Effects of multiple intracerebroventricular injections of [d-Pen2,d-Pen5]enkephalin and [d-Ala2,Glu4]deltorphin II on tolerance to their analgesic action and on brain δ-opioid receptors

doi:10.1016/S0006-8993(96)01156-0

Brain Research

Volume 745, Issues 1–2, 16 January 1997, Pages 243-247

https://doi.org/10.1016/S0006-8993(96)01156-0 Get rights and content

Abstract

Male Swiss–Webster mice were injected intracerebroventricularly (i.c.v.) with [d-Pen²,d-Pen⁵]enkephalin (DPDPE), a δ₁-opioid receptor agonist (20 μg per mouse) twice a day for either 2 or 4 days. Vehicle injected mice served as controls. Treatment of mice with DPDPE for 2 or 4 days decreased its analgesic response by 44 and 76%, respectively in comparison to vehicle injected mice. Treatment of mice with DPDPE for 2 or 4 days decreased the receptor density (B_max) of [³H]DPDPE to bind to brain homogenates by 77 and 76%, respectively, in comparison to vehicle injected controls but the apparent dissociation constant (K_d) values were not altered. The effects of i.c.v. injections of [d-Ala²,Glu⁴]deltorphin II (deltorphin II), a δ₂-opioid receptor agonist (20 μg per mouse) twice a day for either 2 or 4 days on its analgesic response as well as on brain receptors for [³H]DPDPE were also determined. The analgesic response to deltorphin II decreased by 51 and 78%, respectively in mice treated with deltorphin II for 2 or 4 days, respectively. Two or four days treatment with deltorphin II decreased the B_max of [³H]DPDPE by 76 and 87%, respectively. The 2-day treatment also increased the K_d value by 58%, but the 4-day treatment with deltorphin II had no effect on the K_d of [³H]DPDPE to bind to brain membranes. Thus, multiple injections of δ₁- or δ₂-opioid receptor agonists result in the development of tolerance to their analgesic action and the intensity of tolerance increases with the duration of treatment. Both δ₁- and δ₂-opioid receptor agonist, on chronic administration, result in the down-regulation of δ₁-opioid receptors labeled with [³H]DPDPE.

Introduction

It is now well accepted that opioid drugs produce their analgesic action by interacting with three major types of receptors, namely μ, δ, and κ. The agonists at these receptors on chronic administration produced tolerance to their analgesic actions. The molecular mechanisms involved in the production of tolerance are not well delineated, although they may involve first, second or even the third messenger systems [2]. In general it has been reported that tolerance is associated with down-regulation of the specific receptors in the brain and/or spinal cord [1]. Much attention has been paid to the existence of subtypes of each of the opioid receptors. Considerable evidence has been presented for the existence of δ₁- and δ₂-opioid receptors as δ-opioid receptors subtypes. The agonists at these receptors are [d-Pen²,d-Pen⁵]enkephalin (DPDPE) and [d-Ala²,Glu⁴]deltorphin II (deltorphin II), respectively [13]. This classification is based upon the fact that there is a lack of cross-tolerance between DPDPE and deltorphin II [13]. Differential antagonism of δ-opioid receptor agonists, DPDPE and deltorphin II — induced analgesia by the irreversible δ₁- and δ₂-opioid receptor antagonists, [d-Ala²,Leu⁵,Cys⁶]enkephalin and naltrindole-5¹-isothiocyanate, respectively, also suggested the possibility of δ-opioid receptor subtypes [9].

Further behavioral evidence for the heterogeneity of δ-opioid receptors was obtained when chronic administration of highly selective δ₁ antagonist, 7-benzylidene-7-dehydronaltrexone (BNTX) enhanced the analgesic response to DPDPE but not to deltorphin II. Similarly, chronic administration of naltriben, a highly selective δ₂-opioid receptor antagonist enhanced the analgesic response to deltorphin II but not to DPDPE [6].

