Involvement of hypothalamic pituitary adrenal axis on the analgesic cross-tolerance between morphine and nifedipine

Bidirectional cross-tolerance develops between opioids and Ca(2+) channel blockers relating to their antinociceptive effects; however, the role of hypothalamic pituitary adrenal (HPA) axis on this action has not been elucidated yet. We examined the analgesic cross-tolerance between morphine and nifedipine, a dihydropyridine calcium channel blocker, in intact and adrenalectomized (ADX) rats and also evaluated modification of HPA activity during this phenomenon. The tail-flick test was used to assess the nociceptive threshold. The plasma level of corticosterone, as a marker of HPA function, was measured by radioimmunoassay. Our results showed that, in sham operated rats which were chronically treated with morphine, nifedipine failed to affect nociceptive threshold but it could induce significant antinociceptive effect in ADX morphine treated animals. This effect was reversed by corticosterone replacement. Furthermore, morphine could not induce analgesic effect either in sham operated or in ADX animals that received chronic nifedipine. Chronic morphine inhibited the effect of nifedipine on corticosterone secretion but nifedipine treatment had no effect on morphine-induced corticosterone secretion. Based on these results, we can conclude that HPA axis is involved in the induction of cross-tolerance between morphine and nifedipine due to chronic morphine and not nifedipine treatment.     

Attenuation of morphine tolerance, withdrawal-induced hyperalgesia, and associated spinal inflammatory immune responses by propentofylline in rats.

The activation of glial cells and enhanced proinflammatory cytokine expression at the spinal cord has been implicated in the development of morphine tolerance, and morphine withdrawal-induced hyperalgesia. The present study investigated the effect of propentofylline, a glial modulator, on the expression of analgesic tolerance and withdrawal-induced hyperalgesia in chronic morphine-treated rats. Chronic morphine administration through repeated subcutaneous injection induced glial activation and enhanced proinflammatory cytokine levels at the lumbar spinal cord. Moreover, glial activation and enhanced proinflammatory cytokine levels exhibited a temporal correlation with the expression of morphine tolerance and hyperalgesia. Consistently, propentofylline attenuated the development of hyperalgesia and the expression of spinal analgesic tolerance to morphine. The administration of propentofylline during the induction of morphine tolerance also attenuated glial activation and proinflammatory cytokines at the L5 lumbar spinal cord. These results further support the hypothesis that spinal glia and proinflammatory cytokines contribute to the mechanisms of morphine tolerance and associated abnormal pain sensitivity.     

Involvement of hypothalamic pituitary adrenal axis on the effects of nifedipine in the development of morphine tolerance in rats

It has been shown that nifedipine, as a calcium channel blocker, can attenuate the development of tolerance to the antinociceptive effect of morphine; however, the role of HPA axis on this action has not been elucidated. We examined the effect of nifedipine on morphine analgesic tolerance in intact and adrenalectomized (ADX) rats and on HPA activity induced by morphine. Adult male rats were rendered tolerant to morphine by daily injection of morphine (15 mg/kg i.p.) for 8 days. To determine the effect of nifedipine on the development of morphine tolerance, nifedipine (1, 2 and 5 mg/kg i.p.) was injected concomitant with morphine. The tail-flick test was used to assess the nociceptive threshold, before and 30 min after morphine administration in days 1, 3, 5 and 8. Our results showed that despite the demonstration of tolerance in both ADX and sham operated rats, nifedipine in ADX rats prevented morphine tolerance development at a lower dose (2 mg/kg) than in sham operated rats, however corticosterone replacement prevented nifedipine effect in ADX rats. Acute administration of morphine produced significant increase in plasma corticosterone level, and with repeated injection, a tolerance to this neurosecretory effect was developed. Nifedipine (5 mg/kg) attenuated the acute effect of morphine, but could not block its neurosecretory tolerance.     

