitoneal dence had already been established ]. These effects injections of propentofylline attenuated condition-placed were seen with both morphine and oxycodone, with no preference, a measure of drug reward in animals that were changes in plasma morphine levels. Another study shows dependent on methamphetamine and morphine; this atten- that AV411 decreases a morphine-induced increase of uation is thought to be caused by astrocytic activation [ dopamine in the nucleus accumbens, a nucleus known to Propentofylline has also been shown to act as a neuro- be associated with morphine-induced drug reward as well as withdrawal [, •], thus further illustrating thebeneficial role of AV411 in regulation of drug reward and An extract of the tuber of Ranunculaceae Aconitum carmichaeli Debeaux—referred to as PAT or U50488H—has been found to possess KOR agonist activity, without MK-801 is an NMDA-positive glutamate receptor noncom- any significant adverse effects [U50488H has been petitive antagonist that has been shown to attenuate opioid used in China and Japan to treat chronic pain without tolerance and does not influence the antinociceptive effects adverse effects for some time and has shown to be effective of morphine. When injected intrathecally, it has been shown not only in attenuating morphine tolerance when adminis- to decrease morphine tolerance at the spinal level ].
tered initially, but also reversing morphine tolerance after it Proteomic studies have shown there is upregulation of developed. Some studies have shown greater effectiveness GFAP in those animal models with morphine tolerance, of U50488H over MK-801 because U50488H can poten- whereas MK-801 was shown to reduce the GFAP levels in tiate the thermal antinociceptive effect of morphine and can these animals. Interestingly, similar to minocycline, MK- reverse morphine tolerance once it has developed ].
cells is thought to partly occur by suppressing p38 MAPK, which has also shown to reduce tolerance to AV333 (Avigen, Inc., Alameda, CA) is a plasmid that has been shown to be a well-tolerated and effective antineur- Minocycline also affects neuropathic pain. For instance, opathic agent when injected intrathecally. It functions as a minocycline enhances the effects of morphine in neuro- glial cell inhibitor and promotes an increase in the amount pathic pain models and diminishes the development of of the anti-inflammatory cytokine IL-10 in the spinal cord.
morphine tolerance. In a recent study by Mika et al. [ Experimental studies have shown that a single course of minocycline delayed the development of morphine toler- therapy entirely diminishes neuropathic pain symptoms for ance in normal and neuropathic pain conditions, and was 90 days [We expect to learn more about this agent’s associated with decreasing the morphine-induced increase in CD11b/c protein expression in microglial cells withoutinhibiting astroglial cells. Minocycline inhibits the activa- tion of microglial cells, which are thought to initiateneuropathic pain, thus preventing development of neuro- Minocycline is a semisynthetic, second-generation broad pathic pain in animal models. However, once these cells are spectrum, blood-brain barrier permeable tetracycline that activated, minocycline does not seem to be as effective in has been historically used for its antimicrobial properties.
However, it has also been reported to possess neuro- Although minocycline enhances the analgesic efficacy of protective effects with reported benefits in experimental opioids, it may also increase undesirable effects of opioids models of neurodegenerative disease, traumatic brain such as respiratory depression and drug dependence.
