![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
Department of Anesthesiology, University of California-San Diego, La Jolla, California
Received April 8, 2005; accepted May 18, 2005.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
; Abbadie et al., 2001). Inhibition of voltage-gated calcium channels (Schroeder et al., 1991) via the activation of presynaptic µ opioid receptors, which may serve to reduce the release from primary afferents of excitatory neurotransmitters or neuromodulators, such as SP (Jessell and Iversen, 1977; Yaksh et al., 1980; Chang et al., 1989), has been implicated as one of the potential mechanisms in spinal opiate analgesia.
With continuous i.t. administration of µ agonists such as morphine or DAMGO, a progressive time-dependent loss of analgesia has been observed. This loss of effect with the continued presence of drug, defined as tolerance, can be overcome by increasing the agonist dose. Thus, after persistent exposure, there is a right shift in the i.t. morphine or DAMGO dose-response curve (Stevens and Yaksh, 1989b). In this model, the phenomenon of spinal dependence is revealed by the appearance of agitation and hyperalgesia when the spinal opiate is discontinued or a pharmacological antagonist is administered, reflecting withdrawal (Stevens and Yaksh, 1989a).
The cellular and molecular mechanism of opioid tolerance and dependence has long been a subject of interest (Mao et al., 1995; Waldhoer et al., 2004). A variety of mechanisms have been posited, including 1) changes in receptor number, function, or coupling (Harrison et al., 1998; Bohn et al., 2000); 2) changes in system-level function wherein there is an increase in the neuronal excitability secondary to increases in, for example, NMDA receptor functions (Inoue et al., 2003); 3) phosphorylating activity of protein kinase C (Mao et al., 1995; Granados-Soto et al., 2000); and 4) the expression of "antiopiate" systems such as dynorphin or cholecystokinin (Harrison et al., 1998; Ossipov et al., 2004). Given the well defined loss of effect with long-term exposure of spinal morphine and the evident effect of spinal µ agonists on SP release, we were interested in determining whether persistent spinal opioid receptor activation modulates primary afferent SP release and whether this modulation correlates with changes in analgesia and withdrawal observed with continuous spinal opiate exposure. Quantification of NK1r internalization in spinal dorsal horn neurons by immunocytochemistry has been used as a measurement for endogenous SP release, a method that has been widely reported (Abbadie et al., 1997; Marvizon et al., 1997; Trafton et al., 1999). We recently demonstrated that intrathecal (i.t.) morphine and DAMGO, at doses that produce analgesia, prevents afferent stimulation-induced NK1r internalization (Kondo et al., 2005). Accordingly, in the present study, we aimed to investigate 1) whether there are changes in resting or noxious stimulation-evoked spinal SP release during chronic i.t. morphine infusion in association with the development of tolerance; and 2) whether naloxone-precipitated morphine withdrawal would evoke spinal SP release, a reflection of terminal dependence and withdrawal.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Animal Preparation
Intrathecal Catheter Implantation and Morphine Infusion. Rats were implanted with a single i.t. catheter for morphine delivery. Briefly, rats were anesthetized by induction with 4% isoflurane in a room air/oxygen mixture (1:1), and the anesthesia was maintained with 2% isoflurane delivered by mask. The animal was placed in a stereotaxic head-holder with the head flexed forward. A midline incision was made on the back of the occipital bone and the neck to expose the cisternal membrane. The membrane was carefully opened with a stab blade, and a single lumen polyethylene-5 (outer diameter 0.36 mm) catheter (8.5 cm) was inserted and passed into the intrathecal space surrounding L3-L4 spinal segments. The other end of the catheter was connected to an Alzet osmotic mini-pump (flow rate 1 µl/h, model 2001; Alzet, Palo Alto, CA) prefilled with drug solution and inserted into a subcutaneous pouch between medial borders of the scapulas. In studies of dependence, groups of rats were implanted as described above with a double lumen intrathecal catheter (outer diameter 0.36 x 0.71 mm, 8 cm) as described previously (Hayes et al., 2003). After the procedures of i.t. catheter implantation described above, one of the lumens was connected to an osmotic minipump. The other free end was externalized on the forehead and used for drug administration. Rats showing motor weakness or signs of paresis upon recovery from anesthesia were eliminated from the experiment and euthanized immediately.