On the other hand, there have been instances where δ₁- and δ₂-opioid receptor could not be distinguished. For instance, tolerance to both DPDPE and deltorphin II could be blocked by N-methyl-d-aspartate (NMDA) receptor antagonists 3, 15but not by nitric oxide synthase inhibitors 4, 16. Similarly, NMDA receptor antagonists have been shown to antagonize both δ₁- and δ₂-opioid receptor agonist-induced antinociception in mice [5].

In order to further assess the heterogeneity of δ-opioid receptors, the present studies were carried out to determine the effects of twice daily i.c.v. injections of DPDPE and deltorphin II for 2 or 4 days durations on the tolerance development as well brain δ-opioid receptor labeled with [³H]DPDPE.

Section snippets

Animals

Male Swiss–Webster mice weighing 25–30 g (Sasco King Animal Co., Oregon, WI) were housed five to a cage in a room with controlled temperature (23±1°C), humidity (50±10%) and light (06.00 h–18.00 h) for at least 4 days before being used. Food and water were made available continuously.

Chemicals

DPDPE, deltorphin II and [³H]DPDPE (specific activity 18 Ci/mmol) were obtained from the Research Technology Branch, National Institute on Drug Abuse, Rockville, MD, through the courtesy of Mr. Kevin Gormley. DPDPE

Effects of multiple injections of [d-Pen²,d-Pen⁵]enkephalin or deltorphin II on tolerance to their analgesic action

Multiple i.c.v. injections of DPDPE resulted in the development of tolerance to its analgesic action in mice. After 2 days of twice daily injections, the analgesic response to DPDPE (10 μg per mouse) in mice was decreased by 44% (P<0.05) in comparison to vehicle injected control mice (Fig. 1A). After 4 days of twice daily injections, the analgesic response to DPDPE was decreased by 76% (P<0.01) in comparison to vehicle injected control mice (Fig. 1B).

Multiple i.c.v. injections of deltorphin II

Discussion

The present studies were designed to assess the impact of treatment with DPDPE and deltorphin II, the two selective ligands for δ₁- and δ₂-opioid receptor, for different duration on the tolerance development as well as changes in the brain δ-opioid receptor in the mouse. Additionally, the impact of chronic treatment with δ₂-opioid receptor agonist on the brain δ₁-opioid receptor was also determined. Clearly in the present investigation both δ₁- and δ₂-opioid receptor agonists on chronic i.c.v.

Acknowledgements

These studies were supported by Grant DA-08867 and a Research Scientist Development Award, K02-DA-00130, from the National Institute on Drug Abuse. The authors thank Mrs. Celina Tejada for secretarial assistance.

