Preclinical experiments have revealed much about opioid withdrawal, but have failed to discover novel treatments. The preclinical literature is dominated by experiments examining naloxone-precipitated withdrawal from morphine in male rats. These studies report a number of putative treatments for opioid withdrawal, none of which have become clinically approved. A major problem, supported by both human and animal research, is that antagonist-precipitated withdrawal is distinct from the spontaneous opioid withdrawal experienced by most opioid users. A second problem is the widespread focus in animal research on somatic symptoms (e.g., wet dog shakes). Although somatic symptoms can be disruptive, anxiety, anhedonia, and aches are the symptoms that cause distress and drive relapse. Somatic symptoms are also problematic because they are easily suppressed by treatments that produce sedative or motor effects. A potential solution to these problems is the use of voluntary home cage wheel running as a more general measure of opioid withdrawal. Wheel running provides a continuous and objective measure ideal for assessing changes in the magnitude and duration of spontaneous withdrawal over time. The decrease in wheel running caused by opioid withdrawal changes the definition of an effective treatment from suppressing behavior (somatic symptoms) to restoring behavior (wheel running), thereby avoiding confounds produced by sedative or motor effects. This review provides a detailed analysis of rodent experiments on opioid withdrawal, highlighting potential problems with external validity and describing wheel running experiments that align animal experiments with the clinical manifestation of opioid withdrawal to enhance the development of novel treatments.

BACKGROUND:Many people use cannabis to self-medicate for pain. Little is known about the impact of pain on tolerance and spontaneous withdrawal to delta-9-tetrahydrocannabinal (THC), the primary psychoactive compound in cannabis. Our previous research with the opioid morphine suggests persistent pain will increase the magnitude and duration of THC withdrawal. METHODS:Male and female Sprague-Dawley rats were individually housed in a cage with a running wheel to provide a continuous and objective measure of well-being. All rats were injected with Complete Freund's Adjuvant (CFA) into the right hindpaw to induce inflammatory pain. Beginning 1 day later, rats received twice daily THC or vehicle injections for 7 days followed by assessment of tolerance and spontaneous withdrawal. RESULTS:Administration of CFA decreased wheel running. Twice daily injections of THC (3 mg/kg/injection) caused a further reduction in running in male and female rats. Tolerance to the THC-induced decrease in running was more pronounced in male compared to female rats. There was no evidence of spontaneous withdrawal to THC despite continuous assessment for 6 days. Likewise, withdrawal had no effect on body weight. CONCLUSION:The lack of spontaneous withdrawal in rats with hindpaw inflammation is consistent with our recent study showing a lack of spontaneous withdrawal to THC in pain free rats, but opposite to our opioid research showing enhancement of spontaneous withdrawal to morphine in rats with hindpaw inflammation. In sum, persistent inflammatory pain does not appear to alter the effects of repeated THC injections in male or female rats. SIGNIFICANCE:The use of THC as a treatment for pain is limited by side effects and tolerance but not by dependence associated withdrawal symptoms.

INTRODUCTION:Tolerance and dependence are known to occur with prolonged cannabis use. Few animal experiments on spontaneous withdrawal from delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, have been conducted. The experiments that have been conducted use extremely high doses and report relatively mild symptoms. The objective of the present experiment was to determine the magnitude and duration of spontaneous THC withdrawal in male and female rats using voluntary home cage wheel running as a sensitive, objective, and continuous measure of withdrawal. MATERIALS AND METHODS:Male and female Sprague-Dawley rats were injected with THC (3 mg/kg, s.c.) or vehicle twice daily for 7 days to induce tolerance and dependence. Spontaneous withdrawal was assessed for 5 days beginning 24 h after the day 8 tolerance test in which all rats received a THC injection. RESULTS:On day 1, THC profoundly decreased wheel running in male and female rats compared to vehicle-treated rats. On day 8, THC given to vehicle-treated rats produced a significantly greater decrease in running than in rats previously treated with THC, indicating tolerance development. There was no sex difference in the magnitude of the decrease in wheel running caused by THC injections or in the development of tolerance. There were no significant changes in wheel running associated with spontaneous THC withdrawal. DISCUSSION:These data suggest that spontaneous THC withdrawal in male and female rats is mild at best despite profound locomotor suppression and tolerance to repeated injections. The lack of spontaneous THC withdrawal contrasts sharply with the pronounced changes in wheel running produced by opioid withdrawal.