Role of adrenal glucocorticoids in the blockade of the development of analgesic tolerance to morphine by footshock stress exposure in mice

To elucidate the mechanism for the suppression by concurrent footshock (FS) exposure of the development of morphine tolerance, the effect of adrenalectomy and a possible participation of glucocorticoids in the mechanism were examined. The analgesic effect of morphine was potentiated in adrenalectomized (ADX) mice, and further enhancement of the effect was shown by the simultaneous exposure to FS (2 mA, 0.2 Hz, 1 sec duration for 15 min) stress, while no such effects were observed in sham-operated (Sham) animals. Daily morphine treatment developed tolerance in Sham and ADX mice. The combined treatment with FS stress suppressed the development of morphine tolerance in Sham mice, whereas such suppression was abolished by adrenalectomy. The suppression of tolerance development was restored in ADX mice by supplement of prednisolone. In contrast to FS stress which produces analgesia through an opioid receptor, forced swimming stress which exerts analgesia through a non-opioid mechanism did not affect the development of morphine tolerance in both Sham and ADX mice. Thus, an opioid mediated stress, FS, could prevent the development of morphine tolerance, and adrenal glucocorticoids play an essential role in the mechanism.     

The development of cross tolerance between ethanol and morphine

The development of tolerance to ethanol-induced analgesia and cross tolerance between ethanol and morphine was studied in mice and rats. Chronic administration of ethanol resulted in the tolerance to its analgesic effects in rats (2.8 and 3.0 g/kg) as well as in mice (2.8 and 4.0 g/kg). Implantation of morphine pellets caused the development of cross tolerance to analgesic effect of 3.0 g/kg of ethanol in rats and 2.8 g/kg of ethanol in mice. The tolerance developed to antinociceptive effects of morphine (10 mg/kg) in chronic alcoholized mice but not in chronic alcoholized rats. These results seem to support the hypothesis on the opiate-like mechanism of ethanol action.     

Deletion of guanine nucleotide binding protein alpha z subunit in mice induces a gene dose dependent tolerance to morphine

The mechanism underlying the development of tolerance to morphine is still incompletely understood. Morphine binds to opioid receptors, which in turn activates downstream second messenger cascades through heterotrimeric guanine nucleotide binding proteins (G proteins). In this paper, we show that G(z), a member of the inhibitory G protein family, plays an important role in mediating the analgesic and lethality effects of morphine after tolerance development. We blocked signaling through the G(z) second messenger cascade by genetic ablation of the alpha subunit of the G protein in mice. The Galpha(z) knockout mouse develops significantly increased tolerance to morphine, which depends on Galpha(z) gene dosage. Further experiments demonstrate that the enhanced morphine tolerance is not caused by pharmacokinetic and behavioural learning mechanisms. The results suggest that G(z) signaling pathways are involved in transducing the analgesic and lethality effects of morphine following chronic morphine treatment.     

Attenuation of morphine tolerance after antisense oligonucleotide knock-down of spinal mGluR1

1. Chronic systemic treatment of rats with morphine leads to the development of opioid tolerance. This study was designed to examine the effects of intrathecal (i.t.) infusion of a metabotropic glutamate receptor 1 (mGluR1) antisense oligonucleotide, concomitant with chronic morphine treatment, on the development of tolerance to morphine's antinociceptive effects. 2. All rats received chronic (6 day) s.c. administration of morphine to induce opioid tolerance. Additionally, rats were treated with either mGluR1 antisense (AS), missense (MIS) or artificial cerebrospinal fluid (ACSF) by i.t. infusion via chronically implanted i.t. catheters connected to osmotic mini-pumps. The effects of acute i.t. or s.c. morphine on tail-flick latencies were assessed prior to and following chronic s.c. morphine treatment for all chronic i.t. infusion groups. mGluR1 protein level in the spinal cord was determined by Western blot analysis for all treatments, assessing the efficiency of knock-down with AS treatment. 3. Acute i.t. morphine dose-dependently produced antinociception in the tail-flick test in na?ve rats. Systemic morphine-treated rats administered i.t. ACSF or MIS developed tolerance to i.t. morphine. Chronic i.t. infusion with mGluR1 AS significantly reduced the development of tolerance to i.t. morphine. 4. In contrast to i.t. morphine, tolerance developed to the antinociceptive effects of s.c. morphine, in all i.t. infusion groups, including the mGluR1 AS group. 5. The spinal mGluR1 protein level was dramatically decreased after mGluR1 AS infusion when compared to control animals (na?ve and ACSF-treated animals). 6. These findings suggest that the spinal mGluR1 is involved in the development of tolerance to the antinociceptive effects of morphine. Selective blockade of mGluR1 may be beneficial in preventing the development of opioid analgesic tolerance.     