Assessment of Thermal Nociception. To determine the development of morphine tolerance, the latency of the hind paw withdrawal evoked by thermal stimulation was evaluated using a modified Hargreaves Box (Dirig et al., 1997) on days 0, 1, 3, and 5 (day 0 refers to the day of i.t. implantation). Briefly, animals were placed on a 30°C temperature glass surface inside Plexiglas cages. A radiant lamp stimulus was focused on the plantar surface of the hind paw. The lamp and timer were immediately turned off by an abrupt withdrawal of the hind paw to the stimulus by a photocell sensor. In the absence of withdrawal, the lamp and timer automatically turned off at 20 s (cut-off time) after stimulus onset. Thermal escape latency data were expressed as percentage of maximal possible effect, defined as (postdrug latency - baseline) x 100/(cutoff time - baseline).
Study Paradigms
Chronic Morphine-Induced Analgesic Tolerance. Groups of rats were implanted with i.t. catheters linked to osmotic pumps as described above. Pumps were preloaded to deliver saline (1 µl/h) or morphine sulfate (40 nmol/µl/h). Rats were tested at days 0, 1, 3, and 5 after implant for their thermal escape latency.
Paw Compression-Evoked NK1r Internalization in Intrathecal Morphine-Infused Animals. Rats were prepared as described above with intrathecal catheters and subcutaneous minipumps filled to deliver saline or morphine sulfate (40 nmol/µl). On day 1 or 6 after i.t. infusion, animals were anesthetized with sodium pentobarbital (50 mg/kg i.p.). This dose blocked the flexor reflex to hind paw stimulation. The left hind paw was positioned perpendicularly across the midpoint of jaws of a 6' mosquito forceps. The nonserrated jaws were closed to the third click, and the compression was applied for 60 s. Five minutes later, animals were perfusion-fixed, and the spinal cords were harvested for NK1r immunostaining (see Immunocytochemistry).
Morphine Withdrawal-Induced NK1r Internalization. Rats received 6-day i.t. infusions of saline or morphine sulfate (40 nmol/µl). On day 6, morphine withdrawal was induced by a single injection of the opioid antagonist naloxone (0.6 mg/kg i.p.). Thirty minutes before injection of naloxone, animals were placed in Plexiglas cylinder for acclimation. Withdrawal signs were scored at 10, 20, 30, and 60 min after the injection of naloxone. Those signs included allodynia to light touch, spontaneous vocalization, abnormal body posture, ejaculation, urination, diarrhea, exophthalmos, piloerection, headshakes, hind limb extension, chewing/licking, and tremor. The scores ranged from 0 to 3 (0, none; 1, minor; 2, moderate; and 3, severe). In general, minor withdrawal behavior means noticeable change in the parameters being evaluated with occasional episodes, moderate withdrawal shows obvious changes in these clinical observations with frequent episodes, and severe means significant changes with constant occurrence. For example, allodynia was rated as minor, one to three vocalizations during 10 gentle strokes with a light brush; moderate, four to six of 10 strokes; and severe, seven to 10 of 10 strokes. Animals were sacrificed at 10, 30, and 60 min after naloxone, and their spinal cords were dissected out for the examination of NK1r internalization.
In addition, we carried out pharmacological studies to characterize morphine withdrawal-induced NK1r internalization. In these animals prepared with double lumen catheters, spinal morphine was continuously delivered through one of the lumens, and the other lumen was used for the following purposes: 1) spinal NK1r antagonism: a group of rats were pretreated with the NK1r antagonist L-703,606 (50 nmol/10 µl i.t.) (Marvizon et al., 1997), 15 min before naloxone; 2) depletion of SP in small sensory afferent by capsaicin pretreatment: a group of animals was pretreated with capsaicin (75 µg/10 µl i.t.) 3 days before i.p. naloxone injection (Jessell et al., 1978; Gamse et al., 1981); and 3) NMDA receptor antagonism: a group of rats were pretreated with the competitive NMDA receptor antagonist AP-5 (10 µg/10 µl i.t.) (Hua et al., 2004), 15 min before naloxone. All animals were sacrificed 10 min after naloxone for the examination of NK1r internalization.