injury, and cerebral ischemia. Minocycline’s protective role Minocycline is a p-glycoprotein (p-gp) inhibitor, and occurs by suppression of the mitochondrial permeability inhibition of p-gp can cause altered pharmacokinetics of transition, inhibition of caspace-1 and -3 expression, and opioids, thus leading to increased bioavailability and inhibition of microglial activation and proliferation  via ultimately an increase in adverse effects. However, in a antihyperalgesic and antiallodynic effects . The recent study, minocycline was shown to reduce the latter effects occur by reducing proinflammatory factor- morphine-induced decrease in respiratory parameters such mediated nociceptive transmission. This is achieved by as tidal volume, minute volume, inspiratory force, expira- decreasing mRNA expression for IL-1β, TNF-α, each of tory force, and blood oxygen saturations. Minocycline did their converting enzymes, and IL-10 in the dorsal spinal not affect the morphine-induced depression in respiratory cord; reducing IL-1β and TNF-α in cerebrospinal fluid; rate. These data, in concert with some studies reporting the and decreasing serum IL-6 , Inhibition of microglial unsuccessful disruption of morphine tolerance [do not Attenuates glial cell activation; increases IL-10; Reduction of proinflammatory cytokines; attenuates morphine tolerance; beneficial in chemotherapeutic-induced neuropathy,poststroke dizziness, and bronchial asthma Diminishes morphine tolerance through reduced c-JNK Antineuropathic agent; modulates drug reward; neuroprotective Attenuates morphine tolerance when given initially or after Glial cell activation inhibitor; phosphodiesterase Reduction of proinflammatory cytokines; may diminish opioid tolerance and reward by potentially reducing NO andadenosine production Suppression of mitochondrial permeablity transition; Diminishes morphine tolerance and reward; neuroprotective inhibition of caspace-1 and -3 expression; inhibition of microglial activation and proliferation c-JNK c-Jun N-terminal kinase, IL interleukin, KOR κ-Opioid receptor, NF-κB nuclear factor-κB, NMDA N-methyl-D-aspartate, NO nitric oxide support the theory of increased bioavailability of opioids by minocycline administration. In fact, minocycline was alsoshown to suppress morphine reward as measured by There are a number of exciting directions for the use of conditioned place preference, which is a widely accepted glial-modifying agents as opioid adjuncts for the treatment measure of morphine reward, as mentioned previously. Of of acute and chronic pain. Important targets include note, this study used naive animal models, in which glial cytokine receptors, TLRs, NMDA-positive glutamate cells were not activated; thus, it is not known whether receptors, and the κ-opioid receptors. It appears that basic minocycline would continue to have similar effects in and clinical research involving both previously discovered neuropathic pain states, and should be studied further. In agents such as minocycline, pentoxifylline, and U50488H, conclusion, minocycline suppresses microglial cells, which as well as newer agents such as MK-801, AV411, and can lead to attenuation of neuropathic pain, enhance SLC022, may introduce a new era of improved opioid morphine analgesia, decrease certain undesired opioid effects, and delay the development of morphine tolerancein normal and neuropathic pain conditions.
No potential conflicts of interest relevant to this article Pentoxifylline is an inhibitor of glial activation, nonspecificcytokine synthesis, and phosphodiesterase (PDE) ].
Pentoxifylline has been shown to inhibit the production ofmRNA and protein levels of proinflammatory cytokines Papers of particular interest, published recently, have been such as TNF-α, IL-1β, and IL-6, which were associated with reduced neuropathic pain [and inflammatory pain ]. Along with reduction of these cytokines through inhibition of NK-κB, attenuation of pain symptoms has alsobeen shown to be associated with elevated levels of the 1. •• Hutchinson MR, Bland ST, Johnson KW, et al.: Opioid-induced glial activation: mechanisms of activation and implications for anti-inflammatory cytokine, IL-10, in the CNS [In opioid analgesia, dependence, and reward. ScientificWorldJournal prior studies, pentoxifylline was also shown to reduce 2007, 7:98–111. This article discusses TLRs and modifying agents postoperative pain and formalin-induced pain behavior in and their relevance to the future of the management of pain. It also includes detailed information related to the researchregarding naloxone in the management of opioid side effects.
Similar to AV411’s inhibition of PDE, pentoxifylline 2. Coyle DE: Partial peripheral nerve injury leads to activation of reduces cyclic adenosine monophosphate (cAMP) levels, astroglia and microglia which parallels the development of and this in turn results in decreased TNF-α and IL1-β allodynic behavior. Glia 1998, 23:75–83.
production by microglia. These cytokines cause upregula- 3. McMahon SB (2002) Neuropathic pain mechanisms. In: Giamberardino MA (ed) Pain 2002—an updated review.
tion of nitric oxide synthase, which increases nitric oxide (NO) levels. NO is known to affect dopamine levels in the 4. Nakajima K, Kohsaka S: Functional roles of microglia in the mesolimbic system, where increased dopamine levels are brain. Neurosci Res 1993, 17:187–203.