Genetic variation in morphine analgesic tolerance: a survey of 11 inbred mouse strains

The present study assessed the analgesic potency of morphine in 11 inbred mouse strains before and after chronic morphine treatment. Using the 49 degrees C tail-withdrawal test, significant strain differences in morphine AD(50) estimates derived from cumulative dose-response curves were noted prior to tolerance induction on Day 1. AD(50) estimates were reassessed on Day 4, after three daily systemic morphine injections for 3 days using an escalating dose schedule (10, 20, and 40 mg/kg sc). In 9 of 11 strains, morphine potency was significantly reduced from 2-fold to as much as 11-fold. Two strains (129P3 and LP) displayed no evidence whatsoever of tolerance development. Neither initial baseline withdrawal latency nor morphine analgesic sensitivity was significantly correlated with tolerance magnitude. Also observed were strain-dependent alterations (mostly hyperalgesia) in baseline tail-withdrawal latencies as a result of chronic morphine treatment. The magnitude of hyperalgesia and analgesic tolerance was significantly correlated among strains, implicating common genetic substrates and supporting their proposed association. The present work demonstrates that the presence and magnitude of morphine analgesic tolerance is genotype-dependent and identifies strains with widely divergent liabilities that should facilitate identification of trait-relevant genes.     

Involvement of kappa opioid receptors in formalin-induced inhibition of analgesic tolerance to morphine in mice

This study examined the role of kappa opioid receptors (KOR) in the mechanism underlying tolerance to the analgesic effects of morphine induced by chronic pain. The analgesic effect of morphine (10 mg kg(-1)), estimated by the tail-flick test in mice, gradually decreased during repeated daily morphine treatment. A significant decrease in the analgesic effect of morphine was seen on the fifth day of repeated morphine treatment compared with the first day. Chronic pain was induced by subcutaneous administration of 2% formalin into the dorsal part of the left hind paw, which significantly inhibited development of tolerance to morphine analgesia. The effect of formalin-induced pain on inhibition of morphine tolerance was reversed by the KOR antagonist nor-binaltorphimine. Furthermore, an antisense oligodeoxynucleotide, but not a missense oligodeoxynucleotide, against KOR completely suppressed the inhibitory effect of formalin-induced pain on morphine tolerance. Naltrindole, an antagonist of delta opioid receptor, did not affect chronic-pain-induced tolerance to morphine. Our findings show that the inhibitory effect of chronic pain on analgesic tolerance to morphine is mediated by KOR rather than delta opioid receptors.     

Involvement of kappa opioid receptors in the formalin‐induced inhibition of analgesic tolerance to morphine via suppression of conventional protein kinase C activation

