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Anesth Analg 2003;96:1065-1071
© 2003 International Anesthesia Research Society

PAIN MEDICINE

Nifedipine Potentiates the Antinociceptive Effect of Endomorphin-1 Microinjected into the Periaqueductal Gray in Rats

Shuanglin Hao, MD PhD*,{dagger}, Keiko Mamiya, MD*, Osamu Takahata, MD PhD*, Hiroshi Iwasaki, MD PhD*, Marina Mata, MD{dagger}, and David J. Fink, MD{dagger}

*Department of Anesthesiology & Critical Care Medicine, Asahikawa Medical College, Asahikawa, Japan; and {dagger}Department of Neurology, University of Pittsburgh, Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Shuanglin Hao, MD, PhD, Department of Neurology, University of Pittsburgh Medical Center, S-522, BST, Pittsburgh, PA 15213. Address e-mail to haoshuanglin{at}hotmail.com


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Endomorphin-1 is a novel endogenous µ-opioid ligand. We investigated the antinociceptive interaction between endomorphin-1 and nifedipine, an L-type calcium channel blocker, microinjected into the midbrain ventrolateral periaqueductal gray (vPAG), using the spinally-organized tail-flick test and the supraspinally-organized tail-pressure test in rats. Sprague-Dawley rats were stereotaxically implanted with a guide cannula lowered into the vPAG. Microinjection of endomorphin-1 into the vPAG led to dose-related increases in antinociceptive responses in the tail-flick test and tail-pressure test. Pretreatment with the µ-opioid receptor-selective antagonist ß-funaltrexamine blocked the antinociceptive effect of endomorphin-1. Pretreatment with ß-funaltrexamine alone had no effect on the tail-flick latency and tail-pressure threshold. Microinjection of nifedipine alone into the vPAG did not produce an antinociceptive response in the tail-flick test and tail-pressure test. However, injection of nifedipine into the vPAG potentiated the antinociceptive effect of endomorphin-1, producing a significant leftward shift in the dose-response curve of endomorphin-1 in both the tail-flick and tail-pressure tests. This result shows that the potent antinociceptive effect of endomorphin-1 microinjected into the vPAG is mediated through the µ-opioid receptor and is potentiated by concomitant administration of nifedipine.

IMPLICATIONS: This study shows that the potent antinociceptive effect of endomorphin-1 microinjected into the ventrolateral periaqueductal gray is potentiated by concomitant administration of nifedipine. This suggests that calcium channel blockers may enhance the analgesia of opioids in patients with calcium channel blocker treatment.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
The midbrain periaqueductal gray (PAG) is an important brain region for the coordination of µ-opioid-induced pharmacological actions. Electrical stimulation of or morphine microinjection into the PAG produces the antinociceptive effect by activation of the descending inhibitory systems (1–4) . Endomorphin-1 is a novel endogenous opioid ligand that shows the greatest selectivity and affinity in many brain regions for the µ-opioid receptor of endogenous substances (5). Autoradiography with 125I-endomorphin results in a label at the PAG, superior colliculus, interpeduncular nucleus, and spinal cord (6). A large density of endomorphin-1-like immunoreactive fibers has been described in the rat PAG (7).

Calcium influx through voltage-sensitive calcium channels (VSCCs) is believed to play an important role in the regulation of synaptic transmission, and is essential for cellular functions such as neurotransmitter release, enzyme activity, and membrane activity (8); calcium channel inhibitors can interfere with such neurochemical processes. There are at least five types of VSCC (L-, N-, P-, R-, and T-types) with different electrophysiological characteristics and pharmacological sensitivities in neurons (8). Although the physiological roles of these different types of calcium channels are not fully understood, L-type VSCC has been implicated in the release of neurotransmitters from sensory neurons (9).

