AJP - Regu Ad Instruments
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 291: R307-R314, 2006. First published March 23, 2006; doi:10.1152/ajpregu.00824.2005
0363-6119/06 $8.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
291/2/R307    most recent
00824.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ji, Y.
Right arrow Articles by Traub, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ji, Y.
Right arrow Articles by Traub, R. J.

CALL FOR PAPERS
Sex and Gender Differences in Pain and Inflammation

Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated

Yaping Ji,1,2 Anne Z. Murphy,2,3 and Richard J. Traub1,2

1Department of Biomedical Sciences, 2Research Center for Neuroendocrine Influences on Pain, University of Maryland, Baltimore, Maryland; 3Georgia State University, Atlanta, Georgia

Submitted 23 November 2005 ; accepted in final form 14 March 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Increasing evidence suggests there is a sex difference in opioid analgesia of pain arising from somatic tissue. However, the existence of a sex difference in visceral pain and opioid analgesia is unclear. This was examined in the colorectal distention (CRD) model of visceral pain in the current study. The visceromotor response (vmr) to noxious CRD was recorded in gonadally intact male and female rats. Subcutaneous injection of morphine dose-dependently decreased the vmr in both groups without affecting colonic compliance. However, morphine was significantly more potent in male rats than females. Because systemic morphine can act at peripheral tissue and in the central nervous system (CNS), the source of the sex difference in morphine analgesia was determined. The peripherally restricted µ-opioid receptor (MOR) antagonist naloxone methiodide dose-dependently attenuated the effects of systemic morphine. Systemic administration of the peripherally restricted MOR agonist loperamide confirmed peripherally mediated morphine analgesia and revealed greater potency in males compared with females. Spinal administration of morphine dose-dependently attenuated the vmr, but there was no sex difference. Intracerebroventricular administration of morphine also dose-dependently attenuated the vmr with significantly greater potency in male rats. The present study documents a sex difference in morphine analgesia of visceral pain that is both peripherally and supraspinally mediated.

colorectal distention; male; female; µ opioid receptor; visceromotor response; intrathecal; intracerebroventricular

IT IS GENERALLY ACCEPTED THAT females are more sensitive to pain than males (3, 12, 30). Women report lower thresholds, higher pain ratings, and less tolerance to experimental and postsurgical pain compared with men (15, 28). It has also been reported that men have greater activation of the µ-opioid system in the anterior thalamus, ventral basal ganglia, and amygdala than women in response to sustained pain (90), suggesting that sex differences in endogenous opioid receptor activation during painful stimulation might contribute to sex differences in pain.

The existence and direction of sex differences in exogenous opioid-induced analgesia is controversial. Although most animal studies (~66% in rats; see Ref. 22) report that morphine and other µ opioid agonists are more potent in males than females in several tests of acute somatic pain (17, 46, 47, 81), other lines of evidence suggest no difference or differences in the opposite direction. For example, there was no sex difference in the jump test after intracerebroventricular injection of DAMGO, but male rats showed greater analgesic response in the tail flick test (47). Similar studies reported no sex difference in analgesia using systemic fentanyl or buprenorphine in the hot plate or tail withdrawal tests in rats (10) and sex differences in analgesic potency increased when opioid efficacy decreased in the warm water test (81). In persistent pain models, results are mixed. Mu-opioid receptor (MOR) agonists are more potent in male compared with female rats after complete Freund's adjuvant-induced hyperalgesia (20, 84), but buprenorphine was more potent in females than males during capsaicin induced thermal hyperalgesia (9). The potency of µ agonists also varies across strains in rats and mice (19, 49, 81). Together, this suggests that several factors, including agonist efficacy and administration route, stimulus type, and intensity, as well as strain of subjects, affect the outcome in experimental studies (22, 29, 48).

Sex differences in opioid sensitivity have also been reported in human studies. Clinically, women require less {kappa} opioid receptor agonists after oral surgery (33–35). In contrast, women are reported to use more (5, 15, 61) or less (16) morphine to achieve a similar degree of analgesia after other surgical procedures or during emergency room visits compared with men. However, in experimental pain studies, morphine was either equipotent or more potent in women (31, 67). These reports suggest that morphine may be more effective in men with deep tissue pain but not necessarily during experimental pain.

In comparison to the numerous studies examining sex differences in the potency of opioids in somatic pain, few studies have focused on visceral pain (6, 57). Given that visceral pain such as esophagitis, irritable bowel syndrome, and interstitial cystitis are particularly prevalent in women (12), and opioids are prescribed for alleviation of pain under such circumstances (21, 41), it is important to know whether opioids are more potent in males or females. In the current study, we tested the hypotheses that 1) there is a sex difference in systemic morphine-induced analgesia in a visceral pain model (colorectal distention), and 2) central and/or peripheral µ-opioid receptors contribute to the sex difference in morphine sensitivity. Some of these results have appeared in abstract form (39).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Male and female Sprague-Dawley rats (220–250 g) were used in the present study. Rats were housed two per cage in same-sex rooms with free access to food and water, and maintained on a 12:12-h light-dark cycle. All protocols were approved by the University of Maryland Dental School Institutional Animal Care and Use Committee.

Visceromotor response. Five to seven days before recording, electromyogram (EMG) electrodes made from Teflon-coated 32-g stainless-steel wire (Cooner Wire, Chatsworth, CA) were implanted in the lateral abdominal wall to monitor reflexive contraction of the abdominal muscles in response to distending the colon (visceromotor response, vmr) (62, 82). After recovery, animals were single housed in same sex rooms until the time of recording.

Animals were fasted for 24 h before recording. Water was available ad libitum. On the day of the experiment, rats were briefly sedated with halothane, and a 5- to 6-cm balloon, made from the finger of a surgical glove and attached to Tygon tubing, was inserted through the anus into the descending colon and rectum. The secured end of the balloon was maintained 1 cm proximal to the external anal sphincter by taping the tubing to the tail. Rats were loosely restrained in Plexiglas rodent restrainers and allowed 30 min to recover from the halothane. Colorectal distention was produced by inflating the distention balloon with air to 60 mmHg (20-s duration, 3-min interstimulus interval). The pressure was monitored and kept constant by a pressure controller/timing device (Bioengineering, University of Iowa). The rats were first distended 12 times to acclimate to the testing protocol, thereby stabilizing the response (62). Subsequent distentions were run in trials of 6 distentions to establish a baseline vmr. In the rare instance that the mean of the two trials differed by more than 20%, an additional trial was run. After establishment of a stable baseline, morphine was administered and the vmr recorded again.