Objectives Repeated morphine treatment results in a decreased analgesic effect or the development of analgesic tolerance. However, we reported that some inflammatory chronic pain may inhibit morphine tolerance via kappa opioid receptor (KOR) activation. In this study, we further investigated the role of KOR in the inhibition of morphine tolerance in a chronic pain condition with a focus on the regulation of protein kinase C (PKC) activity. Methods Chronic pain was induced by formalin treatment into the dorsal part of the left hind paws of mice. The analgesic effect of morphine was measured by the tail flick method. We analysed the protein expression of PKC and its activity, and G‐protein activity of mu opioid receptor (MOR) under repeated morphine treatment with or without formalin treatment. Key findings We found that conventional subtypes of PKC (cPKC) were up‐regulated by repeated morphine treatment. Also, antisense oligonucleotide (AS‐ODN) targeting cPKC completely suppressed the development of morphine tolerance. The disappearance of the repeated morphine‐induced up‐regulation of cPKC was completely reversed by treatment with AS‐ODN targeting KOR. In addition, AS‐ODN targeting KOR significantly reversed the chronic pain‐induced down‐regulation of PKC activity or up‐regulation of MOR [³⁵S]GTPγS binding activity after repeated morphine treatment. Conclusions These results indicate that KOR plays an important role in the inhibition of repeated morphine‐induced cPKC up‐regulation under chronic pain condition. Furthermore, this may result in the increase of MOR activity and in the inhibition of morphine tolerance under chronic pain condition.     

Opiate and non-opiate mechanisms of stress-induced analgesia: cross-tolerance between stressors

Acute exposure to severe stressors induce profound analgesia. Repeated exposures to the same stressors esult in adaptation in much the same way that repeated administration of opiates results in tolerance. The present study investigated whether two qualitatively different stressors, cold-water swims (CWS) and injections of 2-deoxy-D-glucose (2-DG) share common pain-inhibitory mechanisms by determining whether cross-tolerance developed to their analgesic effects. Cross-tolerance was also examined between 2-DG and morphine. Flinch-jump thresholds were determined in six groups of six rats each. Analgesia was observed 30 min following acute exposure to CWS (2°C for 3.5 min), 2-DG (350 mg/kg) and morphine (10 mg/kg), but not following placebo injections or warm water swims. Chronic exposure to all three analgesic treatments resulted in tolerance and adaptation. Complete and reciprocal cross-tolerance developed between the analgesia induced by CWS and by DG. Complete cross-tolerance to 2-DG analgesia also developed in morphine-tolerant rats, but only partial cross-tolerance to morphine analgesia developed in 2-DG adapted rats. These results support the concept that stressful events induce analgesia through specific activation of an intrinsic pain-inhibitory system which has both opiate and non-opiate branches.     

The effect of melanotrophin release inhibiting factor (MIF) and cyclo (Leu-Gly) on the tolerance to morphine-induced antinociception in the rat: a dose-response study.

1. The effects of melanotrophin release inhibiting factor (MIF) and its cyclic analogue cyclo (Leu-Gly) on tolerance to the analgesic effect of morphine were studied in male Sprague-Dawley rats. 2. Tolerance to morphine was induced by implantation of four morphine pellets (each containing 75 mg of morphine free base) during a 3 day period. 3. Daily subcutaneous administration of MIF and cyclo (Leu-Gly) before and during the morphine pellet implantation inhibited the development of tolerance to morphine analgesia. The minimum daily dose of the peptides required to produce a significant effect was 0.5 mg/kg. 4. The effects of single injections of MIF and cyclo (Leu-Gly) on morphine tolerance revealed that the minimum doses of cyclo (Leu-Gly) and MIF to inhibit morphine tolerance were 4 and 8 mg/kg, respectively. 5. Chronic treatment with morphine resulted in an enhanced hypothermic response to dopamine agonist, apomorphine. The enhancement of this response was blocked by both MIF and cyclo (Leu-Gly) in doses that inhibited morphine tolerance. 6. It is concluded that MIF and cyclo (Leu-Gly) blocked the development of analgesic tolerance as well as dopamine receptor hypersensitivity induced by chronic morphine treatment and the two phenomena may be interrelated.     

Differential roles of the adrenal gland in the suppression of morphine antinociceptive tolerance development by alpha- and beta-adrenergic blockers.