Intracerebroventricular or intrathecal administrations of endomorphin-1 produce antinociception in the acute and inflammatory pain models (5,6,10) . Nifedipine is widely used to treat ischemic heart disease and hypertension in the perioperative period. It is still controversial whether nifedipine produces antinociception. Previous studies have demonstrated that systemic or supraspinal administration of nifedipine produces antinociception (11,12) in the acetic acid writhing test or the formalin test, but no antinociception of nifedipine has been detected in mice with hot-plate and tail-flick tests (13,14) . Evidence shows that nifedipine increases the antinociceptive effect of morphine in both animals and humans (15). The antinociceptive effect of drugs given supraspinally may vary according to the brain region injected (2). The antinociceptive efficacy of drugs may also depend on the species of animal, the nature and intensity of the stimuli, and the routes of administration. It is unclear whether endomorphin-1 or nifedipine microinjected into the PAG produces antinociception in rats. To examine the interaction between endomorphin-1 and nifedipine in the PAG in modulation of nociceptive behavior, we studied the effects of microinjection of nifedipine and endomorphin-1 into the ventrolateral PAG (vPAG) on the spinally-organized tail-flick test and the supraspinally-organized tail-pressure test (3) in rats. The vPAG was chosen because it represents a relatively "pure" analgesia site (16).


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
All procedures were approved by the Institutional Animal Care and Use Committee. Male Sprague-Dawley rats (250–300 g) were housed in individual cages with free access to food and water and were maintained on a 12-h light-dark cycle at an ambient temperature (21°C ± 1°C). Rats were prepared for intracranial drug administration by placing those anesthetized with pentobarbital (40 mg/kg) in a stereotaxic headholder. The skull was exposed, and a stainless-steel guide cannula (23-gauge) was directed toward the vPAG (AP -8.3 mm using bregma as 0, ML 0.5–1.0 mm, DV -5.5 mm from the base of the dura). The coordinates were obtained from the atlas of Paxinos and Watson (17). The guide cannula was cemented in place and secured to the skull by two small stainless-steel screws. A stainless-steel stylet, which extended 1 mm beyond the tip of the outer cannula, was inserted after surgery and left in place until the time of intracranial injection. Animals were allowed a 5- to 7-day recovery period before testing was commenced.

The effects of drugs on thermal nociceptive stimulation were assessed by using an analgesimeter to measure the tail-flick latency response. A snugly fitting Plexiglas holder restrained rats, and no signs of struggle were observed during the experiment. A high-intensity light was focused on the rat’s tail, and the time for the rat to move its tail out of the light beam was automatically recorded (Tail Flick Analgesia Meter; Muromachi Kikai Co., Tokyo, Japan) and referred to as the tail-flick latency. A different patch of the tail was exposed to the light beam on each trial to minimize the risk of tissue damage. The intensity of the radiant heat was adjusted so that the baseline latency was between 2.5 and 3.5 s. A cutoff time of 10 s was predetermined, at which time the trial was terminated if no response had been observed.

For the tail-pressure test, the threshold of the motor response to pressure applied to the tail by an Analgesy-Meter (Ugo Basile, Milan, Italy) was measured. With this device, the distal part of the tail was supported by a plinth while linearly increasing pressure was applied with a cone-shaped pusher. The distal 4 cm of the tail was marked, and with each trial, the pressure point was positioned 0.25 cm proximal to the previous site. The end-point was defined as the first motor response of struggling or squeaking to the pressure. The baseline pressure threshold was between 180 and 220 g. The cutoff pressure was 500 g to avoid tissue damage.

We tested the general behavior changes of each rat after the administration of drugs. Motor function, as previously described (18), was evaluated by the performance of two specific behavioral tasks: the placing/stepping reflex and the righting reflex. Drawing the dorsum of either hind paw over the edge of a tabletop evokes the placing/stepping response. In normal animals, the stimulus elicits an upward lifting of the paw onto the surface of the table, called stepping. Animals with any degree of hind-limb flaccidity will demonstrate an altered or absent reflex. The righting reflex can be demonstrated by placing an animal horizontally with its back on the table. The animal will usually show an immediate coordinated twisting of the body around its longitudinal axis to regain its normal position on its feet. Animals displaying ataxic behavior will show a decreased ability to right themselves.