Immunocytochemistry
Tissue Preparation. Anesthetized animals were perfused transcardially with 50 to 100 ml 0.9% NaCl followed by 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.4. Lumbar spinal cord was removed by laminectomy and postfixed in the same fixative overnight. After cryoprotection in 20% sucrose, 30-µm transverse (coronal) or 35-µm sagittal sections were cut through the lumbar cord using a Leica cryostat. Immunofluorescence staining was performed to examine NK1r expression in the spinal dorsal horn. Briefly, sections were incubated in a rabbit anti-NK1r polyclonal antibody (Advanced Targeting Systems, San Diego, CA) overnight at room temperature. The antibody was diluted to the concentration of 1:3000 in 0.01 M PBS containing 10% normal goat serum and 0.3% Triton X-100. After rinses in PBS, sections were then incubated for 90 min at room temperature in a goat anti-rabbit secondary antibody conjugated with Alexa 488 (Molecular Probes, Eugene, OR) diluted at 1:1000 in 0.01 M PBS containing 5% normal goat serum and 0.5% Triton X-100. All sections were finally rinsed and mounted on silane-coated glass slides (Sigma, St. Louis, MO) and coverslipped with ProLong mounting medium (Molecular Probes).
Quantification of NK1r Internalization. NK1r internalization was counted under an Olympus fluorescence microscope at 40x magnification and followed the standard of the previous reports (Mantyh et al., 1995; Abbadie et al., 1997; Marvizon et al., 1997; Trafton et al., 1999). The total number of NK1r-immunoreactive neurons in lamina I and II, with or without NK1r internalization, was counted and presented as the percentage of NK1r-positive neurons with internalization versus total NK1r-immunoreactive cells. Neuronal profiles that have 10 or more endosomes in their soma and the contiguous proximal dendrites were considered to have internalized NK1r receptors. NK1r neurons in both sides of the dorsal horn, i.e., ipsilateral and contralateral to the noxious stimulation, in each section were counted. The person counting the neurons was blinded to the treatment given to the animals and to the side of the dorsal horns. Three to five sections per segment of the lumbar spinal cord were counted and at least three animals were used for each experiment.
Confocal Microscopy and Image Processing. Confocal images of representative NK1r cells were acquired by a Leica TCS SP2 confocal system equipped with AOBS or a Bio-Rad MRC 1024 system at 100x magnification (numerical aperture 1.40). Images were acquired at a digital size of 1024 x 1024 pixels. Five to 10 adjacent optical sections (approximately 0.5 µm in thickness) along the Z-axis were projected together for demonstration. Images were processed with Adobe Photoshop software and plotted using Freehand software (Macromedia, San Francisco, CA).
Drugs
Drugs used included morphine (morphine sulfate; Merck, Rahway, NJ), naloxone hydrochloride (DuPont, Wilmington, DE), and L-703,606 and capsaicin (both Sigma). Morphine, naloxone, and AP-5 were freshly prepared in sterile 0.9% NaCl solution. Capsaicin and L-703,606 were prepared in a solution of 10% 
-hydroxypropylcyclodextrin (Wacker Chemie, Neuperlach, Germany).
Statistical Analysis
Data acquired were analyzed using Prism 3.0 for Macintosh or 4.01 for PC (GraphPad Software Inc., San Diego, CA). All data presented are presented as mean with S.E.M. The statistical significance was calculated using one-way ANOVA with Bonferroni's post hoc test. The p value of less than 0.05 is defined to be significant. Graphs were plotted using Prism software.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
|
Noxious Stimulation-Induced NK1r Internalization in Chronic Morphine-Infused Rats. Under nonstimulated conditions (naive), NK1r receptors undergo minimal internalization in the spinal dorsal horn (less than 10%). In saline-infused rats, 5 min after a unilateral mechanical paw compression, NK1r internalization was observed in neurons in lamina I of the ipsilateral but not the contralateral side of the lumbar spinal cord (Figs. 2, A and B, and 3A). Moreover, NK1r neurons with internalization were more numerous in the lower lumbar segments (e.g., L5-L6) (Fig. 3A). The profile of internalization evoked by paw compression in the saline-infused rats resembled that of NK1r internalization observed in rats without chronic i.t. infusion (Kondo et al., 2005).