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Differential noxious and motor tolerance of chronic delta opioid receptor agonists in rodents
2009, Neuroscience
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To see whether tolerance to deltorphin II might differently developed in various behaviors, we therefore used mice to measure the effects of deltorphin II in different paradigms. A number of groups have already reported antinociceptive tolerance following repeated exposure to DOPR-selective agonists (Bhargava and Zhao, 1996; Tseng et al., 1997; Zhao and Bhargava, 1997; Broom et al., 2002). Using the hot water immersion tail flick test, we first confirmed that single intrathecal injection of deltorphin II induced a transient antinociceptive effect in mice.
In the present study, we asked whether multiple intrathecal injections of deltorphin II, a selective delta opioid receptor (DOPR) agonist, induced DOPR tolerance in three behavioral assays. Unilateral inflammation caused by complete Freund's adjuvant (CFA) injection into the rat or mouse hind paw (CFA model) induced thermal hyperalgesic response that was transiently and dose-dependently reduced by intrathecal administration of deltorphin II or morphine. In both rodent species, the effect of deltorphin II was not modified by a single prior administration of deltorphin II, suggesting an absence of acute tolerance in this paradigm. Repeated administration of intrathecal deltorphin II or s.c. SB-235863 (five consecutive injections over 60 h) also failed to impair the antihyperalgesic response to delta opioid receptor agonist, whereas repeated intrathecal or s.c. injections of morphine induced a significant decrease in the subsequent thermal antihyperalgesic response to morphine. In mice, deltorphin II also induced a rapid, transient motor incoordination/ataxia-like behavior as tested with the accelerating rotarod. In contrast to the antihyperalgesic responses, tolerance to the motoric effect of deltorphin II was evident in mice previously exposed to multiple intrathecal agonist injections, but not multiple saline administrations. Using the tail flick antinociceptive test, we found that DOPR-mediated analgesia was significantly reduced by repeated exposure to deltorphin II. Altogether, these observations suggest that repeated injections of DOPR agonists induce differential tolerance effects on antihyperalgesic, antinociceptive, and motor incoordination/ataxia-like behaviors related to DOPR activation by deltorphin II.
Modulation Between High- and Low-Frequency Transcutaneous Electric Nerve Stimulation Delays the Development of Analgesic Tolerance in Arthritic Rats
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This tolerance is delayed when compared to previous studies showing that tolerance to either low- or high-frequency TENS develops by the fourth day.4 We propose that the development of tolerance is a result of tolerance at μ- and δ-opioid receptors in the spinal cord as observed in previous studies with TENS4 and in pharmacologic studies that show repeated administration of μ- and δ-opioid agonists spinally or supraspinally leading to a development of tolerance.8,9,30 Both spinally and supraspinally located μ- and δ-opioid receptors mediate the analgesic effects of low- and high-frequency TENS, respectively.6,7
DeSantana JM, Santana-Filho VJ, Sluka KA. Modulation between high- and low-frequency transcutaneous electric nerve stimulation delays the development of analgesic tolerance in arthritic rats.
To investigate whether repeated administration of modulating frequency transcutaneous electric nerve stimulation (TENS) prevents development of analgesic tolerance.
Knee joint inflammation (3% carrageenan and kaolin) was induced in rats. Either mixed or alternating frequency was administered daily (20min) for 2 weeks to the inflamed knee under light halothane anesthesia (1%–2%).
Laboratory.
Adult male Sprague-Dawley rats (N=36).
Mixed- (4Hz and 100Hz) or alternating- (4Hz on 1 day; 100Hz on the next day) frequency TENS at sensory intensity and 100μs pulse duration.
Paw and joint withdrawal thresholds to mechanical stimuli were assessed before induction of inflammation, and before and after daily application of TENS.
The reduced paw and joint withdrawal thresholds that occur 24 hours after the induction of inflammation were significantly reversed by the first administration of TENS when compared with sham treatment or to the condition before TENS treatment, which was observed through day 9. By the tenth day, repeated daily administration of either mixed- or alternating-frequency TENS did not reverse the decreased paw and joint withdrawal thresholds.
These data suggest that repeated administration of modulating frequency TENS leads to a development of opioid tolerance. However, this tolerance effect is delayed by approximately 5 days compared with administration of low- or high-frequency TENS independently. Clinically, we can infer that a treatment schedule of repeated daily TENS administration will result in a tolerance effect. Moreover, modulating low and high frequency TENS seems to produce a better analgesic effect and tolerance is slower to develop.
Blockade of NMDA Receptors Prevents Analgesic Tolerance to Repeated Transcutaneous Electrical Nerve Stimulation (TENS) in Rats
2008, Journal of Pain
Citation Excerpt :
The increase in spinal glutamate in morphine tolerant rats is reduced by pretreatment with NMDA receptor antagonist MK-801.48 In parallel, repeated administration of μ- and δ-opioid agonists increases the MK-801 binding affinity both spinally and supraspinally,50,53 supporting the hypothesis that there is a potentiation of NMDA receptors after the development of tolerance. In contrast, there is an increase in expression of vesicular glutamate transporter 1 in the spinal cord after chronic morphine in mice.44