Initial studies were conducted to determine the analgesic efficacy of different doses of endomorphin-1 and nifedipine. To examine the interaction between endomorphin-1 and µ-opioid receptors, animals were pretreated with ß-funaltrexamine 3 nmol (FNA; a µ-opioid receptor selective antagonist) or saline, 24 h before the time that endomorphin-1 was administered into the vPAG. To determine whether pretreatment with FNA or saline changed the response in the tests, control studies were conducted in which saline was administered 24 h after the injections. In the separate groups, nifedipine was administered into the vPAG 2 min after endomorphin-1 to examine interactions between endomorphin-1 and nifedipine.

Drugs used in the study included endomorphin-1 (Tocris Cookson Ltd., Bristol, UK), FNA (Tocris), dimethylsulfoxide (DMSO) (Sigma, St. Louis, MO), and nifedipine (Tocris). Endomorphin-1 and FNA were dissolved in saline, and nifedipine was dissolved in DMSO. Drugs were administered into the vPAG by a 30-gauge stainless-steel injection cannula, which extended 1.0 mm below the tip of the guide. The injection cannula was connected with polyethylene tubing (PE-10) filled with drug solution. A volume of 0.5 µL was injected over 30 s by means of a hand-operated Hamilton syringe. After administration, the injector was left in situ for an additional 1 min before it was removed and replaced by the guide stylet. At the termination of the experiments, cresyl violet was injected.

After completion of the experimental series, animals were killed with an overdose of sodium pentobarbital and were perfused with 4% paraformaldehyde through the ascending aorta. The brain was removed and kept in the perfusion solution for 12 h and then in 30% sucrose for 2 days. The brain was frozen, and 40-µm transverse sections were cut by using a cryostat microtome. Cannula tip placements were verified from the sections stained with cresyl violet. Only those rats that had accurate injections in the vPAG were chosen for analysis.

In the tail flick and tail-pressure tests, the antinociceptive effects of drugs were represented as a percentage of maximum possible effect (%MPE) by using the formula:



The mean ± SEM value of %MPE was calculated for each group. The area under the curve (AUC), depicting MPE versus time, was calculated by the trapezoidal rule to express the overall magnitude and duration of effect for the tail-flick and tail-pressure tests and is presented as mean ± SEM for each group. The ED50 value (dose of drugs that produced 50% analgesia) and 95% confidence intervals (CI95) were derived by log-linear interpolation by using points between 16 and 84 of %MPE on the dose-response curve. To determine significant differences among ED50 values, Student’s t-test was used. Data were compared by analysis of variance (StatView J 4.2; SAS Institute, Cary, NC). Post hoc comparisons were performed with the Scheffé F test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
All rats displayed normal symmetrical ambulation and no detectable change in motor strength. There was no significant difference in the nociceptive behaviors between the different control treatments for the respective groups (saline or DMSO into the vPAG; P > 0.05).

Microinjection of endomorphin-1 into the vPAG produced a time-dependent and dose-dependent antinociceptive effect, with the peak of the effect seen at 5–10 min in the tail-flick test (Fig. 1A) and tail-pressure test (Fig. 2A). The antinociceptive effect produced by endomorphin-1 in the tail-flick and tail-pressure tests waned at 30–45 min and 60–90 min, respectively (Figs. 1A and 2A). The ED50 (CI95) values of antinociception of endomorphin-1 in the tail-flick and tail-pressure tests were 1.9 nmol (1.33–2.8 nmol) and 1.3 nmol (0.79–2.15 nmol), respectively.