|
|
In contrast to the saline-infused animals, continuous i.t. infusion of morphine (40 nmol/µl/h) for 1 day significantly decreased paw compression-induced NK1r internalization in the ipsilateral dorsal horn (Figs. 2, C and D, and 3, B and D). This effect is in parallel with the full expression of morphine analgesia on day 1, indicating that after 24-h morphine infusion, the ability of morphine to suppress spinal SP release is intact. However, once analgesic tolerance to morphine has been developed on day 6 (Fig. 1A), the paw compression evoked spinal NK1r internalization was no longer blocked by morphine (Figs. 2, E and F, and 3, C and D), indicating that after 6 days of morphine infusion and at a time when there was no observable antinociception, morphine also failed to inhibit noxious stimulation-induced SP release. Importantly, examination of the percentage of the overall NK1r internalization (total numbers of cells with internalized NK1r versus total numbers of NK1r cells without internalization) in the dorsal horn of 6-day morphine-infused rats ipsilateral to the paw compression revealed that the degree of internalization was not different from that observed in saline-infused rats (p > 0.05). Unexpectedly, the percentage of the NK1r internalization in the dorsal horn contralateral to the compression in 6-day morphine-infused rats was slightly but significantly higher than that in rats that had received i.t. saline (p < 0.05) (Table 1).
|
NK1r Internalization in Response to Morphine Withdrawal. Concomitant with the withdrawal behaviors described above, naloxone-precipitated morphine withdrawal produced an increase in NK1r internalization in lamina I neurons of the lumbar dorsal horn (66.6 ± 3.5% at 10 min) that is significantly higher than that observed in saline-infused animals that received naloxone (i.p.) (27.5 ± 2.4%; p < 0.05) or in morphine-infused animals that received saline (i.p.) injection (26.3 ± 3.9%; p < 0.05) (Figs. 4, A-C, and 5A). The time course of naloxone-evoked NK1r internalization paralleled to the time course of naloxone-induced withdrawal signs, i.e., peaking at 10 min and declining after 30 min (Fig. 5A).
|
|
). Intrathecal capsaicin pretreatment (75 µg; 3 days prior), a well known technique to deplete afferent SP (Gamse et al., 1981), which was also confirmed in the present study (SP fentomoles per milligram dorsal cord tissue extract: vehicle, 68 ± 16 versus capsaicin, 26 ± 5; p < 0.05; n = 4), blocked naloxone-evoked spinal NK1r internalization (Fig. 5B). These two observations indicate that morphine withdrawal-induced NK1r internalization is due to an increase in endogenous SP release from the primary afferents and reflects the activation of NK1r. However, AP-5, a competitive NMDA receptor antagonist, at a given dose (10 µg i.t.) which is potently antihyperalgesic (Hua et al., 2004) and effectively blocks withdrawal symptoms (data not shown; Jhamandas et al., 1996), did not alter the evoked NK1r internalization (Fig. 5B), suggesting that presynaptic NMDA receptors on primary afferents are not involved in morphine withdrawal-induced spinal SP release. |
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
; Dunbar and Yaksh, 1996). Our recent work has shown that the intrathecal delivery of µ and 
opioid agonists produces a dose-dependent, naloxone-reversible suppression of dorsal horn NK1r internalization evoked by a noxious stimulus (Kondo et al., 2005). We set out here to examine three questions with regard to the effects of chronic morphine exposure. First, is the suppression of the stimulus-evoked SP release by acute morphine lost after continuous morphine exposure, e.g., does it show tolerance? During the initial 24 h of i.t. infusion, morphine (40 nmol/h) elevated thermal escape latencies and inhibited the noxious stimulus-evoked release of SP. This finding is consistent with the effects produced by acute bolus intrathecal delivery of morphine. It indicates that the infusion paradigm was indeed associated with a behaviorally effective analgesic dose. After 6 days of morphine exposure, animals developed analgesic tolerance, i.e., they showed baseline escape latencies that were not different from preinfusion control or from animals receiving intrathecal saline infusion. At this time, the magnitude of the noxious stimulus-evoked NK1r internalization was not different from that noted in control or i.t. saline-infused animals. Thus, coincident with the loss of behavioral effect, chronic morphine had no effect upon the evoked afferent terminal release. These observations indicate that these terminals display a prominent tolerance to the inhibitory effects of opioids.
Second, does naloxone-evoked spinal SP release reflect terminal dependence? In animals exposed to chronic morphine, naloxone evoked prominent agitation, a mild hyperalgesia, and importantly, a significant increase in NK1r internalization in the dorsal horn in the absence of other stimulation. These results suggest that small afferent terminals indeed display a state of opioid dependence and a large SP release in the presence of naloxone, e.g., withdrawal.