The EMG data were collected and analyzed with a CED 1401plus using Spike 2 for Windows software (Cambridge Electronic Design, Cambridge, UK). The EMG was rectified and the area under the curve (AUC) for the 20 s before distention subtracted from the AUC during the 20-s distention to give the magnitude of the vmr.

Catheter implantation and drug administration. The existence of a sex difference in systemic morphine-induced analgesia to noxious colorectal distension (CRD) was first established. To test whether spinal or supraspinal µ-opioid receptors mediate the sex difference, morphine was injected either intrathecally or intracerebroventricularly. The peripheral component of morphine was examined by using naloxone methiodide and loperamide.

Systemic injection. After insertion of the distention balloon, a polyethylene (PE)-10 catheter was subcutaneously implanted in the back of the neck for drug administration. Multiple doses of morphine (actual doses: 0.1, 0.2, 0.7, 2, and 7 mg/kg sc) or loperamide (1, 2, 7, and 10 mg/kg) were administered, and the vmr to CRD was recorded beginning 20 min after each injection. The responses to six distentions were averaged. The interval between each dose of drug was 40 min.

In separate animals, the half-maximal effective dose (ED50) of morphine was administered subcutaneously, and starting 10 min after morphine administration, the vmr was recorded three times over 10 min. A single dose of naloxone methiodide (0.1, 0.3 or 1.0 mg/kg sc) was administered immediately after the third distention, and the vmr was recorded over the next 20 min. The response to five distentions after naloxone methiodide was averaged.

Intrathecal injection. Catheters were implanted at the same time as the EMG electrodes. The rat was anesthetized with halothane and secured in a head holder. The atlantooccipital membrane was exposed, and an incision was made in the membrane. A catheter made of 32 g polyethylene tubing (ReCathCo, Allison Park, PA) was inserted 7.8 cm in the subdural space to reach to the lumbosacral spinal cord (L6-S2). The catheter and electrode leads were exteriorized at the back of the neck. Animals displaying any sign of paralysis were immediately removed from the study and euthanized (n = 2). During the experiment, multiple doses of morphine (0.1, 0.2, 0.7, 2, 7 µg, in 5 µl saline) were administered intrathecally over a 2-min period and the vmr to CRD was recorded starting 1 min after each injection. The response to five distentions was averaged. The interval between each dose of drug was 20 min. At the completion of each experiment, Evan's blue (2 µl) was injected to confirm catheter placement.

Intracerebroventricular injection. The rat was anesthetized with a mixture of 55 mg/kg ketamine, 5.5 mg/kg xylazine, and 1.1 mg/kg acepromazine. After EMG electrode placement, the rat was placed into a stereotaxic apparatus. A craniotomy was made dorsal to the lateral ventricle and a stainless steel guide cannula (22 G, C313G, PlasticOne, Roanoke, VA) was implanted at the following coordinates (mm) [bregma: –1.0; ML: 1.2; dorsoventral (DV): 3.2] (64). Two small screws were placed on either side of the sagittal suture to hold the guide cannula in place with cranioplastic cement. During the experiment, increasing doses of morphine (0.1, 0.2, 0.7, 2, 7, and 20 µg, in 2 µl saline) were administered to the ventricle through a 30 gauge inner catheter over a 2-min period, and the vmr to CRD was recorded starting 1 min after each injection. The response to five distentions was averaged. The interval between each dose of drug was 20 min. Evan's blue (1 µl) was injected to confirm injection into the ventricle at the completion of each experiment.

Compliance. The effect of morphine on colonic compliance was measured in awake rats. The volume in the distention balloon was increased from 0–8 ml in 0.5-ml increments, and the pressure was recorded at each volume. Rats were then given 10 mg/ml morphine (sc), and the compliance was measured again 15 min later.

Drugs. Morphine sulfate (supplied by the National Institute on Drug Abuse gift supply program) and naloxone methiodide (Sigma, St. Louis, MO) were dissolved in saline to desired concentrations. Doses used in the present experiment were selected according to previous studies (18, 46, 71). Loperamide (Sigma) was first dissolved in DMSO and brought to the desired concentration with saline (the final concentration of DMSO was 20%). Actual doses administered are listed in the appropriate section of METHODS, cumulative doses are shown in the figures when appropriate.

Statistics. The vmr data are reported as AUC, percent baseline response (%baseline) or percent maximum possible effect (%MPE = [postdrug AUC-predrug AUC]/[0-predrug AUC] x 100%), as appropriate and expressed as means ± SE. The dose that reduced the magnitude of the vmr to 50% of baseline (ED50) was determined by nonlinear regression carried out in PRISM (GraphPad Software, San Diego, CA). Data were analyzed using the Student's t-test or one or two-way repeated-measures (RM) ANOVA followed by Student-Newman-Keuls test for multiple comparisons as appropriate. The compliance data were analyzed by three-way RM ANOVA in SPSS. P < 0.05 was considered significant.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Baseline response to CRD. In a pilot study, we collected data from a group of female rats for which the stage of the estrous cycle was determined by taking vaginal smears for at least 2 cycles. Because no difference in the magnitude of vmr for rats in proestrus, estrus, and metestrus/diestrus stages was observed (48.8 ± 9.4, 47.6 ± 8.7, and 45.3 ± 4.5, respectively, n = 3–6/phase, one-way ANOVA, P = 0.95), the estrous phases for female rats in the present study were not measured.

The baseline vmr was compared between the male and female rats. There were no differences in the baseline responses from same-sex animals in the different experimental paradigms, so the data were pooled (male n = 38, female n = 35). The mean baseline vmr (AUC) for the female rats was significantly greater than male rats (47.6 ± 2.3 vs. 36.4 ± 1.9, Student's t-test, P < 0.001).

Effect of systemic morphine. Systemic morphine dose-dependently decreased the vmr in both male (n = 9) and female (n = 6) rats (Fig. 1A; one-way RM ANOVA, P < 0.001, dose for each sex). The potency of morphine was significantly greater in male rats compared with female rats, as reflected by the difference in ED50s (Table 1).


Figure 1
View larger version (12K):
[in this window]
[in a new window]
  		Fig. 1. A: Dose-response curves for male and female rats receiving subcutaneous injections of morphine in a cumulative dosing paradigm. Starting 20 min after each dose of morphine, the visceromotor response (vmr) to colorectal distention (CRD) was recorded. The interval between each injection of morphine was 40 min. B: baseline response before morphine administration. The half-maximal effective dose (ED50) for the female rats was significantly higher than for the male rats (see Table 1). B: volume-pressure curves for male and female rats before and after administration of 10 mg/kg morphine. Error bars are hidden under the symbols. There was no change in compliance in either sex.