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  		Figure 1. The effects of endomorphin-1 (Endo-1) and the antagonism by ß-funaltrexamine (FNA) in the tail-flick test. A, The time course of endomorphin-1 microinjected into the PAG. B, Pretreatment with FNA, but not saline, significantly reversed the antinociception produced by endomorphin-1 (n = 8–10; **P < 0.01). The results reflected the peak antinociceptive values. 24h BT = administration 24 h before testing; BT = administration before testing; %MPE = percentage of maximum possible effect.

 


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  		Figure 2. The effects of endomorphin-1 (Endo-1) and the antagonism by ß-funaltrexamine (FNA) in the tail-pressure test. A, The time-course of endomorphin-1 microinjected into the PAG. B, Pretreatment with FNA, but not saline, significantly reversed the antinociception produced by endomorphin-1 (n = 8–10; **P < 0.01). The results reflected the peak antinociceptive values. 24h BT = administration 24 h before testing; BT = administration before testing; %MPE = percentage of maximum possible effect.

 
Pretreatment with FNA alone into the vPAG did not change the tail-flick latency and tail-pressure threshold. Animals that received FNA into the vPAG 24 h before testing followed by vPAG saline treatment exhibited no difference in tail-flick latency and tail-pressure threshold when compared with animals that received vPAG saline 24 h before testing followed by vPAG saline treatment (left two bars of Fig. 1B and Fig. 2B). However, the tail-flick latency and the tail-pressure threshold of animals that received FNA into the vPAG 24 h before testing followed by endomorphin-1 were significantly less than those of animals receiving saline 24 h before testing followed by endomorphin-1 (P < 0.001) (right two bars of Fig. 1B and Fig. 2B).

Figure 3 shows the comparisons of AUC induced by endomorphin-1 between the tail-flick test and the tail-pressure test. Unexpectedly, endomorphin-1 produced the bigger AUC in the tail-pressure test compared with that in the tail-flick test (Fig. 3).



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  		Figure 3. The comparison of the area under the curve (AUC) of antinociception produced by endomorphin-1 between the tail-flick test (TF) and the tail-pressure test (TP). The AUC induced by endomorphin-1 in the tail-pressure test was bigger than that in the tail-flick test: *P < 0.05; **P < 0.01 versus the tail-flick test.

 
Nifedipine at the doses (3–30 µg) into the vPAG did not produce an antinociceptive effect compared with the control group in the tail-flick test (Fig. 4A) or in the tail-pressure test (Fig. 4B). However, microinjection of nifedipine (3 µg) into the vPAG resulted in a significant leftward shift of dose-effect curves of endomorphin-1 (Fig. 5A and 5B), with 78% and 76% decreases of ED50 values of endomorphin-1 in the tail-flick test and tail-pressure test, respectively (P < 0.01). Pretreatment with FNA significantly antagonized the potentiation of the antinociception induced by a combination of endomorphin-1 and nifedipine (data not shown).



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  		Figure 4. The time-effect curves of nifedipine (µg) microinjected into the PAG in the tail-flick test (A) and in the tail-pressure test (B). Nifedipine did not produce significant antinociception in either nociceptive model (n = 8–10). DMSO = dimethylsulfoxide; %MPE = percentage of maximum possible effect.

 


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  		Figure 5. Log dose-response curves showing the antinociceptive potentiation of endomorphin-1 by concomitant nifedipine (3 µg) microinjected into the PAG in the tail-flick test (A) and tail-pressure test (B). Groups of rats (n = 8–10) received enomorphin-1 either alone ({blacktriangleup}) or combined with nifedipine ({blacksquare}). The results reflected the peak antinociceptive values. Endomorphin-1 produced antinociception in a dose-dependent manner. Combination with nifedipine resulted in a 4.7-fold and 4.2-fold leftward shift in the antinociceptive dose-response curves for endomorphin-1 in the tail-flick test and tail-pressure test, respectively (P < 0.01). %MPE = percentage of maximum possible effect.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
The results of these experiments demonstrated 1) that endomorphin-1 microinjected into the vPAG produced dose-dependent, µ-antagonist-sensitive antinociceptive effects in the rat tail-flick test and tail-pressure test; 2) that nifedipine at the doses used did not produce an antinociceptive effect; and 3) that nifedipine microinjected at a small dose (3 µg) into the vPAG significantly potentiated the analgesic effects of endomorphin-1.