Concomitant treatment with phentolamine, an alpha-blocker, or with propranolol, a beta-blocker, suppressed the development of morphine tolerance in sham-operated (Sham) mice. In adrenalectomized (ADX) mice, daily morphine developed tolerance as well as in the Sham group, and concurrent phentolamine suppressed the development of tolerance, whereas such suppression by propranolol was abolished. Supplemental treatment of ADX mice with dexamethasone did not restore the suppressive effect of propranolol. These results suggest that different mechanisms underlie the prevention of tolerance development by alpha- and beta-blockers, and that adrenal cortex does not seem to participate in the suppression by beta-blockers.     

Chronic variable stress or chronic morphine facilitates immobility in a forced swim test: reversal by naloxone

The behaviors displayed in a forced swim test were investigated in rats previously exposed to a chronic variable stress treatment or chronic administration of morphine. In addition, to further explore the participation of an endogenous opiate mechanism in these behavioral effects, naloxone was either administered during the chronic treatment (prior to each stress or morphine exposure) or immediately prior to the forced swim test. Animals were submitted daily to a different stressor for 1 week or injected with morphine (10 mg/kg, IP) for 6 days, whereas controls were unmanipulated except for the injection process. On the day following the last stressor, control and stressed animals were administered saline or naloxone (2 mg/kg, IP) 15 min prior to the forced swim test. Morphine treated animals were similarly tested on the third day following the last morphine injection. In a separate group of rats, naloxone (2 mg/kg, IP) was administered daily 10 min prior to each stressor of the chronic stress regime or each daily morphine injection. A significant increase in the time spent in immobility was observed in stressed animals as well as in rats chronically treated with morphine. In both groups, this potentiated immobility was attenuated by naloxone pretreatment prior to the forced swim test or when given before each daily stressor or morphine injection. In addition, the concurrent exposure to stress or morphine along with naloxone administration enhanced struggling in the first 5 min of the forced swim test. Taken together, the results of these experiments support the conclusion that the increase in immobility seen following chronic variable stress or repeated morphine exposure is modulated by the activation of an endogenous opiate mechanism, given that this effect is attenuated by naloxone administration.     

CI988, a selective antagonist of cholecystokininB receptors, prevents morphine tolerance in the rat.

1. The effect of chronic treatment with CI988, a recently developed selective antagonist of cholecystokinin type-B receptors (CCKB receptors) on the tolerance to morphine analgesia was studied in rats with the hot plate test. 2. Morphine tolerance was induced with the use of two paradigms. Morphine was injected i.p. either in a schedule of increasing doses (1-32 mg kg-1) twice daily for 6 days or at a fixed dose (3 mg kg-1) daily for 29 days. 3. In both series of experiments, tolerance to the analgesic effect of morphine was prevented by simultaneous treatment with i.p. CI988. Chronic treatment with only CI988 daily for up to 29 days did not reduce the analgesic effect of a weekly injection of morphine. 4. CI988 did not diminish the physical dependence to morphine, as examined with naloxone precipitated withdrawal. 5. The present results provide evidence that chronic treatment with a selective CCKB receptor antagonist could prevent tolerance to the analgesic effect of morphine without affecting morphine-induced physical dependence. Application of CCK antagonists may be clinically important in treating chronic pain patients by preventing morphine tolerance and by eliminating the need to increase morphine doses to unacceptable levels.     