Third, does chronic opiate exposure enhance the excitability of the SP-releasing terminals? If chronic exposure leads to enhanced terminal excitability, then there might be an increase in resting SP release and/or an enhanced release in response to a given noxious stimulus in spinal morphine-tolerant animals, indicating exaggerated reactivity to a peripheral stimulus. In the present work, after 6 days of spinal morphine infusion, baseline thermal escape latencies were not different from either preinfusion baseline or from the escape latency of i.t. saline-infused controls. Hence, these animals were not hyperalgesic. Thus, at this time, the paw compression yielded a comparable increase of NK1r internalization in the ipsilateral spinal dorsal horn in either 6-day morphine- or saline-infused animals. Examination of the basal NK1r internalization, however, in the contralateral spinal dorsal horn at the sixth day after morphine exposure revealed that there was a slight increase in constitutive NK1r internalization over that in i.t. saline-infused animals. The principal observation, however, is that in the chronic morphine-infused animals, the magnitude of SP release evoked by the stimulus is not different from that in i.t. saline-infused animals. These observations suggest that in the chronic morphine-infused animal there was an evident failure of opiate-mediated inhibition. Of equal importance is that there was no apparent facilitated excitability in primary afferent terminals.
Opiate Regulation of Primary Afferent Release of SP. In agreement with previous reports (Jessell and Iversen, 1977; Yaksh et al., 1980) as well as with our recent work (Kondo et al., 2005), data in the present study indicate that short-term (24-h) exposure to i.t. morphine at doses that are behaviorally analgesic reduces the stimulus-evoked NK1r internalization. This direct effect is considered to be an important component of the drug action leading to the potent analgesia initiated by i.t. µ opioids. Although other investigators did not see such an intrathecal block (Trafton et al., 1999), this difference is thought to reflect use of subanalgesic doses in those studies (Kondo et al., 2005). The mechanism of the opiate inhibition is by block of the opening of voltage-gated calcium channels necessary to mobilize transmitter release. This inhibitory action is thought to be mediated via activation of the Gi/Go protein and the subsequent interaction of its /
subunits with the calcium channel (Herlitze et al., 1996).
Morphine Tolerance and Spinal SP Release. The present studies emphasize that in the continuous presence of opiate agonists, there is a loss of regulatory effect. Based on the role of SP-releasing terminals in nociception, it is plausible that when morphine loses its inhibitory effect on afferent evoked release during chronic treatment, its analgesic action is correspondingly attenuated. This loss of effect with chronic exposure does not seem to be associated with an enhanced response to afferent stimuli. Hence, for the primary afferent, we do not think that the loss of opiate effect is related to a physiological antagonism, secondary to a facilitation of terminal release. A number of alternatives have been suggested, including the increased expression of antiopioid peptides such as cholecystokinin and dynorphin (Ossipov et al., 2004) or altered signaling involving the appearance of opiate coupling with stimulatory G protein (Gintzler and Chakrabarti, 2004). These results are consistent with the absence of hyperalgesia at day 6. However, our observations are in distinction to other reports (Mayer et al., 1999). We note that in such cases, once or twice daily bolus deliveries are often administered. Given the half-life of the intrathecal morphine, we suggest that this hyperalgesia is possibly a reflection of periodic withdrawal in which, as shown in these studies, spontaneous increases in C-fiber release are in fact observed. Such increases in afferent terminal release of SP or glutamate would initiate a variety of downstream events that by local effects (such as the release of prostaglandins) (Jhamandas et al., 1996; Yaksh et al., 1999) or by extra spinal circuitry (Vanderah et al., 2001) that would lead to a facilitated state of spinal nociceptive processing. Given the opioid blockade of voltage-dependent calcium channel function in regulating terminal release, it is plausible to assume that it is the failure of this coupling that accounts for the failure of inhibition. Such failure of coupling may occur in a number of ways. Previous work has shown that PKC phosphorylates receptor-coupled G protein, thereby suppressing its ability to mediate receptor-evoked inhibition of adenylyl cyclase (Katada et al., 1985; Nestler, 1993) and to regulate calcium channels (Connor et al., 1999). Intrathecal infusion of PKC inhibitors has indeed been shown to attenuate tolerance (Granados-Soto et al., 2000).