Neuroanatomical evidence shows that the PAG receives significant afferents from many nuclei in the diencephalons and brainstem in rat and projects to the rostromedial pericoerulear region, the nucleus paragigantocellularis, and the nucleus raphe magnus. The latter sends axons that project to the medullary dorsal horn and then descend in the dorsolateral funiculus of the spinal cord to send terminals to laminae I, IIo, IV–VI, and X. A direct PAG-spinal projection system, which bypasses the medullary nuclei, projects directly to the medullary dorsal horn and then descends in the dorsolateral funiculus to send terminals to laminae I, IIo, V, and X (19,20) . The µ-opioid receptor has been localized to the PAG and to the nucleus raphe magnus by using ligand-binding autoradiography (21), immunocytochemistry (22), and electrophysiology (23). Pharmacological evidence suggests that the PAG is an important site for modulation of nociceptive sensory input through descending controls acting at the level of the spinal cord (1,2) . Evidence that the PAG is involved in controlling the descending pain-inhibitory pathway in humans has been reported with high-resolution functional magnetic resonance imaging (24).

Morphine, a naturally occurring alkaloid present in the poppy plant Papaver somniferum, has a 30- to 50-fold higher affinity at µ-opioid receptors than at {delta}- and {kappa}-opioid receptors (25). Endomorphin-1, a recently isolated endogenous opioid tetrapeptide, has a high affinity and selectivity (4,000- and 15,000-fold preference over the {delta} and {kappa} receptors, respectively) for the µ receptor (5). Regional distribution studies of 125I-endomorphin binding in mouse brain showed that endomorphin-1 labels the PAG (6) and that endomorphin-1 increases [35S]GTP{gamma}S binding by selectively stimulating µ-opioid receptors with intrinsic activity (26), suggesting that the endogenous ligand might be an agonist for µ-opioid receptors in the PAG.

Stimulation of all regions of the PAG can generate analgesia, but stimulation of the ventrolateral part is most effective and produces "pure" analgesia, free from motor side effects or signs of aversion. In contrast, stimulation of the dorsolateral part of the PAG produces analgesia and aversive motor reaction, making it difficult to separate the antinociception from the aversive behavior (16). Therefore, in this study, only those rats that had successful injections in the vPAG were chosen for data analysis.

Stimulation of the PAG or the microinjection of opioid agonists into the PAG has been widely shown to produce an antinociceptive effect in a variety of analgesimetric tests, including the nociceptive thermal tail flick reflex test (1–4) . Inhibition of the spinally-mediated tail-flick reflex in such studies has been assumed to result from activation of a descending inhibitory system (1–4) . Our results showed that endomorphin-1 microinjected into the PAG produced dose-dependent antinociception in the tail-flick test, which is consistent with previous studies of microinjection of morphine into the PAG (1–3) . Thus, we think that endomorphin-1 microinjected into the PAG may inhibit the spinal nociceptive response by activating descending pain-control systems. This is the first demonstration that endomorphin-1 microinjected into the PAG produced dose-dependent antinociception in the tail-flick and tail-pressure test. The tail-pressure test is a supraspinally-integrated response (3). Although the ED50 values of endomorphin-1 in the tail-flick test and tail-pressure test were not different, the fact that endomorphin-1 produced a bigger effect measured by AUC in the tail-pressure test than in the tail-flick test showed that the duration of antinociception in the supraspinal nociceptive model was longer than that in the spinal nociceptive model. These results suggest that endomorphin-1 acts by inhibition of supraspinal nociceptive loops.