Opioids such as morphine and fentanyl are widely prescribed treatments for pain. Unfortunately, opioid use is limited by side effects, dependence, and the development of tolerance with repeated use. A major goal of preclinical opioid research is to identify the neural mechanisms underlying tolerance to opioids to provide better pain management and reduce side effects caused by high opioid doses. To that end, preclinical pain researchers have reported well over 101 mechanisms of opioid tolerance. The objective of this review is to describe both the scientific explanations for multiple mechanisms of opioid tolerance (eg, different types of opioid tolerance, different mechanisms at different locations and for different opioids) and the methodological problems that cause false positives. For example, many changes correlate with but do not cause tolerance. Opioid binding to mu-opioid receptors (MOR) activates a signaling cascade that includes numerous molecules and cells making it difficult to identify the precise mechanism causing tolerance. Other problems, such as lack of appropriate control groups or confounds produced by antinociceptive or motor effects of the treatment, are surprisingly common. Solutions to these problems are presented at the end of the article in the hope of guiding future research. Although the focus is on opioid tolerance, the problems and solutions presented here apply to tolerance to other drugs and any neural change that occurs over time such as learning.

Background Sex differences in inflammatory bowel disease (IBD) have been reported in humans, and gonadal steroid hormones are implicated in these sex differences. Despite the fact that pain is a primary complaint among IBD patients, and pain often does not correlate with colon pathology, most animal studies focus on physiological rather than behavioral measures of IBD. Thus, the present study determined whether IBD-like pain is greater in female than male rats, and whether testosterone ameliorates IBD-like pain in females. Methods Blank capsules were implanted into gonadally intact adult females and males, and another group of females was implanted with testosterone-filled capsules. Three weeks later, trinitrobenzene sulphonic acid (TNBS) was administered intracolonically to induce colitis. Body weight and continuous, home-cage wheel running were measured daily, before and for 10 days after colitis induction. Estrous cycle was monitored for 21 days in a subset of females. At the end of the study, serum testosterone and estradiol were determined, in addition to clitoral/preputial gland size. Results TNBS significantly suppressed body weight and home-cage wheel running, which partially recovered within 10 days. There were no group differences in magnitude or time course of these effects. Serum testosterone was elevated in testosterone-treated compared to control females and did not differ significantly from males, whereas serum estradiol was similar across groups. Testosterone exposure suppressed females’ estrous cycling and increased clitoral gland size. At the end of the study, serum estradiol but not testosterone was found to be correlated with suppression of body weight and wheel running during the previous 10 days. Conclusions These results do not support the hypotheses of sex differences in IBD-like pain, or that testosterone ameliorates IBD-like pain in females, but corroborate human and rodent data suggesting that estradiol is associated with IBD severity in both sexes.

To understand the experiences of Death Café attendees and facilitators, the current qualitative study entailed interviews with nine participants focused on mortality awareness. Discussion of findings explores how mortality awareness influences culture and values. Implications explore how death and mortality can be addressed in counseling practice.

Testosterone may reduce pain in cisgender women and transgender men. Rodents can provide a useful model for investigating physiological effects of hormone therapy. To this end, continuous-release testosterone or blank (placebo) capsules were implanted s.c. into young adult female rats, and three weeks later rats were either ovariectomized or sham-ovariectomized. Testosterone treatment that mimicked previously reported endogenous levels in males eliminated estrous cycling and decreased uterine weight. Testosterone also significantly increased body weight and suppressed the increases in daily wheel running observed in placebo controls over time. Subsequent ovariectomy or sham-ovariectomy decreased wheel running in all groups, but testosterone-treated rats recovered significantly more quickly than did placebo-treated rats. Neither testosterone nor ovariectomy significantly altered hindpaw mechanical threshold. Two weeks after sham/ovariectomy surgery, injection of Complete Freund Adjuvant (CFA) into one hindpaw reduced wheel running and mechanical threshold in all groups; running significantly decreased from the first to second day after CFA in testosterone- but not in placebotreated rats. Morphine 1.0 but not 3.2 mg/kg increased CFA-suppressed wheel running similarly in all groups, whereas both doses of morphine increased CFA-suppressed mechanical threshold. These data suggest that weekslong testosterone treatment with or without ovariectomy may provide a useful physiological model of testosterone therapy as used in human gender transition. Although testosterone administered at levels similar to those in gonadally intact males tended to hasten female rats' recovery from surgery, it did not decrease maximal painrelated behaviors after surgery or hindpaw inflammatory insult, nor did it alter opioid antinociception.