Withdrawal Evoked Release of SP. Our data clearly suggest that morphine withdrawal-induced NK1r internalization is due to the induction of SP release presynaptically from primary afferents and activation on the NK1r, since the internalization was blocked by the pretreatment of capsaicin that depletes afferent SP and by NK1r antagonist L-703,606. Although the mechanism underlying the induction of SP release by morphine withdrawal is not clear, many factors may contribute to this phenomenon. An increase in excitability of NMDA receptors has been considered to play a primary role in the development of tolerance as well as withdrawal behavior. Blockade of spinal NMDA receptors effectively attenuate withdrawal symptoms (Mao et al., 1995; Dunbar and Yaksh 1996; Jhamandas et al., 1996). Enhancement of spinal release of excitatory amino acids, including glutamate during morphine withdrawal, has been observed (Jhamandas et al., 1996; Ibuki et al., 2003). NMDA receptors are located on a variety of spinal neurons and dendrites and also on presynaptic terminals of SP-containing afferents (Liu et al., 1997). Thus, glutamate could activate presynaptic NMDA receptors that stimulate SP release (Liu et al., 1997; Marvizon et al., 1997). In the present study, however, AP-5, a competitive NMDA antagonist given at a dose adequate to block nociceptive transmission, did not affect withdrawal-evoked NK1r internalization. Our data may indicate that withdrawal-evoked SP release is not regulated via the activation of NMDA receptors. Moreover, the presynaptic NMDA effect may itself be complicated. Activation of presynaptic NMDA receptors could initiate primary afferent depolarization and inhibit glutamate release (Bardoni et al., 2004).
Although it was not investigated in the present study, other work has suggested that protein kinases such as PKC could facilitate SP release from primary sensory afferents (Frayer et al., 1999). Expression and/or phosphorylation of this enzyme are elevated in spinal cord after chronic opiate exposure (Granados-Soto et al., 2000). Moreover, morphine-induced "superactivation" of cAMP in the sensory neurons could also be involved in the withdrawal SP release (Waldhoer et al., 2004). An increase of cAMP response element-binding protein in the dorsal root ganglion in chronic morphine-treated animals has been reported (Ma et al., 2001). Upon removal of morphine, elevated cAMP may promote the release of SP (Hingtgen et al., 1995). Further studies are needed to test the hypotheses.
In conclusion, inability to suppress endogenous SP release from the primary sensory afferents seems to be an important component in spinal morphine tolerance, and excessive SP release from the primary afferents is an important component in spinal morphine withdrawal.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: SP, substance P; DAMGO, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; NMDA, N-methyl-D-aspartate; NK1r, neurokinin 1 receptor; L-703,606, cis-2-(diphenylmethyl)-N-[(2-iodophenyl)methyl]-1 azabicyclo[2.2.2]octan-3-amine; AP-5, 2-amino 5-phosphonovaleric acid; PBS, phosphate-buffered saline; ANOVA, analysis of variance; PKC, protein kinase C.
1 These authors contributed equally to this work. 
Address correspondence to. Dr. Tony L. Yaksh, Department of Anesthesiology, University of California-San Diego, 9500 Gilman Dr., La Jolla, CA 92093-0818. E-mail: tyaksh{at}ucsd.edu
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Abbadie C, Pasternak GW, and Aicher SA (2001) Presynaptic localization of the carboxy-terminus epitopes of the mu opioid receptor splice variants MOR-1C and MOR-1D in the superficial laminae of the rat spinal cord. Neuroscience 106: 833-842.[CrossRef][Medline]
Abbadie C, Trafton J, Liu H, Mantyh PW, and Basbaum AI (1997) Inflammation increases the distribution of dorsal horn neurons that internalize the neurokinin-1 receptor in response to noxious and non-noxious stimulation. J Neurosci 17: 8049-8060.
Bardoni R, Torsney C, Tong CK, Prandini M, and MacDermott AB (2004) Presynaptic NMDA receptors modulate glutamate release from primary sensory-neurons in rat spinal cord dorsal horn. J Neurosci 24: 2774-2781.