 

View this table:
[in this window]
[in a new window]
  		Table 1. ED50s of morphine given through different routes in male and female rats

 
There was no difference in colonic compliance between male and female rats (n = 4 each) before administering morphine. Morphine (10 mg/kg sc) did not significantly alter compliance in either the male or female rats (Fig. 1B).

Time course for ED50 morphine. To determine the appropriate time period during which the peripheral component of systemic morphine could be compared between the two groups, the time course of the ED50 dose (sc) of morphine was obtained. The ED50 calculated from the previous experiment was given to the rats, and the vmr to CRD was recorded during the next 90 min (Fig. 2A, n = 5–6 per group). In both groups, the effect of morphine peaked by 10–20 min after the injection. Twenty minutes after administering the ED50 dose of morphine, the vmr to CRD was 50.2 ± 6.8% and 46.8 ± 7.5% of their baseline responses in male and female rats, respectively, validating the ED50 values derived from the previous cumulative dose experiment. The vmr to CRD remained at 50% of baseline for 45 min after morphine injection, and no difference was noted between the two sexes during this time (two-way RM ANOVA; sex, dose; P = 0.621). Approximately 50 min after morphine administration, the analgesic effect began to decrease in both groups. The vmr in male rats returned to baseline by 70 min; in contrast, females had not returned to baseline by 90 min when the experiment was terminated. Subsequent subcutaneous morphine studies were conducted within the 40-min window in which the analgesic effect of morphine was constant in both males and females.


Figure 2
View larger version (9K):
[in this window]
[in a new window]
  		Fig. 2. The contribution of peripheral µ-opioid receptors to morphine-induced analgesia. A: time course for analgesia produced by the ED50 dose of morphine in male and female rats. The vmr to CRD was recorded starting 10 min after morphine administration. There was no difference in the percent maximal possible effect (%MPE) for 45 min after morphine injection during which the naloxone methiodide study was done. B: dose-response curves showing naloxone methiodide reversing the effect of the ED50 dose of morphine in male and female rats, suggesting there is a peripheral component to morphine analgesia of the vmr. C: dose-response curves for subcutaneous loperamide in male and female rats, showing a sex difference in the peripheral activation of µ-opioid receptors.

 
Effect of naloxone methiodide. Naloxone methiodide (NalMet), a µ opioid receptor preferring quaternary salt that has limited accessibility to the central nervous system (CNS) if given systemically, was used to determine the peripheral component of the analgesic effect of subcutaneous morphine. In this experiment, the vmr was measured before and after subcutaneous administration of the ED50 dose of morphine (n = 4 or 5 per sex/dose) and then following subcutaneous NalMet administration. Each rat received one dose of NalMet. In both male and female rats, NalMet at 0.1 mg/kg did not affect morphine antinociception to noxious CRD (Fig. 2B). NalMet at 0.3 and 1.0 mg/kg dose-dependently reversed the effect of morphine in both sexes with greater potency in males compared with females (Fig. 2B; Two way ANOVA; sex, dose; P < 0.05). As a control, 1 mg/kg NalMet alone had no effect on the vmr (n = 4/sex, data not shown).

Effect of loperamide. Loperamide, a peripherally active µ-opioid agonist, was used to determine whether there is a sex difference in peripheral µ-opioid receptor activity. Loperamide dose-dependently attenuated the vmr to CRD in both male (n = 6) and female (n = 8) rats (Fig. 2C; one-way RM ANOVA, P < 0.01, dose for each sex). At the highest dose tested, the vmr was attenuated by 77% in male rats, but only 42% in female rats.

Effect of intrathecal morphine. To determine whether the sex difference in the potency of systemic morphine was mediated by spinal µ-opioid receptors, the effect of intrathecal morphine was compared in male (n = 5) and female (n = 5) rats. Intrathecal morphine dose-dependently decreased the vmr to CRD in both male and female rats (Fig. 3A; one-way RM ANOVA, P < 0.001, dose for each sex), but no sex difference in the ED50 dose of morphine was observed (Table 1).


Figure 3
View larger version (9K):
[in this window]
[in a new window]
  		Fig. 3. A: dose-response curves for male and female rats receiving intrathecal injections of morphine. There was no sex difference in the effect of intrathecal. morphine. B: dose-response curves for male and female rats receiving intracerebroventricular injections of morphine. Morphine was significantly more potent in males than females (see Table 1). C: dose-response curves for intracerebroventricular and intrathecal morphine in male and female rats. Intracerebroventricular morphine was significantly less potent than intrathecal morphine in both male and female rats.

 
In a separate group of animals (n = 2–3 per sex), 1 mg/kg naloxone methiodide (sc) was administered 20 min after 10 µg morphine (it). NalMet did not reverse the effect of morphine, confirming the effect of morphine was restricted in the CNS and NalMet acted peripherally.

Effect of intracerebroventricular morphine. To determine whether the difference in the potency of systemic morphine was mediated by supraspinal µ-opioid receptors, the effect of intracerebroventricular morphine was compared in male (n = 5) and female (n = 5) rats. Intracerebroventricular morphine dose-dependently decreased the vmr to CRD in each group (Fig. 3B; one-way RM ANOVA, P < 0.001, dose for each sex). Morphine was more potent in male rats compared with female rats, as reflected by the significant difference in the ED50 dose of morphine (Table 1).

The effects of intrathecal and intracerebroventricular morphine were compared within the same sex group. The baseline AUC for male rats was not different between the intracerebroventricular and intrathecal injection groups (36.5 ± 6.9 vs. 39.1 ± 4.6, t-test, P = 0.76). Similarly, no difference in baseline AUC was found in female rats receiving intracerebroventricular or intrathecal injection of morphine (49.1 ± 8.4 vs. 42.9 ± 5.5, Student's t-test, P = 0.55). However, intracerebroventricular morphine was less potent in attenuating the vmr compared with intrathecal injection for both sexes (two-way RM ANOVA; male, P < 0.05. female, P < 0.001; Fig. 3C).


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
The present study documents a sex difference in the analgesic response to systemic morphine in a visceral pain model. More importantly, our experiments reveal that the sex difference in the potency of systemic morphine is mediated by peripheral and supraspinal, but not spinal, MOR.