Animal studies modeling recreational opioid use show more severe withdrawal symptoms in male compared to female rats, whereas our study modeling opioid use for pain showed a greater withdrawal-induced decrease in wheel running in female rats. The objective of this experiment was to determine whether sex differences in spontaneous morphine withdrawal are caused by differences in assessment method (i.e., wheel running vs. somatic symptoms). Twice daily injections of morphine (5 - 20mg/kg, s.c.) for 5 days produced a dose and time dependent decrease in wheel running that was greater in male compared to female rats. Termination of morphine administration resulted in an overall decrease in running and a decrease in the amount of running during the dark phase of the light cycle from 95% to approximately 75%. In male rats, this decrease in the percent of dark running was caused by a large decrease in dark phase running, whereas female rats had a slightly higher increase in light phase running. Withdrawal also reduced maximal running speed and caused a decrease in body weight that was larger in male than female rats. Withdrawal symptoms were greatest on the day following the last morphine injection, but persisted for all 3 days of assessment. Morphine withdrawal produced a greater decrease in dark phase wheel running and body weight in male rats and a greater increase in light phase running in female rats. Voluntary home cage wheel running provides a continuous measure of opioid withdrawal that is consistent with other measures of opioid withdrawal.

Although opioids are the most effective treatment for pain, their use in treating chronic pain is limited by the development of tolerance with prolonged use. A major goal of preclinical research is to identify the neural mechanisms underlying opioid tolerance so these mechanisms can be disrupted to prolong the analgesic effects. Approximately 100 neural mechanisms of opioid tolerance have been reported. Some of these mechanisms are the result of distinct types of tolerance and some of these are the result of poor experimental design. Tolerance can occur because of pharmacokinetic or pharmacodynamic changes. Moreover, pharmacodynamic mechanisms differ for associative and non-associative tolerance. Data also show distinct mechanism for tolerance depending on the opioid (morphine vs. fentanyl) and location of opioid action (PAG vs. spinal cord). However, most of the reported mechanisms underlying opioid tolerance are the result of poor methodology. Chronic opioid administration will produce many changes that correlate with, but do not cause tolerance. Common methodological confounds include behavioral tolerance produced by repeated testing and antinociceptive effects produced by manipulations used to disrupt tolerance. Identifying the molecular change underlying tolerance requires systematic assessment of upstream and downstream signaling pathways. Disruption of upstream pathways will block the development of tolerance, whereas disruption of downstream pathways will block the expression of tolerance. These studies must include non-treated control groups in which tolerance is assessed by comparing dose-response curves in all groups following removal of all treatments. Implementation of these methods are needed to identify the precise molecular changes underlying opioid tolerance.

Fentanyl is a potent analgesic with a rapid onset and short half-life that make it a useful treatment for pain and a lethal drug of abuse. The present study used voluntary home cage wheel running to assess the effect of hindpaw inflammation, fentanyl administration, and spontaneous fentanyl withdrawal. Fentanyl (0.32 or 1.0 mg/kg/day) or placebo osmotic pumps were implanted subcutaneously and rats received an intraplantar injection of Complete Freund's Adjuvant (CFA) or saline. Rats with hindpaw inflammation caused by CFA administration were less active than rats injected with saline into the hindpaw. The antinociceptive effect of 0.32 mg/kg/day of fentanyl was evident as a recovery of wheel running in these rats. Administration of 1 mg/kg/day of fentanyl almost completely inhibited wheel running during the first day in rats with and without hindpaw inflammation. Wheel running increased each subsequent day until the pumps were surgically removed after day 3. Withdrawal from 0.32 or 1 mg/kg/day of fentanyl caused a decrease in wheel running that lasted 2 days in rats without hindpaw inflammation. In contrast, withdrawal was only evident following termination of 1 mg/kg/day of fentanyl in rats with hindpaw inflammation. This decrease in running seemed to persist beyond the 3 days of assessment. These data demonstrate that fentanyl can either depress or restore activity depending on the dose and pain condition. Moreover, termination of 3 days of continuous fentanyl administration resulted in a dose and time dependent decrease in wheel running consistent with opioid withdrawal.

Introduction: The analgesic effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, have been widely promoted. Unfortunately, animal research is limited by the use of high doses and pain-evoked tests. Motor and psychoactive effects of THC may suppress evoked responses in the absence of antinociceptive effects.Materials and Methods: This study overcomes these problems by assessing the antinociceptive effect of low doses of subcutaneous THC on depression of home cage wheel running caused by hindpaw inflammation. Female and male Long-Evans rats were individually housed in a cage with a running wheel.Results: Female rats ran significantly more than male rats. Administration of Complete Freund's Adjuvant into the right hindpaw produced inflammatory pain that significantly depressed wheel running in female and male rats. Administration of a low dose of THC (0.32, but not 0.56 or 1.0 mg/kg) restored wheel running in the hour after administration in female rats. Administration of these doses had no effect on pain-depressed wheel running in male rats.Conclusions: These data are consistent with previous studies showing greater antinociceptive effects of THC in female compared with male rats. These data extend previous findings by showing that low doses of THC can restore pain-depressed behaviors.