The antinociceptive potency of nifedipine is not well understood. Because an influx of calcium ions into nerve endings is required for the release of neurotransmitters by exocytosis, the movement of calcium ions through calcium channels of neurons is an important determinant in the functioning of nervous systems. Several studies have indicated that nifedipine has an antinociceptive effect. These studies have used the acetic acid writhing test or the formalin test in mice and rats (13,27) . No antinociceptive effect of nifedipine alone has been detected in mice with hot-plate and tail-flick tests (13,14) . However, one recent report showed that systemic nifedipine had an antinociceptive effect in the rat tail-flick test (11). There is no doubt that different pharmacological results of analgesics depend on the noxious tests, routes of drug administration, and species of animals. This is the first report to show that nifedipine microinjected into the PAG does not produce antinociception in the tail-flick test or tail-pressure test in the rat.

Systemic morphine mainly acts at supraspinal structures. Previous studies have indicated that systemically administered calcium channel blockers potentiate the analgesic effects of systemically administered opioids (15,28) ; this is consistent with our results, which show that nifedipine potentiated the antinociceptive effect of endomorphin-1 at the supraspinal level. This potentiation was confirmed by the fact that the ED50 with CI95 for the endomorphin-1 combined with the calcium channel blocker did not overlap the ED50 with CI95 for the endomorphin-1 alone.

The mechanism by which nifedipine potentiates the antinociceptive effects of endomorphin-1 microinjected into the PAG is still unclear. Evidence has shown that the activation of µ receptors inhibits L-type VSCCs (29). Both opioid drugs and calcium channel blockers inhibit calcium channel activity. Pharmacologically, calcium decreases the antinociceptive effect of morphine microinjected into the PAG (30); L-type VSCC blockers, which have little antinociceptive effect alone, potentiate the antinociceptive effects of spinal morphine in the thermal nociceptive tests (31). Electrophysiologically, endomorphin-1 inhibits calcium channel currents in mouse PAG neurons with whole-cell patch-clamp techniques (32). There are also reports indicating that opioids may increase Ca2+ uptake into synaptosomes from certain brain regions, raising the possibility that enhanced Ca2+ entry into nerve terminals contributes to the release of neurotransmitters (33). Evidence suggests that opioid agonists inhibit the L-type current in PAG neurons and strongly modulate N- and/or P-type channels as well (34,35) . The combination of endomorphin-1 and nifedipine appears to be effective because it inhibits two (or more) different types of calcium channels.

The role of calcium in opioid analgesia has important clinical implications. Nifedipine, as well as other calcium antagonists, is widely used to treat ischemic heart disease and systemic hypertension in the perioperative period. Pretreatment with nifedipine increases both the antinociceptive effect of morphine in rats and the analgesic effect of morphine in postoperative pain management (15).

In conclusion, this study demonstrates that endomorphin-1, but not nifedipine, microinjected into the PAG produced antinociceptive effects in the rat tail-flick test and tail-pressure test, and that nifedipine increased the antinociceptive effects of endomorphin-1. The study suggests that there is a possibility of a potentiation effect for this combination. Thus, physicians might reconsider the dose of opioids with respect to calcium blockers.


   Acknowledgments
 
Supported in part by the Japan-China Medical Association (SH) and a grant from the National Institute of Neurological Disorders and Stroke (DJF).