Sex differences in the analgesic potency of morphine to visceral pain. Controversial results have been reported as to whether there is a sex difference in the analgesic effect of morphine. Investigators using different strains of animals and pain assays report males being more sensitive (5, 6, 15, 17, 20, 46, 47, 84), equally sensitive (10, 47), or less sensitive (49) than females to the antinociceptive effect of morphine. The first part of our study, using colorectal distention as a model of visceral pain, shows a clear sex difference in the potency of systemically administered morphine. This is consistent with findings using the hot-plate, tail-flick, and writhing tests (6, 17, 47). Previous studies report no difference in the peak concentration of morphine in the blood and brain and the half-life (t1/2) in male and female rats after subcutaneous injection of morphine (18) or in concentrations of morphine or its metabolites in men and women after intravenous injection (67), suggesting that sex-related differences in the antinociceptive activity of morphine were not due to the difference in absorption or distribution. On the other hand, female rats are reported to have a higher morphine-3-glucuronide (M3G)/morphine ratio after subcutaneous injection of morphine (7). Given that M3G could act as a functional antagonist to the actions of morphine (32, 36, 72), sex differences in plasma M3G/morphine ratio after systemic injection may play a role in sex differences in morphine antinociception.

It should be noted that although the ED50 of systemic morphine in male rats was much lower than that in female rats, the analgesic effect of the ED50 morphine had a shorter duration in the male rats. However, when the same dose of morphine was given to female and male rats, the effect of morphine lasted longer in the males (17). Therefore, it is important to consider both the dose and time elapsed after injection when comparing the analgesic potency of morphine between the sexes.

Do peripheral µ-opioid receptors contribute to sex differences in morphine analgesia? In vivo and in vitro studies report modest or no effect of µ-opioid receptor agonists on resting activity of primary afferent fibers (2). Under painful stimulation (noxious urinary bladder distention), neither morphine nor fentanyl altered the pelvic nerve afferent fiber activity (80). These observations seem to support the widely accepted notion that the analgesic effects of opioids are exclusively mediated by actions in the CNS. However, peripheral opioid receptor activity is regulated by the status of the peripheral tissue/nerve, based on the fact that these receptors become functional after the induction of inflammation (42, 74–76).

The functions of peripheral µ-opioid receptors and the existence of sex differences in their functions in visceral pain have not been well documented, partly because of the location of the visceral organs that makes it hard for local application of a precise amount of drugs. In our study, we used a peripherally restricted µ-opioid receptor-preferring antagonist, naloxone methiodide, and showed that it dose-dependently reversed the effect of systemic morphine, suggesting peripheral µ-opioid receptors are involved in morphine-induced analgesia to noxious CRD. This was further supported by the finding that loperamide, a peripherally active µ-opioid agonist that has minimal access to the CNS (26, 69), also dose-dependently attenuated the vmr. These observations are in line with several recent studies demonstrating peripheral antinociceptive effects of opioids in the absence of peripheral inflammation (51, 52) (for reviews, see Refs. 8, 74, 75). This notion is further supported by the findings that: 1) µ-opioid receptors are present in normal dorsal root ganglia (DRG) neurons (38), including those innervating the colon (unpublished observations), as well as nerve endings in human skin and gastrointestinal tract (73, 77); 2) The µ agonist DAMGO-induced MOR G-protein coupling in DRG of noninflamed animals (38, 89); 3) in vitro calcium imaging shows that morphine inhibited the increase in the free intracellular Ca2+ concentration evoked by depolarization of DRG neurons (50). However, our observations are in contrast to some of the previous studies showing no effect of intra-arterial morphine on gastric vagal afferent fiber responses to gastric distention or pelvic nerve fiber responses to urinary bladder or colorectal distention (63, 70, 79). The discrepancy between our observation and others might be due to the different route of morphine administration and different experimental preparation. Morphine, when given through the artery, has been reported to have no effect on the somatocardiac sympathetic reflexes, whereas application of morphine into the femoral vein was effective (1). Therefore, it is possible that intra-arterially administered morphine may be quickly removed from the body before it gets to the peripheral µ-opioid receptors. Furthermore, cutting dorsal roots to record from teased fibers may cause changes in peripheral expression of µ-opioid receptors (78, 88), which may explain the ineffectiveness of morphine in neuropathic pain models (25).

Differences in the magnitude of reversal of morphine analgesia by naloxone methiodide was noted between the sexes, suggesting that peripheral µ-opioid receptors contribute to sex differences in visceral analgesia induced by systemic morphine. This was confirmed by the difference in the dose-response curves for systemic loperamide. Because there was no difference in colonic compliance or colon plasma extravasation between male and female rats (40, 83), the sex difference in the peripheral effect of morphine was not due to differences in the peripheral tissue and likely resulted from differences in the colonic afferent neurons. In contrast, a recent study demonstrated loperamide had no effect on paw withdrawal pressure threshold in both male and female rats (20). This difference suggests that peripheral morphine analgesia, in general, and sex differences, in particular, may differ by organ and experimental design.

Do spinal µ-opioid receptors contribute to sex differences in morphine analgesia? We next determined whether the sex difference in the response to systemic morphine was mediated by opioid receptors in the CNS. As a first step, morphine was administered intrathecally, and a potent antinociceptive effect was achieved in both male and female rats with no sex difference. These observations are consistent with the findings that MOR immunoreactivity is enriched in the superficial laminae of the dorsal horn (4), and studies reporting intrathecal morphine to be potent in eliciting antinociceptive effects in both male and female subjects (23, 58, 68). Given there is no difference in the dose-response curves to intrathecal morphine between ovariectomized and estrogen replacement rats (39) when the effects of estrogen would be expected to be greatest, the lack of a sex difference is not surprising. Similarly, no sex difference or gonadal hormone-regulated effect of intrathecal morphine has been observed in other somatic or visceral pain models (24, 53, 71).

Supraspinal action. Mu-opioid receptors are present in a number of brain areas, including the cerebral cortex, striatum, hippocampus, locus coeruleus, parabrachial nuclei, rostroventromedial medulla (RVM), and periaqueductal gray (PAG) (4, 43), and several of these regions show sexually dimorphic expression of MOR (27). Accordingly, a sex difference in the analgesic effect of supraspinally administered morphine has been reported with tests on somatic tissue (6, 46). Injection of µ-opioid receptor agonists into the RVM and PAG elicited a greater magnitude of antinociception on the tail flick and jump tests in male than female rats (13, 54). After hindpaw inflammation, morphine injected into the PAG is more potent in male compared with female rats (59). To date, however, the effect of intracerebroventricular morphine on visceral pain has not been examined. The result of our study shows for the first time that activation of supraspinal µ-opioid receptors produces a profound sex difference in morphine-induced analgesia in a visceral pain model. No sex difference was noted in the analgesic potency of spinal morphine suggesting a supraspinal mode of action for intracerebroventricular morphine. Further studies need to be carried out to reveal the brain areas where sex differences in the antinociceptive potency of morphine is mediated.