Large-amplitude 5-HT1A receptor activation: a new mechanism of profound,central analgesia

We report the discovery of F 13640 and evidence suggesting this agent to produce powerful, broad-spectrum analgesia by novel molecular and neuroadaptative mechanisms. F 13640 stimulates G(alphaomicron) protein coupling to 5-HT(1A) receptors to an extent unprecedented by selective, non-native 5-HT(1A) ligands. Fifteen minutes after its injection in normal rats, F 13640 (0.01-2.5 mg/kg) decreases the vocalization threshold to paw pressure; 15 min upon injection in rats that are exposed to formalin-induced tonic nociception, F 13640 inhibits pain behavior. The initial hyperalgesia induced by 0.63 mg/kg F 13640 was followed, 8 hrs later, by paradoxical hypo-algesia; 5 mg/kg of morphine produces the opposite effects (i.e., hypo-algesia followed by hyper-algesia). Repeated F 13640 injections cause an increase in the basal vocalization threshold and a reduction of F 13640-produced hyperalgesia; in these conditions, morphine causes basal hyperalgesia and antinociceptive tolerance. Continuous two-week infusion of F 13640 (0.63 mg/day) exerts little effect on the threshold in normal rats, but markedly reduces analgesic self-administration in arthritic rats. F 13640 infusion also decreases allodynic responses to tactile and thermal stimulations in rats sustaining spinal cord or sciatic nerve injury. In these models of chronic nociceptive and neuropathic pain, the analgesia afforded by F 13640 consistently surpasses that of morphine (5 mg/day), imipramine (2.5 mg/day), ketamine (20 mg/day) and gabapentin (10 mg/day). Very-high-efficacy 5-HT(1A) receptor activation constitutes a novel mechanism of central analgesia that grows rather than decays with chronicity, that is amplified by nociceptive stimulation, and that may uniquely relieve persistent nociceptive and neuropathic pains.     

Anxiolytic-like effects of morphine and buprenorphine in the rat model of fear-potentiated startle: tolerance,cross-tolerance,and blockade by naloxone

Rationale Morphine and buprenorphine have analgesic and anxiolytic-like properties. While their analgesic effects have been well characterized, their anxiolytic-like properties have not. Objectives Effects of acute morphine and buprenorphine on the expression of acoustic fear-potentiated startle (FPS) and naloxone pretreatment were assessed. Effects of chronic morphine and buprenorphine on tolerance, cross-tolerance, and withdrawal were also examined. Materials and methods Fear-conditioned rats were given subcutaneous drug treatment immediately before testing for FPS. Experiment 1, rats were administered morphine (0.03, 0.25, 0.63, 2.5, or 10 mg/kg) or buprenorphine (0.004, 0.0075, 0.015, 0.03, or 0.25 mg/kg). Experiment 2, rats were given saline or naloxone (0.5 mg/kg) and 5min later given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg). Experiment 3, rats received once-daily injections of saline, morphine (10 mg/kg), or buprenorphine (0.25 mg/kg) for 7 days. Immediately before testing, saline-treated rats were given saline, morphine (2.5 mg/kg), or buprenorphine (0.03 mg/kg), morphine-treated rats were given morphine (2.5 mg/kg) or buprenorphine (0.03 mg/kg), and buprenorphine-treated rats were given buprenorphine (0.03 mg/kg) or morphine (2.5 mg/kg). Tolerance and cross-tolerance in analgesia were assessed via the tail-flick test, as were naloxone-precipitated withdrawal. Results Morphine and buprenorphine had parallel dose–response curves in blocking FPS, with buprenorphine 40 times more potent than morphine. Naloxone reversed these effects. Morphine and buprenorphine showed tolerance and cross-tolerance in their anxiolytic-like and analgesic effects. Chronic buprenorphine produced less withdrawal than chronic morphine. Conclusions Cross-tolerance between morphine and buprenorphine suggests a common receptor mediating their anxiolytic-like and analgesic effects.     