The authors would like to thank Dr. Ishimoto and Prof. Chiba, Department of Psychiatry and Neurology, Asahikawa Medical College, Japan, for their help.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

  1. Mohrland JS, McManus DQ, Gebhart GF. Lesions in nucleus reticularis gigantocellularis: effect on the antinociception produced by micro-injection of morphine and focal electrical stimulation in the periaqueductal gray matter. Brain Res 1982; 231: 143–52.[Web of Science][Medline]
  2. Jensen TS, Yaksh TL. Comparison of the antinociceptive action of mu and delta opioid receptor ligands in the periaqueductal gray matter, medial and paramedial ventral medulla in the rat as studied by the microinjection technique. Brain Res 1986; 372: 301–12.[Web of Science][Medline]
  3. Smith DJ, Perrotti JM, Crisp T, et al. The mu opiate receptor is responsible for descending pain inhibition originating in the periaqueductal gray region of the rat brain. Eur J Pharmacol 1988; 156: 47–54.[Web of Science][Medline]
  4. Akil H, Mayer DJ, Liebeskind JC. Antagonism of stimulation-produced analgesia by naloxone, a narcotic antagonist. Science 1976; 191: 961–2.[Abstract/Free Full Text]
  5. Zadina JE, Hackler L, Ge LJ, Kastin AJ. A potent and selective endogenous agonist for the µ-opiate receptor. Nature 1997; 386: 499–502.[Medline]
  6. Goldberg IE, Rossi GC, Letchworth SR, et al. Pharmacological characterization of endomorphin-1 and endomorphin-2 in mouse brain. J Pharmacol Exp Ther 1998; 286: 1007–13.[Abstract/Free Full Text]
  7. Martin-Schild S, Gerall AA, Kastin AJ, Zadina JE. Differential distribution of endomorphin 1- and endomorphin 2-like immunoreactivities in the CNS of the rodent. J Comp Neurol 1999; 405: 450–71.[Web of Science][Medline]
  8. Catterall WA. Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell Calcium 1998; 24: 307–23.[Web of Science][Medline]
  9. Perney TM, Hirning LD, Leeman SE, Miller RJ. Multiple calcium channels mediate neurotransmitter release from peripheral neurons. Proc Natl Acad Sci U S A 1986; 83: 6656–9.[Abstract/Free Full Text]
  10. Hao S, Takahata O, Iwasaki H. Electroacupuncture potentiates the antinociceptive effect of intrathecal endomorphin-1 in the rat formalin test. Neurosci Lett 2000; 287: 9–12.[Web of Science][Medline]
  11. Wong CH, Wu WH, Zbuzek VK. Hypotension does not alter the antinociceptive effect of nifedipine. Life Sci 1998; 63: PL343–8.[Web of Science][Medline]
  12. Miranda HF, Pelissier T, Sierralta F. Analgesic effects of intracerebroventricular administration of calcium channel blockers in mice. Gen Pharmacol 1993; 24: 201–4.[Web of Science][Medline]
  13. al-Humayyd MS. Effect of diltiazem, nifedipine and verapamil on the antinociceptive action of acetylsalicylic acid in mice. Gen Pharmacol 1991; 22: 121–5.[Web of Science][Medline]
  14. Pavone F, Battaglia M, Sansone M. Nifedipine-morphine interaction: a further investigation on nociception and locomotor activity in mice. J Pharm Pharmacol 1992; 44: 773–6.[Web of Science][Medline]
  15. Carta F, Bianchi M, Argenton S, Cervi D. Effect of nifedipine on morphine-induced analgesia. Anesth Analg 1990; 70: 493–8.[Abstract/Free Full Text]
  16. Lovick TA. Integrated activity of cardiovascular and pain regulatory systems: role in adaptive behavioural responses. Prog Neurobiol 1993; 40: 631–44.[Web of Science][Medline]
  17. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 2nd ed. Sydney: Academic Press, 1986.
  18. Tiseo PJ, Inturrisi CE. Attenuation and reversal of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist, LY-274614. J Pharmacol Exp Ther 1993; 264: 1090–6.[Abstract/Free Full Text]