associated with opioid reward. Thus, these PDE inhibitors 5. Milligan ED, Watkins LR: Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 2009, 10:23–36.
can potentially modulate drug reward and dependence 6. Halassa MM, Fellin T, Haydon PG: The tripartite synapse: roles •]. Another suggested mechanism of attenuating mor- for gliotransmission in health and disease. Trends Mol Med 2007, phine reward relates to a reduced production of adenosine by limited cAMP hydrolization. Adenosine causes inhibi- 7. Pocock JM, Kettenmann H: Neurotransmitter receptors on micro- glia. Trends Neurosci 2007, 30:527–535.
tion of the inhibitory GABA pathways, which modulate 8. Cao H, Zhang YQ: Spinal glial activation contributes to pathological pathways in the ventral tegmental area (VTA) of the pain states. Neurosci Biobehav Rev 2008, 32:972–983.
mesolimbic system. The VTA contains cells that project to 9. Ji RR, Gereau RW 4th, Malcangio M, Strichartz GR: MAP kinase the nucleus accumbens and are a source of dopamine.
and pain. Brain Res Rev 2009, 60:135–148.
10. Watkins LR, Maier SF: The pain of being sick: implications of Therefore, with reduced adenosine levels by PDE inhib- immune-to-brain communication for understanding pain. Annu itors, there may be attenuation of morphine reward through decreased dopamine in the nucleus accumbens and activa- 11. Minghetti L, Levi G: Microglia as effector cells in brain damage tion of cells in the VTA as well as glial cells •]. In and repair: focus on prostanoids and nitric oxide. Prog Neurobiol1998, 54:99–125.
conclusion, pentoxifylline has been shown to attenuate 12. Hutchinson MR, Coats BD, Lewis SS, et al.: Proinflammatory neuropathic pain states and may also contribute to reduction cytokines oppose opioid-induced acute and chronic analgesia.
of morphine-induced tolerance and reward (Table ).
Brain Behav Immun 2008, 22:1178–1189.
13. Malcangio M, Bowery NG, Flower RJ, Perretti M: Effect of 32. McMahon SB, Cafferty WB, Marchand F: Immune and glial cell interleukin-1 on the release of substance P from rat isolated spinal factors as pain mediators and modulators. Exp Neurol 2005, cord. Eur J Pharmacol 1996, 299:113–118.
14. •• Mika J: Modulation of microglia can attenuate neuropathic pain 33. •• Hutchinson MR, Zhang Y, Shridhar M, et al.: Evidence that symptoms and enhance morphine effectiveness. Pharmacol Rep opioids may have toll-like receptor 4 and MD-2 effects. Brain 2008, 60:297–307. This review discusses the roles of various Behav Immun 2010, 24:83–95. This paper summarizes recent cytokine-related cascades in addition to other TLR-related information regarding the highly central role of TLR-4 receptors mechanisms in the generation of nonopioid receptor-mediated with implications to the current developments in the opioid- opioid effects and the agents that may be employed to modify related tolerance and dependence modifying agents.
34. Juni A, Klein G, Pintar JE, Kest B: Nociception increases during 15. Obreja O, Rathee PK, Lips KS, et al.: IL-1 potentiates heat- opioid infusion in opioid receptor triple knock-out mice. Neuro- activated currents in rat sensory neurons: involvement of IL-1RI, tyrosine kinase, and protein kinase C. FASEB J 2002, 16:1497– 35. Shu H, Hayashida M, Huang W, et al.: The comparison of effects of processed Aconiti tuber, U50488H and MK-801 on the 16. Flatters SJ, Fox AJ, Dickenson AH: Spinal interleukin-6 (IL-6) antinociceptive tolerance to morphine. J Ethnopharmacol 2008, inhibits nociceptive transmission following neuropathy. Brain Res 36. •• Ueda H, Ueda M: Mechanisms underlying morphine analgesic 17. Moore KW, O’Garra A, de Waal Malefyt R, et al.: Interleukin-10.
tolerance and dependence. Front Biosci 2009, 14:5260–5272. This is a highly detailed review of the protein pathways responsible for 18. Avigen, Inc.: Available at www.avigen.com. Accessed November the development of opioid tolerance and dependence. This review includes discussions on protein kinase receptor phosphorylations, 19. Sawada M, Suzumura A, Hosoya H, et al.: Interleukin-10 inhibits NMDA receptors, neurotrophins, and various other neuropep- both production of cytokines and expression of cytokine receptors in microglia. J Neurochem 1999, 72:1466–1471.