Spinal vs. supraspinal morphine. Although both spinal and supraspinal administration of µ-opioid receptor agonists produce potent analgesia in male and female rats, supraspinal morphine was significantly less potent than spinal morphine. This difference likely reflects the difference in the mechanism of action of spinal and supraspinal morphine. Supraspinal morphine alleviates pain indirectly by activating a descending inhibitory system. Morphine in the PAG or RVM inhibits "ON" cells and indirectly excites "OFF" cells leading to antinociception (37). In contrast, intrathecal morphine acts directly on receptors localized in the spinal cord, inhibiting post synaptic neurons and decreasing transmitter release presynaptically (60). Given this, it is not surprising to observe synergistic antinociceptive effects of spinal and supraspinal morphine (86, 87).

Possible mechanisms underlying sex differences in µ-opioid receptor-mediated antinociception. Laboratory experiments point to a biological basis for sex differences in opioid analgesia. Opioid receptor density in several pain-related areas [PAG, parabrachial nucleus (PBn)] is significantly lower in female rats during proestrus compared with diestrus and metestrus phases or male rats (27). Because rats in proestrus have the greatest plasma estrogen concentration than the other phases (14), a possible role of 17beta-estradiol in modulating µ-opioid receptor expression has been proposed. In fact, short-term treatment with estrogen in ovariectomized rats decreased the number of opioid binding sites in the brain, decreasing the analgesic effects of morphine (11, 66, 85). In addition, estrogen modulates the potency of morphine by influencing G protein coupling (44, 45, 55, 56, 65). Unpublished data from our lab show ovariectomized rats had similar dose-response curves to male rats when morphine was injected systemically, intrathecally, or intracerebroventricularly. Furthermore, morphine is more potent in ovariectomized rats compared with ovariectomized rats with estrogen replacement (39). These data suggest that estrogen decreases MOR function by decreasing available receptors and/or altering receptor coupling to G proteins and may underlie the sex difference in morphine-induced analgesia.

Alternatively, the sex difference in morphine potency may be caused by the higher nociceptive responses to CRD in female rats. However, this seems unlikely since the difference in the baseline response were small (~25%) but statistically significant. In contrast the ED50 dose of morphine differed by more than twofold, suggesting that differences in the baseline nociceptive response likely does not fully account for the differences in morphine potency.

In conclusion, the present experiment reveals a sex difference in the attenuation of colorectal pain produced by systemic morphine. We show clear evidence that morphine analgesia is mediated by peripheral, spinal, and supraspinal µ-opioid receptors. However, the sex difference is supraspinally, and to a lesser extent, peripherally mediated. Although activation of spinal MORs is the most potent site for morphine analgesia, it does not contribute to the sex difference in the analgesic effects of morphine.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This study was supported by National Institutes of Health Grants P50-AR-49555 and R01-NS-37424.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. Traub, Dept. of Biomedical Science, Univ. of Maryland Dental School, Rm. 5-A-22, 666 W. Baltimore St., Baltimore, MD 21201 (E-mail: rtraub{at}umaryland.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 