Bohn LM, Gainetdinov RR, Lin FT, Lefkowitz RJ, and Caron MG (2000) Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence. Nature (Lond) 408: 720-723.[CrossRef][Medline]
Chang HM, Berde CB, Holz GG, Steward GF, and Kream RM (1989) Sufentanil, morphine, met-enkephalin and kappa-agonist (U-50,488H) inhibit substance P release from primary sensory neurons: a model for presynaptic spinal opioid actions. Anesthesiology 70: 672-677.[CrossRef][Medline]
Connor M, Borgland SL, and Christie MJ (1999) Continued morphine modulation of calcium channel currents in acutely isolated locus coeruleus neurons from morphine-dependent rats. Br J Pharmacol 128: 1561-1569.[CrossRef][Medline]
Dirig DM, Salami A, Rathbun ML, Ozaki GT, and Yaksh TL (1997) Characterization of variables defining hindpaw withdrawal latency evoked by radiant thermal stimuli. J Neurosci Methods 76: 183-191.[CrossRef][Medline]
Dunbar S and Yaksh TL (1996) Concurrent spinal infusion of MK801 blocks spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Anesthesiology 84: 1177-1188.[CrossRef][Medline]
Fields HL, Emson PC, Leigh BK, Gilbert RF, and Iversen LL (1980) Multiple opiate receptor sites on primary afferent fibers. Nature (Lond) 284: 351-353.[CrossRef][Medline]
Frayer SM, Barber LA, and Vasko MR (1999) Activation of protein kinase C enhances peptide release from rat spinal cord slices. Neurosci Lett 265: 17-20.[CrossRef][Medline]
Gamse R, Lackner D, Gamse G, and Leeman SE (1981) Effect of capsaicin pretreatment on capsaicin-evoked release of immunoreactive somatostatin and substance P from primary sensory neurons. Naunyn-Schmiedeberg's Arch Pharmacol 316: 38-41.[CrossRef][Medline]
Gintzler AR and Chakrabarti S (2004) Chronic morphine-induced plasticity among signaling molecules. Novartis Found Symp 261: 167-176; discussion 176-180, 191-163.[Medline]
Granados-Soto V, Kalcheva I, Hua X, Newton A, and Yaksh TL (2000) Spinal PKC activity and expression: role in tolerance produced by continuous spinal morphine infusion. Pain 85: 395-404.[CrossRef][Medline]
Harrison LM, Kastin AJ, and Zadina JE (1998) Opiate tolerance and dependence: receptors, G-proteins and antiopiates. Peptides 19: 1603-1630.[CrossRef][Medline]
Hayes CS, Mulkmus SA, Cizkova D, Yaksh TL, and Hua XY (2003) A double-lumen intrathecal catheter for studies of modulation of spinal opiate tolerance. J Neurosci Methods 126: 165-173.[CrossRef][Medline]
Herlitze S, Garcia DE, Mackie K, Hille B, Scheuer T, and Catterall WA (1996) Modulation of Ca2+ channels by G-protein beta gamma subunits. Nature (Lond) 380: 258-262.[CrossRef][Medline]
Hingtgen CM, Waite KJ, and Vasko MR (1995) Prostaglandins facilitate peptide release from rat sensory neurons by activating the adenosine 3',5'-cyclic monophosphate transduction cascade. J Neurosci 15: 5411-5419.[Abstract]
Hua XY, Hayes CS, Hofer A, Fitzsimmons B, Kilk K, Langel U, Bartfai T, and Yaksh TL (2004) Galanin acts at GalR1 receptors in spinal antinociception: synergy with morphine and AP-5. J Pharmacol Exp Ther 308: 574-582.
Ibuki T, Marsala M, Masuyama T, and Yaksh TL (2003) Spinal amino acid release and repeated withdrawal in spinal morphine tolerant rats. Br J Pharmacol 138: 689-697.[CrossRef][Medline]
Inoue M, Mishina M, and Ueda H (2003) Locus-specific rescue of GluRepsilon1 NMDA receptors in mutant mice identifies the brain regions important for morphine tolerance and dependence. J Neurosci 23: 6529-6536.
Jessell TM and Iversen LL (1977) Opiate analgesics inhibit substance P release from rat trigeminal nucleus. Nature (Lond) 268: 549-551.[CrossRef][Medline]
Jessell TM, Iversen LL, and Cuello AC (1978) Capsaicin-induced depletion of substance P from primary sensory neurones. Brain Res 152: 183-188.[CrossRef][Medline]
Jhamandas KH, Marsala M, Ibuki T, and Yaksh TL (1996) Spinal amino acid release and precipitated withdrawal in rats chronically infused with spinal morphine. J Neurosci 16: 2758-2766.