37. Xu M, Bruchas MR, Ippolito DL, et al.: Sciatic nerve ligation- 20. Huber TS, Gaines GC, Welborn MB 3rd, et al.: Anticytokine induced proliferation of spinal cord astrocytes is mediated by therapies for acute inflammation and the systemic inflammatory kappa opioid activation of p38 mitogen-activated protein kinase. J response syndrome: IL-10 and ischemia/reperfusion injury as a new paradigm. Shock 2000, 13:425–434.
38. • Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW: 21. Merrill JE, Benveniste EN: Cytokines in inflammatory brain Ibudilast (AV-411). A new class therapeutic candidate for lesions: helpful and harmful. Trends Neurosci 1996, 19:331– neuropathic pain and opioid withdrawal syndromes. Expert Opin Investig Drugs 2007, 16:935–950. This review details the 22. Fontaine V, Mohand-Said S, Hanoteau N, et al.: Neurodegener- effectiveness of ibudilast in the management of opioid tolerance ative and neuroprotective effects of tumor necrosis factor (TNF) in retinal ischemia: opposite roles of TNF receptor 1 and TNF 39. Kishi Y, Ohta S, Kasuya N, et al.: Ibudilast: a non-selective PDE receptor 2. J Neurosci 2002, 22:RC216.
inhibitor with multiple actions on blood cells and the vascular 23. Tanga FY, Nutile-McMenemy N, Deleo JA: The CNS role of Toll- wall. Cardiovasc Drug Rev 2001, 19:215–225.
like receptor 4 in innate neuroimmunity and painful neuropathy.
40. Fujimoto T, Sakoda S, Fujimura H, Yanagihara T: Ibudilast, a Proc Natl Acad Sci U S A 2005, 102: 5856–5861.
phosphodiesterase inhibitor, ameliorates experimental autoim- 24. Kim D, Kim MA, Cho IH, et al.: A critical role of toll-like mune encephalomyelitis in Dark August rats. J Neuroimmunol receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem 2007, 41. Feng J, Misu T, Fujihara K, et al.: Ibudilast, a nonselective phosphodiesterase inhibitor, regulates Th1/Th2 balance and NKT 25. Muzio M, Mantovani A: Toll-like receptors (TLRs) signalling and cell subset in multiple sclerosis. Mult Scler 2004, 10:494–498.
expression pattern. J Endotoxin Res 2001, 7:297–300.
42. Harris GC, Aston-Jones G: Involvement of D2 dopamine 26. •• Guo LH, Schluesener HJ: The innate immunity of the central receptors in the nucleus accumbens in the opiate withdrawal nervous system in chronic pain: the role of Toll-like receptors.
syndrome. Nature 1994, 371:155–157.
Cell Mol Life Sci 2007, 64:1128–1136. This article offers a 43. • Bland ST, Hutchinson MR, Maier SF, et al.: The glial activation detailed discussion on TLRs and their role in the development of inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release. Brain Behav Immun 2009, 23:492–497. This 27. Takeda K, Akira S: TLR signaling pathways. Semin Immunol review discusses the mechanism of action of AV411 and its 28. •• Watkins LR, Hutchinson MR, Rice KC, Maier SF: The “toll” of 44. Kest B, Mogil JS, Shamgar BE, et al.: The NMDA receptor opioid-induced glial activation: improving the clinical efficacy of antagonist MK-801 protects against the development of morphine opioids by targeting glia. Trends Pharmacol Sci 2009, 30:581– tolerance after intrathecal administration. Proc West Pharmacol 591. This is a very recent review of TLR receptors and the current foci of interest in the management of dependence, reward, and 45. Guo RX, Zhang M, Liu W, et al.: NMDA receptors are involved in upstream of the spinal JNK activation in morphine antinoci- 29. Kakimura J, Kitamura Y, Takata K, et al.: Microglial activation ceptive tolerance. Neurosci Lett 2009, 467:95–99.