  1. Adachi T, Sato A, Sato Y, and Schmidt RF. Depending on the mode of application morphine enhances or depresses somatocardiac sympathetic A- and C-reflexes in anesthetized rats. Neurosci Res 15: 281–288, 1992.[CrossRef][Web of Science][Medline]
  2. Andreev N, Urban L, and Dray A. Opioids suppress spontaneous activity of polymodal nociceptors in rat paw skin induced by ultraviolet irradiation. Neuroscience 58: 793–798, 1994.[CrossRef][Web of Science][Medline]
  3. Arendt-Nielsen L, Bajaj P, and Drewes AM. Visceral pain: gender differences in response to experimental and clinical pain. Eur J Pain 8: 465–472, 2004.[CrossRef][Web of Science][Medline]
  4. Arvidsson U, Riedl M, Chakrabarti S, Lee JH, Nakano AH, Dado RJ, Loh HH, Law PY, Wessendorf MW, and Elde R. Distribution and targeting of a mu-opioid receptor (MOR1) in brain and spinal cord. J Neurosci 15: 3328–3341, 1995.[Abstract]
  5. Aubrun F, Salvi N, Coriat P, and Riou B. Sex- and age-related differences in morphine requirements for postoperative pain relief. Anesthesiology 103: 156–160, 2005.[CrossRef][Web of Science][Medline]
  6. Baamonde AI, Hidalgo A, and Andres-Trelles F. Sex-related differences in the effects of morphine and stress on visceral pain. Neuropharmacology 28: 967–970, 1989.[CrossRef][Web of Science][Medline]
  7. Baker L and Ratka A. Sex-specific differences in levels of morphine, morphine-3-glucuronide, and morphine antinociception in rats. Pain 95: 65–74, 2002.[CrossRef][Web of Science][Medline]
  8. Barber A and Gottschlich R. Opioid agonists and antagonists: an evaluation of their peripheral actions in inflammation. Med Res Rev 12: 525–562, 1992.[Web of Science][Medline]
  9. Barrett AC, Smith ES, and Picker MJ. Capsaicin-induced hyperalgesia and mu-opioid-induced antihyperalgesia in male and female Fischer 344 rats. J Pharmacol Exp Ther 307: 237–245, 2003.[Abstract/Free Full Text]
  10. Bartok RE and Craft RM. Sex differences in opioid antinociception. J Pharmacol Exp Ther 282: 769–778, 1997.[Abstract/Free Full Text]
  11. Berglund LA, Derendorf H, and Simpkins JW. Desensitization of brain opiate receptor mechanisms by gonadal steroid treatments that stimulate luteinizing hormone secretion. Endocrinology 122: 2718–2726, 1988.[Abstract/Free Full Text]
  12. Berkley KJ. Sex differences in pain. Behav Brain Sci 20: 371–380, 1997.[CrossRef][Web of Science][Medline]
  13. Boyer JS, Morgan MM, and Craft RM. Microinjection of morphine into the rostral ventromedial medulla produces greater antinociception in male compared to female rats. Brain Res 796: 315–318, 1998.[CrossRef][Web of Science][Medline]
  14. Cameron VA, Autelitano DJ, Evans JJ, Ellmers LJ, Espiner EA, Nicholls MG, and Richards AM. Adrenomedullin expression in rat uterus is correlated with plasma estradiol. Am J Physiol Endocrinol Metab 282: E139–E146, 2002.[Abstract/Free Full Text]
  15. Cepeda MS and Carr DB. Women experience more pain and require more morphine than men to achieve a similar degree of analgesia. Anesth Analg 97: 1464–1468, 2003.[Abstract/Free Full Text]
  16. Chia YY, Chow LH, Hung CC, Liu K, Ger LP, and Wang PN. Gender and pain upon movement are associated with the requirements for postoperative patient-controlled iv analgesia: a prospective survey of 2,298 Chinese patients: [Les besoins d'analgesie iv auto-controlee sont lies au sexe du sujet et a la douleur au mouvement : une enquete aupres de 2 298 Chinois]. Can J Anesth 49: 249–255, 2002.[Web of Science][Medline]
  17. Cicero TJ, Nock B, and Meyer ER. Gender-related differences in the antinociceptive properties of morphine. J Pharmacol Exp Ther 279: 767–773, 1996.[Abstract/Free Full Text]
  18. Cicero TJ, Nock B, and Meyer ER. Sex-related differences in morphine's antinociceptive activity: relationship to serum and brain morphine concentrations. J Pharmacol Exp Ther 282: 939–944, 1997.[Abstract/Free Full Text]
  19. Cook CD, Barrett AC, Roach EL, Bowman JR, and Picker MJ. Sex-related differences in the antinociceptive effects of opioids: importance of rat genotype, nociceptive stimulus intensity, and efficacy at the µ opioid receptor. Psychopharmacology (Berl) 150: 430–442, 2000.[CrossRef][Medline]
  20. Cook CD and Nickerson MD. Nociceptive sensitivity and opioid antinociception and antihyperalgesia in Freund's adjuvant-induced arthritic male and female rats. J Pharmacol Exp Ther 313: 449–459, 2005.[Abstract/Free Full Text]
  21. Corazziari E. Role of opioid ligands in the irritable bowel syndrome. Can J Gastroenterol 13 Suppl A: 71A-75A, 1999.
  22. Craft RM. Sex differences in opioid analgesia: "from mouse to man". Clin J Pain 19: 175–186, 2003.[CrossRef][Web of Science][Medline]
  23. Danzebrink RM, Green SA, and Gebhart GF. Spinal mu and delta, but not kappa, opioid-receptor agonists attenuate responses to noxious colorectal distension in the rat. Pain 63: 39–47, 1995.[CrossRef][Web of Science][Medline]
  24. Dawson-Basoa ME and Gintzler AR. Estrogen and progesterone activate spinal kappa-opiate receptor analgesic mechanisms. Pain 64: 608–615, 1996.[CrossRef][Medline]
  25. Decosterd I, Allchorne A, and Woolf CJ. Differential analgesic sensitivity of two distinct neuropathic pain models. Anesth Analg 99: 457–463, 2004.[Abstract/Free Full Text]
  26. DeHaven-Hudkins DL, Burgos LC, Cassel JA, Daubert JD, DeHaven RN, Mansson E, Nagasaka H, Yu G, and Yaksh T. Loperamide (ADL 2–1294), an opioid antihyperalgesic agent with peripheral selectivity. J Pharmacol Exp Ther 289: 494–502, 1999.[Abstract/Free Full Text]
  27. Duncan KA and Murphy A. Sex-linked differences in mu opiate receptor expression in the rat brain. In: Proceedings of the 11th World Congress on Pain, Program No. 214 Abstract Viewer. Sydney, Australia: International Association for the Study of Pain, 2005, p. 191.
  28. Fillingim RB, Edwards RR, and Powell T. The relationship of sex and clinical pain to experimental pain responses. Pain 83: 419–425, 1999.[CrossRef][Web of Science][Medline]
  29. Fillingim RB and Gear RW. Sex differences in opioid analgesia: clinical and experimental findings. Eur J Pain 8: 413–425, 2004.[CrossRef][Web of Science][Medline]
  30. Fillingim RB and Ness TJ. Sex-related hormonal influences on pain and analgesic responses. Neurosci Biobehav Rev 24: 485–501, 2000.[CrossRef][Web of Science][Medline]
  31. Fillingim RB, Ness TJ, Glover TL, Campbell CM, Hastie BA, Price DD, and Staud R. Morphine responses and experimental pain: sex differences in side effects and cardiovascular responses but not analgesia. J Pain 6: 116–124, 2005.[CrossRef][Web of Science][Medline]