Repeated daily application of transcutaneous electrical nerve stimulation (TENS) results in tolerance, at spinal opioid receptors, to the antihyperalgesia produced by TENS. Since N-methyl-D-aspartate (NMDA) receptor antagonists prevent analgesic tolerance to opioid agonists, we hypothesized that blockade of NMDA receptors will prevent tolerance to TENS. In rats with knee joint inflammation, TENS was applied for 20 minutes daily at high-frequency (100 Hz), low-frequency (4 Hz), or sham TENS. Rats were treated with the NMDA antagonist MK-801 (0.01 mg/kg to 0.1 mg/kg) or vehicle daily before TENS. Paw withdrawal thresholds were tested before and after inflammation and before and after TENS treatment for 4 days. On day 1, TENS reversed the decreased mechanical withdrawal threshold induced by joint inflammation. On day 4, TENS had no effect on the decreased withdrawal threshold in the group treated with vehicle, demonstrating development of tolerance. However, in the group treated with 0.1 mg/kg MK-801, TENS significantly reversed the mechanical withdrawal thresholds on day 4, demonstrating that tolerance did not develop. Vehicle-treated animals developed cross-tolerance at spinal opioid receptors. Treatment with MK-801 reversed this cross-tolerance at spinal opioid receptors. In summary, blockade of NMDA receptors prevents analgesic tolerance to daily TENS by preventing tolerance at spinal opioid receptors.
Observed tolerance to the clinical treatment of TENS could be prevented by administration of pharmaceutical agents with NMDA receptors activity such as ketamine or dextromethorphan.
Melatonin attenuates the development of antinociceptive tolerance to delta-, but not to mu-opioid receptor agonist in mice
2007, Behavioural Brain Research
The effects of melatonin (Mel) on the development of tolerance to antinociceptive actions induced by mu- and delta-opioid receptor agonists were determined in male Kunming mice. In the mouse tail-flick tests, selective mu and delta receptor agonists were repeatedly administered to mice supraspinally (intracerebroventricularly, i.c.v.) in the absence or presence of melatonin. Administration of endomorphin-1 (EM-1, a mu-opioid receptor agonist) or deltorphin I (del I, a delta-opioid receptor agonist) twice daily for 4 days produced antinociceptive tolerance compared with vehicle controls. Co-administration with melatonin prevented the development of tolerance to deltorphin I analgesia, and this effect was dose dependent. However, melatonin did not affect the development of antinociceptive tolerance to endomorphin-1. Additionally, the attenuation of deltorphin I tolerance by melatonin was reduced by chronic treatment with luzindole (luz), a selective antagonist on the MT₂ receptor subtype. Taken together, these data suggest that melatonin interferes with the neural mechanisms involved in the development of tolerance to delta-opioid agonist analgesia via its receptor.
Development of opioid tolerance with repeated transcutaneous electrical nerve stimulation administration
2003, Pain
The analgesia produced by low and high frequency transcutaneous electrical nerve stimulation (TENS) is mediated by the release of μ- or δ-opioids, respectively in the central nervous system. Repeated administration of either μ- or δ-opioid agonists induce opioid analgesic tolerance. Thus, we tested if repeated administration of TENS (either low or high frequency) in rats leads to a development of tolerance to its antihyperalgesic effects with a corresponding cross-tolerance to μ- and δ-opioid agonists. Unilateral knee joint inflammation (3% carrageenan) was induced in adult Sprague–Dawley rats. Either low (4 Hz) or high frequency (100 Hz) TENS was administered for 6 days (20 min daily) to the inflamed knee joint under halothane anesthesia. The no TENS controls were administered anesthesia only for the same period. Withdrawal threshold to mechanical stimuli was measured before and after administration of TENS on each day and also on the sixth day. A separate group of animals was tested for tolerance to either the μ-opioid agonist, morphine (1.32, 3.95, 13.2 nmol/10 ml, intrathecal (i.t.)) or the δ-opioid agonist, SNC-80 (6, 20, 60, 120 nmol/10 ml, i.t.) 30 min after i.t. administration. The reduced mechanical withdrawal threshold following the induction of inflammation was reversed by the application of TENS. However, repeatedly administering either low or high frequency TENS for 6 days, lead to a diminution in its effectiveness in reversing the ipsilateral secondary mechanical hyperalgesia by the fourth day. The effects of morphine in the low and SNC-80 in the high frequency TENS groups were significantly less than the group that did not receive TENS. On the other hand, morphine and SNC-80 were similar to the no TENS control in the high and low frequency TENS groups, respectively. Thus, repeated administration of low and high frequency TENS leads to a development of opioid tolerance with a corresponding cross-tolerance to i.t. administered μ- and δ-opioid agonists, respectively. Clinically, it can be inferred that a treatment schedule of repeated daily TENS administration should be avoided to possibly obviate the induction of tolerance.
Agonist-specific down-regulation of the human δ-opioid receptor
2003, European Journal of Pharmacology
Down-regulation of the δ-opioid receptor contributes to the development of tolerance to δ-opioid receptor agonists. The involvement of the carboxy terminus of the mouse δ-opioid receptor in peptide agonist-mediated down-regulation has been established. In the present study, we examined the down-regulation of the truncated human δ-opioid receptor by structurally distinct δ-opioid receptor agonists. Chinese hamster ovary (CHO) cells, expressing the full-length or truncated epitope-tagged human δ-opioid receptors were incubated with various δ-opioid receptor agonists (100 nM, 24 h), and membrane receptor levels were determined by [³H]naltrindole saturation binding. Each δ-opioid receptor agonist tested down-regulated the full-length receptor. Truncation of the carboxy terminus abolished down-regulation by all δ-opioid receptor agonists, except SNC80 ((+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]N,N-diethylbenzamide). In addition, truncation of the C-terminus completely attenuated [d-Pen²-d-Pen⁵]enkephalin (DPDPE), but not SNC80-mediated [³²P] incorporation into the protein immunoreactive with an anti-epitope-tagged antibody. These findings suggest that SNC80-mediated phosphorylation and down-regulation of the human δ-opioid receptor involves other receptor domains in addition to the carboxy terminus. Pertussis toxin treatment did not block SNC80-mediated down-regulation of the truncated Et-hDOR, indicating that the down-regulation is independent of G_i/o protein activation and subsequent downstream signaling.