Katada T, Gilman AG, Watanabe Y, Bauer S, and Jakobs KH (1985) Protein kinase C phosphorylates the inhibitory guanine-nucleotide-binding regulatory component and apparently suppresses its function in hormonal inhibition of adenylate cyclase. Eur J Biochem 151: 431-437.[Medline]
Kondo I, Marvizon JC, Song B, Salgado F, Codeluppi S, Hua XY, and Yaksh TY (2005) Inhibition by spinal µ- and 
-opioid agonists of afferent-evoked substance P release. J Neurosci 25: 3651-3660.
Liu H, Mantyh PW, and Basbaum AI (1997) NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature (Lond) 386: 721-724.[CrossRef][Medline]
Ma W, Zheng WH, Powell K, Jhamandas K, and Quirion R (2001) Chronic morphine exposure increases the phosphorylation of MAP kinases and the transcription factor CREB in dorsal root ganglion neurons: an in vitro and in vivo study. Eur J Neurosci 14: 1091-1104.[CrossRef][Medline]
Mantyh PW, Allen CJ, Ghilardi JR, Rogers SD, Mantyh CR, Liu H, Basbaum AI, Vigna SR, and Maggio JE (1995) Rapid endocytosis of a G protein-coupled receptor: substance P evoked internalization of its receptor in the rat striatum in vivo. Proc Natl Acad Sci USA 92: 2622-2626.
Mao J, Price DD, and Mayer DJ (1995) Mechanisms of hyperalgesia and morphine tolerance: a current view of their possible interactions. Pain 62: 259-274.[CrossRef][Medline]
Marvizon JC, Martinez V, Grady EF, Bunnett NW, and Mayer EA (1997) Neurokinin 1 receptor internalization in spinal cord slices induced by dorsal root stimulation is mediated by NMDA receptors. J Neurosci 17: 8129-8136.
Mayer DJ, Mao J, Holt J, and Price DD (1999) Cellular mechanisms of neuropathic pain, morphine tolerance and their interactions. Proc Natl Acad Sci USA 96: 7731-7736.
Nestler EJ (1993) Cellular responses to chronic treatment with drugs of abuse. Crit Rev Neurobiol 7: 23-39.[Medline]
Ossipov MH, Lai J, King T, Vanderah TW, Malan TP Jr, Hruby VJ, and Porreca F (2004) Antinociceptive and nociceptive actions of opioids. J Neurobiol 61: 126-148.[CrossRef][Medline]
Schroeder JE, Fischbach PS, Zheng D, and McCleskey EW (1991) Activation of mu opioid receptors inhibits transient high- and low-threshold Ca2+ currents, but spares a sustained current. Neuron 6: 13-20.[CrossRef][Medline]
Stevens CW and Yaksh TL (1989a) Opioid dependence after continuous intrathecal infusion of mu and delta opioids in the rat. NIDA Res Monogr 95: 544-545.[Medline]
Stevens CW and Yaksh TL (1989b) Potency of infused spinal antinociceptive agents is inversely related to magnitude of tolerance after continuous infusion. J Pharmacol Exp Ther 250: 1-8.
Trafton JA, Abbadie C, Marchand S, Mantyh PW, and Basbaum AI (1999) Spinal opioid analgesia: how critical is the regulation of substance P signaling? J Neurosci 19: 9642-9653.
Vanderah TW, Suenaga NM, Ossipov MH, Malan TP Jr, Lai J, and Porreca F (2001) Tonic descending facilitation from the rostral ventromedial medulla mediates opioid-induced abnormal pain and antinociceptive tolerance. J Neurosci 21: 279-286.
Waldhoer M, Bartlett SE, and Whistler JL (2004) Opioid receptors. Annu Rev Biochem 73: 953-990.[CrossRef][Medline]
Yaksh TL, Hua X-Y, Kalcheva I, Nozaki-Taguchi N, and Marsala M (1999) The spinal biology in humans and animals of pain states generated by persistent small afferent input. Proc Natl Acad Sci USA 96: 7680-7686.
Yaksh TL, Jessell TM, Gamse R, Mudge AW, and Leeman SE (1980) Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature (Lond) 286: 155-157.[CrossRef][Medline]
This article has been cited by other articles:
|
|
 |
|
  R. H. Kline IV and R. G. Wiley Spinal {micro}-Opioid Receptor-Expressing Dorsal Horn Neurons: Role in Nociception and Morphine Antinociception J. Neurosci., January 23, 2008; 28(4): 904 - 913. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
, p < 0.05.