  32. Gardmark M, Karlsson MO, Jonsson F, and Hammarlund-Udenaes M. Morphine-3-glucuronide has a minor effect on morphine antinociception. Pharmacodynamic modeling. J Pharm Sci 87: 813–820, 1998.[CrossRef][Web of Science][Medline]
  33. Gear RW, Gordon NC, Miaskowski C, Paul SM, Heller PH, and Levine JD. Sexual dimorphism in very low dose nalbuphine postoperative analgesia. Neurosci Lett 339: 1–4, 2003.[CrossRef][Web of Science][Medline]
  34. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, and Levine JD. Kappa-opioids produce significantly greater analgesia in women than in men. Nat Med 2: 1248–1250, 1996.[CrossRef][Web of Science][Medline]
  35. Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, and Levine JD. The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in patients with postoperative pain. Pain 83: 339–345, 1999.[CrossRef][Web of Science][Medline]
  36. Gong QL, Hedner J, Bjorkman R, and Hedner T. Morphine-3-glucuronide may functionally antagonize morphine-6-glucuronide induced antinociception and ventilatory depression in the rat. Pain 48: 249–255, 1992.[CrossRef][Web of Science][Medline]
  37. Heinricher MM, Morgan MM, and Fields HL. Direct and indirect actions of morphine on medullary neurons that modulate nociception. Neuroscience 48: 533–543, 1992.[CrossRef][Web of Science][Medline]
  38. Ji RR, Zhang Q, Law PY, Low HH, Elde R, and Hokfelt T. Expression of mu-, delta-, and kappa-opioid receptor-like immunoreactivities in rat dorsal root ganglia after carrageenan-induced inflammation. J Neurosci 15: 8156–8166, 1995.[Abstract]
  39. Ji Y, Murphy AZ, and Traub RJ. Sex differences in morphine analgesia of visceral pain are supraspinally mediated. Society for Neuroscience Abstracts Abstract viewer: 294.5, 2005.
  40. Ji Y, Tang B, and Traub RJ. Estrogen increases and progesterone decreases behavioral and neuronal responses to colorectal distention following colonic inflammation in the rat. Pain 117: 433–442, 2005.[CrossRef][Web of Science][Medline]
  41. Jonsson E, Coombs DW, Hunstad D, Richardson JR Jr, von Reyn CF, Saunders RL and Heaney JA. Continuous infusion of intrathecal morphine to control acquired immunodeficiency syndrome-associated bladder pain. J Urol 147: 687–689, 1992.[Web of Science][Medline]
  42. Joris JL, Dubner R, and Hargreaves KM. Opioid analgesia at peripheral sites: a target for opioids released during stress and inflammation? Anesth Analg 66: 1277–1281, 1987.[Abstract/Free Full Text]
  43. Kalyuzhny AE, Arvidsson U, Wu W, and Wessendorf MW. mu-Opioid and delta-opioid receptors are expressed in brainstem antinociceptive circuits: studies using immunocytochemistry and retrograde tract-tracing. J Neurosci 16: 6490–6503, 1996.[Abstract/Free Full Text]
  44. Kelly MJ, Lagrange AH, Wagner EJ, and Ronnekleiv OK. Rapid effects of estrogen to modulate G protein-coupled receptors via activation of protein kinase A and protein kinase C pathways. Steroids 64: 64–75, 1999.[CrossRef][Web of Science][Medline]
  45. Kelly MJ, Loose MD, and Ronnekleiv OK. Estrogen suppresses mu-opioid- and GABAB-mediated hyperpolarization of hypothalamic arcuate neurons. J Neurosci 12: 2745–2750, 1992.[Abstract]
  46. Kepler KL, Kest B, Kiefel JM, Cooper ML, and Bodnar RJ. Roles of gender, gonadectomy and estrous phase in the analgesic effects of intracerebroventricular morphine in rats. Pharmacol Biochem Behav 34: 119–127, 1989.[CrossRef][Web of Science][Medline]
  47. Kepler KL, Standifer KM, Paul D, Kest B, Pasternak GW, and Bodnar RJ. Gender effects and central opioid analgesia. Pain 45: 87–94, 1991.[CrossRef][Web of Science][Medline]
  48. Kest B, Sarton E, and Dahan A. Gender differences in opioid-mediated analgesia: animal and human studies. Anesthesiology 93: 539–547, 2000.[CrossRef][Web of Science][Medline]
  49. Kest B, Wilson SG, and Mogil JS. Sex differences in supraspinal morphine analgesia are dependent on genotype. J Pharmacol Exp Ther 289: 1370–1375, 1999.[Abstract/Free Full Text]
  50. Khasabova IA, Harding-Rose C, Simone DA, and Seybold VS. Differential effects of CB1 and opioid agonists on two populations of adult rat dorsal root ganglion neurons. J Neurosci 24: 1744–1753, 2004.[Abstract/Free Full Text]
  51. Kolesnikov Y and Pasternak GW. Topical opioids in mice: analgesia and reversal of tolerance by a topical N-methyl-D-aspartate antagonist. J Pharmacol Exp Ther 290: 247–252, 1999.[Abstract/Free Full Text]
  52. Kolesnikov YA, Jain S, Wilson R, and Pasternak GW. Peripheral morphine analgesia: synergy with central sites and a target of morphine tolerance. J Pharmacol Exp Ther 279: 502–506, 1996.[Abstract/Free Full Text]
  53. Kroin JS, Buvanendran A, Nagalla SK, and Tuman KJ. Postoperative pain and analgesic responses are similar in male and female Sprague-Dawley rats. Can J Anaesth 50: 904–908, 2003.[Web of Science][Medline]
  54. Krzanowska EK and Bodnar RJ. Morphine antinociception elicited from the ventrolateral periaqueductal gray is sensitive to sex and gonadectomy differences in rats. Brain Res 821: 224–230, 1999.[CrossRef][Web of Science][Medline]
  55. Lagrange AH, Ronnekleiv OK, and Kelly MJ. The potency of mu-opioid hyperpolarization of hypothalamic arcuate neurons is rapidly attenuated by 17 beta-estradiol. J Neurosci 14: 6196–6204, 1994.[Abstract]
  56. Lagrange AH, Ronnekleiv OK, and Kelly MJ. Modulation of G protein-coupled receptors by an estrogen receptor that activates protein kinase A. Mol Pharmacol 51: 605–612, 1997.[Abstract/Free Full Text]
  57. Larsson M, Arvidsson S, Ekman C, and Bayati A. A model for chronic quantitative studies of colorectal sensitivity using balloon distension in conscious mice—effects of opioid receptor agonists. Neurogastroenterol Motil 15: 371–381, 2003.[CrossRef][Web of Science][Medline]
  58. Leighton BL, DeSimone CA, Norris MC, and Ben David B. Intrathecal narcotics for labor revisited: the combination of fentanyl and morphine intrathecally provides rapid onset of profound, prolonged analgesia. Anesth Analg 69: 122–125, 1989.[Free Full Text]
  59. Loyd D, Wang X, and Murphy AZ. Morphine injection into the periaqueductal gray produces a sexually dimorphic response in a model of persistent inflammatory pain. Society for Neuroscience Abstracts Abstract viewer: 394.3, 2005.
  60. Millan MJ. Descending control of pain. Prog Neurobiol 66: 355–474, 2002.[CrossRef][Web of Science][Medline]
  61. Miller PL and Ernst AA. Sex differences in analgesia: a randomized trial of mu versus kappa opioid agonists. South Med J 97: 35–41, 2004.[Web of Science][Medline]
  62. Ness TJ and Gebhart GF. Colorectal distention as a noxious visceral stimulus: physiologic and pharmacologic characterization of pseudaffective responses in the rat. Brain Res 450: 153–169, 1988.[CrossRef][Web of Science][Medline]