and amyloid-beta clearance induced by exogenous heat-shock 46. Morgan MM, Bobeck EN, Ingram SL: Glutamate modulation of proteins. FASEB J 2002, 16:601–603.
antinociception, but not tolerance, produced by morphine micro- 30. Tsuda M, Shigemoto-Mogami Y, Koizumi S, et al.: P2X4 injection into the periaqueductal gray of the rat. Brain Res 2009, receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003, 424:778–783.
47. Schmidt AP, Tort AB, Silveira PP, et al.: The NMDA antagonist 31. Horvath RJ, DeLeo JA: Morphine enhances microglial migration MK-801 induces hyperalgesia and increases CSF excitatory amino through modulation of P2X4 receptor signaling. J Neurosci 2009, acids in rats: reversal by guanosine. Pharmacol Biochem Behav 48. Sweitzer SM, Pahl JL, DeLeo JA: Propentofylline attenuates 55. Zanjani TM, Sabetkasaei M, Mosaffa N, et al.: Suppression of vincristine-induced peripheral neuropathy in the rat. Neurosci Lett interleukin-6 by minocycline in a rat model of neuropathic pain.
49. Gwak YS, Crown ED, Unabia GC, Hulsebosch CE: Propentofylline 56. Piao ZG, Cho IH, Park CK, et al.: Activation of glia and attenuates allodynia, glial activation and modulates GABAergic tone microglial p38 MAPK in medullary dorsal horn contributes to after spinal cord injury in the rat. Pain 2008, 138:410–422.
tactile hypersensitivity following trigeminal sensory nerve injury.
50. Narita M, Miyatake M, Narita M, et al.: Direct evidence of astrocytic modulation in the development of rewarding effects 57. Cui Y, Liao XX, Liu W, et al.: A novel role of minocycline: induced by drugs of abuse. Neuropsychopharmacology 2006, attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia. Brain Behav Immun 51. Mika J, Wawrzczak-Bargiela A, Osikowicz M, et al.: Attenua- tion of morphine tolerance by minocycline and pentoxifylline in 58. Wei T, Sabsovich I, Guo TZ, et al.: Pentoxifylline attenuates naive and neuropathic mice. Brain Behav Immun 2009, 23:75– nociceptive sensitization and cytokine expression in a tibia fracture rat model of complex regional pain syndrome. Eur J Pain 52. Kim HS, Suh YH: Minocycline and neurodegenerative diseases.
Behav Brain Res 2009, 196:168–179.
59. Dorazil-Dudzik M, Mika J, Schafer MK, et al.: The effects of 53. Li WW, Setzu A, Zhao C, Franklin RJ: Minocycline-mediated local pentoxifylline and propentofylline treatment on formalin- inhibition of microglia activation impairs oligodendrocyte pro- induced pain and tumor necrosis factor-alpha messenger RNA genitor cell responses and remyelination in a non-immune model levels in the inflamed tissue of the rat paw. Anesth Analg 2004, of demyelination. J Neuroimmunol 2005, 158:58–66.
54. Ledeboer A, Sloane EM, Milligan ED, et al.: Minocycline attenuates 60. Liu J, Feng X, Yu M, et al.: Pentoxifylline attenuates the mechanical allodynia and proinflammatory cytokine expression in rat development of hyperalgesia in a rat model of neuropathic pain.
models of pain facilitation. Pain 2005, 115:71–83.
1. Introduction An eZee electric bicycle looks exactly like a conventional bicycle, but is fitted with a state of the art electric motor, battery and controller system. It encourages cycling through providing all the gain of conventional cycling, but without the pain. Off course, at any time the bicycle can be peddled like a normal bicycle if desired, with the electric motor augmenting