The disruptive effects of pain on quality of life are greater in men than in women, but the disruptive effects of opioid administration and withdrawal tend to be greater in women. These sex differences in pain, acute opioid effects, and opioid withdrawal tend to be opposite to sex differences reported in laboratory rats. We hypothesized that sex differences in humans and rats would more closely align if animal research measured quality of life as opposed to traditional evoked behaviors of pain (e.g., nociceptive reflexes) and opioid withdrawal (e.g., wet dog shakes). The present study assessed quality of life in adult female and male rats by measuring voluntary wheel running in the rat's home cage. Hindpaw inflammation induced by administration of Complete Freund's Adjuvant (CFA) into the right hindpaw caused a greater depression of wheel running in male compared to female rats. Twice daily injections of high morphine doses (5-20 mg/kg) and the subsequent morphine withdrawal caused a greater depression of wheel running in female compared to male rats. These sex differences are consistent with human data that shows the impact of pain on quality of life is greater in men than women, but the negative effects of opioid administration and withdrawal are greater in women. The present data indicate that the clinical significance of animal research would be enhanced by shifting the endpoint from pain and opioid evoked behaviors to measures of quality of life such as voluntary wheel running.

Empathy and compassion are critical elements in counselling presence and practice. The present interpretive phenomenological study explored counsellor lived experiences of empathy and compassion. Through interpretative phenomenological analysis, findings highlighted how counsellors experience compassion and empathy, how boundaries shape wellness and practice with clients, and the impact of empathy and compassion over a career. The findings suggest that self-other differentiation is key while using empathy to develop a strong therapeutic alliance and counsellor self-care. Implications inform how counsellors can maintain wellness and learn to foster empathy and compassion in practice.

The overarching mission of Death Cafes is to raise people’s consciousness about life’s temporality so that they make the most of their finite lives. Death Cafés create a space for people to gather and have an open dialogue about death and dying. The current qualitative research study explores the experience of nine participants who engage in Death Cafes as facilitators or attendees. Findings including themes of “The Setting”, “The Players”, and “The Conversation” explore the experiences of Death Cafe participation. Discussion of findings and implications include death rituals, commercialization of death experiences, and the supportive community of the Death Cafe.

The increased use of opioids to treat pain has led to a dramatic increase in opioid abuse. Our previous data indicate that pain may facilitate the development of opioid abuse by increasing the magnitude and duration of opioid withdrawal. The present study tested the hypothesis that social housing would facilitate recovery of activity depressed by pain and opioid withdrawal. Male Sprague Dawley rats were housed either in pairs or alone and then moved to a cage with a running wheel for 6 h daily to assess pain- and opioid withdrawal-induced depression of wheel running. Rats were implanted with two morphine (75 mg each) or placebo pellets to induce opioid dependence and were simultaneously injected with Complete Freund's Adjuvant or saline into the right hind paw to induce persistent inflammatory pain. Hind paw inflammation depressed wheel running whether rats were implanted with a morphine or placebo pellet. Pair-housed rats showed greater recovery of wheel running than individually housed rats. Spontaneous morphine withdrawal precipitated by removal of the morphine pellets caused a reduction in wheel running that was greater in rats with hind paw inflammation compared to pain free rats. Social housing facilitated recovery from withdrawal in rats with hind paw inflammation, but slowed recovery in pain free rats. These data suggest that social housing facilitates recovery by reducing pain both before and during opioid withdrawal. Our findings are consistent with previous studies showing that social buffering reduces pain-evoked responses.