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Brain Research

Research reportEffects of multiple intracerebroventricular injections of [d-Pen2,d-Pen5]enkephalin and [d-Ala2,Glu4]deltorphin II on tolerance to their analgesic action and on brain δ-opioid receptors

Abstract

Introduction

Section snippets

Animals

Chemicals

Effects of multiple injections of [d-Pen2,d-Pen5]enkephalin or deltorphin II on tolerance to their analgesic action

Discussion

Acknowledgements

Differential noxious and motor tolerance of chronic delta opioid receptor agonists in rodents

Modulation Between High- and Low-Frequency Transcutaneous Electric Nerve Stimulation Delays the Development of Analgesic Tolerance in Arthritic Rats

Blockade of NMDA Receptors Prevents Analgesic Tolerance to Repeated Transcutaneous Electrical Nerve Stimulation (TENS) in Rats

Melatonin attenuates the development of antinociceptive tolerance to delta-, but not to mu-opioid receptor agonist in mice

Development of opioid tolerance with repeated transcutaneous electrical nerve stimulation administration

Agonist-specific down-regulation of the human δ-opioid receptor

Research report
Effects of multiple intracerebroventricular injections of [d-Pen²,d-Pen⁵]enkephalin and [d-Ala²,Glu⁴]deltorphin II on tolerance to their analgesic action and on brain δ-opioid receptors

Effects of multiple injections of [d-Pen²,d-Pen⁵]enkephalin or deltorphin II on tolerance to their analgesic action