N-methyl-D-aspartate receptor antagonist MK-801 suppresses glial pro-inflammatory cytokine expression in morphine-tolerant rats

Chronic opioid therapy induces tolerance and hyperalgesia, which hinders the efficacy of opioid treatment. Previous studies have shown that inhibition of neuroinflammation and glutamatergic receptor activation prevents the development of morphine tolerance. The aim of the present study was to examine whether N-Methyl-d-aspartate receptors are involved in the regulation of chronic morphine-induced neuroinflammation in morphine-tolerant rats.Morphine tolerance was induced in male Wistar rats by intrathecal infusion of morphine (15 μg/h) for 5 days. Tail-flick latency was measured to estimate the antinociceptive effect of morphine. Morphine challenge (15 μg, intrathecally) on day 5 at 3 h after discontinuation of morphine infusion produced a significant antinociceptive effect in saline-infused rats, but not in morphine-tolerant rats. Pretreatment with MK-801 (20 μg, intrathecally) 30 min before morphine challenge preserved its antinociceptive effect in morphine-tolerant rats. Morphine-tolerant rats expressed high levels of the pro-inflammatory cytokines interleukin-1β, interleukin-6, and tumor necrosis factor-α and the increase in interleukin-1β and interleukin-6, and tumor necrosis factor-α levels was prevented by MK-801 pre-treatment at both the protein and mRNA levels.The results show that a single dose of MK-801 reduces the increase in pro-inflammatory cytokines in the spinal cord, thus re-sensitizing neurons to the antinociceptive effect of morphine in morphine-tolerant rats. This study provides a piece of theoretical evidence that NMDA antagonist can be a therapeutic adjuvant in treating morphine tolerant patients for pain relief.     

Involvement of neuropeptide FF receptors in neuroadaptive responses to acute and chronic opiate treatments

BACKGROUND AND PURPOSE Opiates remain the most effective compounds for alleviating severe pain across a wide range of conditions. However, their use is associated with significant side effects. Neuropeptide FF (NPFF) receptors have been implicated in several opiate-induced neuroadaptive changes including the development of tolerance. In this study, we investigated the consequences of NPFF receptor blockade on acute and chronic stimulation of opioid receptors in mice by using RF9, a potent and selective antagonist of NPFF receptors that can be administered systemically. EXPERIMENTAL APPROACH The effects of RF9 were investigated on opioid pharmacological responses including locomotor activity, antinociception, opioid-induced hyperalgesia, rewarding properties and physical dependence. KEY RESULTS RF9 had no effect on morphine-induced horizontal hyperlocomotion and slightly attenuated the decrease induced in vertical activity. Furthermore, RF9 dose-dependently blocked the long-lasting hyperalgesia produced by either acute fentanyl or chronic morphine administration. RF9 also potentiated opiate early analgesic effects and prevented the development of morphine tolerance. Finally, RF9 increased morphine-induced conditioned place preference without producing any rewarding effect by itself and decreased naltrexone-precipitated withdrawal syndrome following chronic morphine treatment. CONCLUSION AND IMPLICATIONS The NPFF system is involved in the development of two major undesirable effects: tolerance and dependence, which are clinically associated with prolonged exposure to opiates. Our findings suggest that NPFF receptors are interesting therapeutic targets to improve the analgesic efficacy of opiates by limiting the development of tolerance, and for the treatment of opioid dependence.     

Peripheral analgesic action of clonidine: mediation by release of endogenous enkephalin-like substances

Clonidine analgesia was tested on the hyperalgesia induced by intraplantar injection of prostaglandin E2 or carrageenin. The antinociceptive effect of clonidine was dose-dependent and was abolished by local administration of the selective alpha 2-adrenoceptor blocker, yohimbine or of the opioid antagonists naloxone or quaternary nalorphine. St-91, a clonidine analog which does not cross the blood-brain barrier also promoted significant antinociception. Repeated administration of drugs possessing a central mechanism of analgesic action leads to the development of tolerance in this test. Significant analgesic tolerance was observed following repeated (5 days) morphine (8 mg/kg) or high doses of clonidine (0.5 mg/kg). In contrast, no tolerance was detected to the analgesic effect of low doses of clonidine (0.15 mg/kg) or of St-91 (0.5 mg/kg). These results suggest that, in addition to its central analgesic action, clonidine can induce peripheral antinociception by an alpha 2-adrenoceptor-mediated local release of enkephalin-like substances.