  63. Ozaki N, Sengupta JN, and Gebhart GF. Differential effects of mu-, delta-, and kappa-opioid receptor agonists on mechanosensitive gastric vagal afferent fibers in the rat. J Neurophysiol 83: 2209–2216, 2000.[Abstract/Free Full Text]
  64. Paxinos G and Watson C. The Rat Brain in Stereotaxic Coordinates. San Diego: Academic, 1986.
  65. Qiu J, Bosch MA, Tobias SC, Grandy DK, Scanlan TS, Ronnekleiv OK, and Kelly MJ. Rapid signaling of estrogen in hypothalamic neurons involves a novel G-protein-coupled estrogen receptor that activates protein kinase C. J Neurosci 23: 9529–9540, 2003.[Abstract/Free Full Text]
  66. Ratka A and Simpkins JW. Effects of estradiol and progesterone on the sensitivity to pain and on morphine-induced antinociception in female rats. Horm Behav 25: 217–228, 1991.[CrossRef][Medline]
  67. Sarton E, Olofsen E, Romberg R, Den Hartigh J, Kest B, Nieuwenhuijs D, Burm A, Teppema L, and Dahan A. Sex differences in morphine analgesia—an experimental study in healthy volunteers. Anesthesiology 93: 1245–1254, 2000.[CrossRef][Web of Science][Medline]
  68. Sato T, Sakurada S, Takahashi N, Sakurada T, Tan-No K, Wako K, and Kisara K. Contribution of spinal mu1-opioid receptors to morphine-induced antinociception. Eur J Pharmacol 369: 183–187, 1999.[CrossRef][Web of Science][Medline]
  69. Schinkel AH, Wagenaar E, Mol CA, and van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J Clin Invest 97: 2517–2524, 1996.[Web of Science][Medline]
  70. Sengupta JN, Snider A, Su X, and Gebhart GF. Effects of kappa opioids in the inflamed rat colon. Pain 79: 175–185, 1999.[CrossRef][Web of Science][Medline]
  71. Shin SW and Eisenach JC. Intrathecal morphine reduces the visceromotor response to acute uterine cervical distension in an estrogen-independent manner. Anesthesiology 98: 1467–1471, 2003.[CrossRef][Web of Science][Medline]
  72. Smith MT, Watt JA, and Cramond T. Morphine-3-glucuronide–a potent antagonist of morphine analgesia. Life Sci 47: 579–585, 1990.[CrossRef][Web of Science][Medline]
  73. Stander S, Gunzer M, Metze D, Luger T, and Steinhoff M. Localization of mu-opioid receptor 1A on sensory nerve fibers in human skin. Regul Pept 110: 75–83, 2002.[CrossRef][Web of Science][Medline]
  74. Stein C. Peripheral mechanisms of opioid analgesia. Anesth Analg 76: 182–191, 1993.[Abstract/Free Full Text]
  75. Stein C. The control of pain in peripheral tissue by opioids. N Engl J Med 332: 1685–1690, 1995.[Free Full Text]
  76. Stein C, Millan MJ, Yassouridis A, and Herz A. Antinociceptive effects of mu- and kappa-agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism. Eur J Pharmacol 155: 255–264, 1988.[CrossRef][Web of Science][Medline]
  77. Sternini C, Patierno S, Selmer IS, and Kirchgessner A. The opioid system in the gastrointestinal tract. Neurogastroenterol Motil 16 Suppl 2: 3–16: 3–16, 2004.[Web of Science][Medline]
  78. Stucky CL, Gold MS, and Zhang X. Mechanisms of pain. Proc Natl Acad Sci USA 98: 11845–11846, 2001.[Abstract/Free Full Text]
  79. Su X, Sengupta JN, and Gebhart GF. Effects of kappa opioid receptor-selective agonists on responses of pelvic nerve afferents to noxious colorectal distension. J Neurophysiol 78: 1003–1012, 1997.[Abstract/Free Full Text]
  80. Su X, Wachtel RE, and Gebhart GF. Inhibition of calcium currents in rat colon sensory neurons by K- but not µ- or {delta}-opioids. J Neurophysiol 80: 3112–3119, 1998.[Abstract/Free Full Text]
  81. Terner JM, Lomas LM, Smith ES, Barrett AC, and Picker MJ. Pharmacogenetic analysis of sex differences in opioid antinociception in rats. Pain 106: 381–391, 2003.[CrossRef][Web of Science][Medline]
  82. Traub RJ, Zhai QZ, Ji Y, and Kovalenko M. NMDA receptor antagonists attenuate noxious and nonnoxious colorectal distention-induced Fos expression and the visceromotor reflex. Neuroscience 113: 205–211, 2002.[CrossRef][Web of Science][Medline]
  83. Wang G, Tang B, and Traub RJ. Differential processing of noxious colonic input by thoracolumbar and lumbosacral dorsal horn neurons in the rat. J Neurophysiol 94: 3788–3794, 2005.[Abstract/Free Full Text]
  84. Wang X, Traub RJ, and Murphy AZ. Persistent pain model reveals sex difference in morphine potency. Am J Physiol Regul Integr Comp Physiol 291: R300–R306, 2006.[Abstract/Free Full Text]
  85. Weiland NG and Wise PM. Estrogen and progesterone regulate opiate receptor densities in multiple brain regions. Endocrinology 126: 804–808, 1990.[Abstract/Free Full Text]
  86. Wigdor S and Wilcox GL. Central and systemic morphine-induced antinociception in mice: contribution of descending serotonergic and noradrenergic pathways. J Pharmacol Exp Ther 242: 90–95, 1987.[Abstract/Free Full Text]
  87. Yeung JC and Rudy TA. Multiplicative interaction between narcotic agonisms expressed at spinal and supraspinal sites of antinociceptive action as revealed by concurrent intrathecal and intracerebroventricular injections of morphine. J Pharmacol Exp Ther 215: 633–642, 1980.[Abstract/Free Full Text]
  88. Zhang X, Bao L, Shi TJ, Ju G, Elde R, and Hokfelt T. Down-regulation of mu-opioid receptors in rat and monkey dorsal root ganglion neurons and spinal cord after peripheral axotomy. Neuroscience 82: 223–240, 1998.[Web of Science][Medline]
  89. Zollner C, Shaqura MA, Bopaiah CP, Mousa S, Stein C, and Schafer M. Painful inflammation-induced increase in µ-opioid receptor binding and G-protein coupling in primary afferent neurons. Mol Pharmacol 64: 202–210, 2003.[Abstract/Free Full Text]
  90. Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Jewett DM, Meyer CR, Koeppe RA, and Stohler CS. mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci 22: 5100–5107, 2002.[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 J. Neurosci.Home page
D. R. Loyd, X. Wang, and A. Z. Murphy
Sex Differences in {micro}-Opioid Receptor Expression in the Rat Midbrain Periaqueductal Gray Are Essential for Eliciting Sex Differences in Morphine Analgesia
J. Neurosci., December 24, 2008; 28(52): 14007 - 14017.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
K. J. Berkley, S. S. Zalcman, and V. R. Simon
Sex and gender differences in pain and inflammation: a rapidly maturing field
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R241 - R244.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
291/2/R307    most recent
00824.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Web of Science (17)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ji, Y.
Right arrow Articles by Traub, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ji, Y.
Right arrow Articles by Traub, R. J.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2006 by the American Physiological Society.