Social support and opioid replacement therapy are commonly used to treat opioid withdrawal. The present study tested the hypothesis that social housing and buprenorphine administration can restore wheel running depressed by morphine withdrawal in rats. Experiment 1 assessed disruptive side effects of buprenorphine and found that administration of low doses (3.2, 10, & 32 µg/kg, s.c.) had no impact on voluntary wheel running. Experiment 2 assessed the impact of social housing and acute buprenorphine administration (10 µg/kg) on morphine withdrawal. Two 75 mg morphine pellets were implanted for 3 days to induce dependence. Removal of the morphine pellets caused a decrease in body weight, increase in wet dog shakes, and depression of wheel running during the normally active dark phase of the circadian cycle. Social housing restored wheel running and reduced the number of wet dog shakes but did not affect body weight. Administration of buprenorphine restored wheel running depressed by morphine withdrawal for 2 days in individually housed rats and produced time-dependent changes in socially housed rats: Depression of wheel running in the 3 h following administration and restoration of running subsequently compared to saline-treated controls. The impact of buprenorphine and social housing to reduce the effect of morphine withdrawal in rats is consistent with the use of opioid substitution therapy and psychotherapy/social support to treat opioid withdrawal in humans. These data provide further validation for the clinical relevance for the use of wheel running to assess spontaneous opioid withdrawal.

Inflammatory Bowel Disease (IBD) is a life-long disorder that often begins between the ages of 15 and 30. Anecdotal reports suggest cannabinoids may be an effective treatment. This study sought to determine whether home cage wheel running is an effective method to assess IBD, and whether Tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis, can restore wheel running depressed by IBD. Adolescent and adult female Sprague-Dawley rats were individually housed in a cage with a running wheel. Rats were injected with trinitrobenzene sulphonic acid (TNBS) into the rectum to induce IBD-like symptoms. One day later, both vehicle and TNBS treated rats were injected with a low dose of THC (0.32 mg/kg, s.c.) or vehicle. Administration of TNBS depressed wheel running in adolescent and adult rats. No antinociceptive effect of THC was evident when administered 1 day after TNBS. In fact, administration of THC prolonged TNBS-induced depression of wheel running for over 5 days in adolescent and adult rats. These results show that home cage wheel running is depressed by TNBS-induced IBD, making it a useful tool to evaluate the behavioral consequences of IBD, and that administration of THC, instead of producing antinociception, exacerbates TNBS-induced IBD. PERSPECTIVE: This article advances research on inflammatory bowel disease in two important ways: 1) Home cage wheel running is a new and sensitive tool to assess the behavioral consequences of IBD in adolescent and adult rats; and 2) Administration of the cannabinoid THC exacerbates the negative behavioral effects of IBD.

Opioid abuse is a major health problem. The objective of the present study was to evaluate the potentially disruptive side effects and therapeutic potential of a novel antagonist (D24M) of the mu-/delta-opioid receptor (MOR/DOR) heterodimer in male rats. Administration of high doses of D24M (1 & 10 nmol) into the lateral ventricle did not disrupt home cage wheel running. Repeated twice daily administration of increasing doses of morphine (5-20 mg/kg) over 5 days depressed wheel running and induced antinociceptive tolerance measured with the hot plate test. Administration of D24M had no effect on morphine tolerance, but tended to prolong morphine antinociception in non-tolerant rats. Spontaneous morphine withdrawal was evident as a decrease in body weight, a reduction in wheel running and an increase in sleep during the normally active dark phase of the circadian cycle, and an increase in wheel running and wakefulness in the normally inactive light phase. Administration of D24M during the dark phase on the third day of withdrawal had no effect on wheel running. These data provide additional evidence for the clinical relevance of home cage wheel running as a method to assess spontaneous opioid withdrawal in rats. These data also demonstrate that blocking the MOR/DOR heterodimer does not produce disruptive side effects or block the antinociceptive effects of morphine. Although administration of D24M had no effect on morphine withdrawal, additional studies are needed to evaluate withdrawal to continuous morphine administration and other opioids in rats with persistent pain.

Opioids such as morphine are the most effective treatment for pain, but termination of opioid use can produce severe withdrawal symptoms. The present study models this process by using home cage wheel running to assess well-being as a result of pain, morphine analgesia, and opioid withdrawal. Injection of CFA into the right hindpaw caused a dramatic decrease in wheel running and body weight. Implantation of two morphine pellets (75 mg each) resulted in an increase in body weight on Day 1 of administration and a more gradual restoration of wheel running that was only evident during the dark phase of the circadian cycle on Days 3 and 4 of morphine administration. Continuous morphine administration decreased wheel running during the relatively inactive light phase. These findings are consistent with the clinical goal of pain therapeutics to restore normal activity during the day and facilitate sleep at night. Administration of naloxone (1 mg/kg) on Day 5 of morphine administration depressed wheel running for approximately 4 h and caused an increase in wet dog shakes. Naloxone-precipitated changes were no longer evident 6 h after administration. These findings demonstrate that the use of morphine to treat pain does not protect against opioid withdrawal. Moreover, this study provides additional support for the use of home cage wheel running as a method to assess changes in well-being as a result of pain, analgesia, and opioid withdrawal.