  19. Stamford JA. Descending control of pain. Br J Anaesth 1995; 75: 217–27.[Abstract/Free Full Text]
  20. Bonica JJ. Biochemistry and modulation of nociception and pain. In: Bonica JJ, ed. The management of pain. Philadelphia: Lea & Febiger, 1990: 95–121.
  21. Tempel A, Zukin RS. Neuroanatomical patterns of the mu, delta, and kappa opioid receptors of rat brain as determined by quantitative in vitro autoradiography. Proc Natl Acad Sci U S A 1987; 84: 4308–12.[Abstract/Free Full Text]
  22. Mansour A, Fox CA, Burke S, et al. Immunocytochemical localization of cloned mu opioid receptor in the rat CNS. J Chem Neuroanat 1995; 8: 283–305.[Web of Science][Medline]
  23. Chieng B, Christie MJ. Hyperpolarization by opioids acting on mu-receptors of a sub-population of rat periaqueductal gray neurones in vitro. Br J Pharmacol 1994; 113: 121–8.[Web of Science][Medline]
  24. Tracey I, Ploghaus A, Gati JS, et al. Imaging attentional modulation of pain in the periaqueductal gray in humans. J Neurosci 2002; 22: 2748–52.[Abstract/Free Full Text]
  25. Corbett AD, Paterson SJ, Kosterlitz HW. Selectivity of ligands for opioid receptors. In: Herz A, ed. Handbook of experimental pharmacology, opioids. I. New York: Springer, 1993: 645.
  26. Narita M, Mizoguchi H, Narita M, et al. G protein activation by endomorphins in the mouse periaqueductal gray matter. J Biomed Sci 2000; 7: 221–5.[Web of Science][Medline]
  27. Bustamante D, Miranda HF, Pelissier T, Paeile C. Analgesic action of clonixin, nifedipine and morphine using the formalin test. Gen Pharmacol 1989; 20: 319–22.[Web of Science][Medline]
  28. Michaluk J, Karolewicz B, Antkiewicz-Michaluk L, Vetulani J. Effects of various Ca2+ channel antagonists on morphine analgesia, tolerance and dependence, and on blood pressure in the rat. Eur J Pharmacol 1998; 352: 189–97.[Web of Science][Medline]
  29. Piros ET, Prather PL, Law PY, et al. Voltage-dependent inhibition of Ca2+ channels in GH3 cells by cloned mu- and delta-opioid receptors. Mol Pharmacol 1996; 50: 947–56.[Abstract]
  30. Guerrero-Munoz F, Adames C, Fearon Z, Way EL. Calcium-opiate antagonism in the periaqueductal grey (PGA) region. Eur J Pharmacol 1981; 76: 417–9.[Web of Science][Medline]
  31. Dogrul A, Yesilyurt O, Isimer A, Guzeldemir ME. L-type and T-type calcium channel blockade potentiate the analgesic effects of morphine and selective mu opioid agonist, but not to selective delta and kappa agonist at the level of the spinal cord in mice. Pain 2001; 93: 61–8.[Web of Science][Medline]
  32. Connor M, Schuller A, Pintar JE, Christie MJ. Mu-opioid receptor modulation of calcium channel current in periaqueductal grey neurons from C57B16/J mice and mutant mice lacking MOR-1. Br J Pharmacol 1999; 126: 1553–8.[Web of Science][Medline]
  33. Yamamoto HA, McCain HW, Misawa S, Way EL. Effects of amino acids, especially taurine and gamma-aminobutyric acid (GABA), on analgesia and calcium depletion induced by morphine in mice. Eur J Pharmacol 1981; 71: 177–84.[Web of Science][Medline]
  34. Connor M, Christie MJ. Modulation of Ca2+ channel currents of acutely dissociated rat periaqueductal grey neurons. J Physiol 1998; 509: 47–58.[Abstract/Free Full Text]
  35. Kim CJ, Rhee JS, Akaike N. Modulation of high-voltage activated Ca2+ channels in the rat periaqueductal gray neurons by mu-type opioid agonist. J Neurophysiol 1997; 77: 1418–24.[Abstract/Free Full Text]
Accepted for publication November 19, 2002.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press