Biobehavioral Predictors of Pain Intensity, Pain Interference, and Chronic Pain Episodes: A Prospective Cohort Study of African-American Adults.

Racial disparities in pain experiences are well-established, with African-American (AA) adults reporting higher rates of daily pain, increased pain severity, and greater pain-related interference compared to non-Hispanic Whites. However, the biobehavioral factors that predict the transition to chronic pain among AA adults are not well understood. This prospective cohort study provided a unique opportunity to evaluate predictors of chronic pain onset among 130 AA adults (81 women), ages 18 to 44, who did not report chronic pain at their baseline assessment and subsequently completed follow-up assessments at 6- and 12-months. Outcome measures included pain intensity, pain-related interference, and chronic pain status. Comprehensive assessments of sociodemographic and biobehavioral factors were used to evaluate demographics, socioeconomic status, stress exposure, psychosocial factors, prolonged hypothalamic-pituitary-adrenal secretion, and quantitative sensory testing responses. At baseline, 30 adults (23.1%) reported a history of prior chronic pain. Over the 12-month follow-up period, 13 adults (10.0%) developed a new chronic pain episode, and 18 adults (13.8%) developed a recurrent chronic pain episode. Whereas socioeconomic status measures (ie, annual income, education) predicted changes in pain intensity over the follow-up period, quantitative sensory testing measures (ie, pain threshold, temporal summation of pain) predicted changes in pain interference. A history of chronic pain and higher depressive symptoms at baseline independently predicted the onset of a new chronic pain episode. The present findings highlight distinct subsets of biobehavioral factors that are differentially associated with trajectories of pain intensity, pain-related interference, and onset of chronic pain episodes in AA adults. PERSPECTIVE: This prospective study sought to advance understanding of biobehavioral factors that predicted pain outcomes over a 12-month follow-up period among AA adults without chronic pain at their initial assessment. Findings revealed distinct subsets of factors that were differentially associated with pain intensity, pain-related interference, and onset of chronic pain episodes.

Physical activity, sitting time, and thermal quantitative sensory testing responses in African Americans.

Introduction: Prior research suggests that African Americans (AAs) have more frequent, intense, and debilitating pain and functional disability compared with non-Hispanic Whites (NHWs). Potential contributing factors to this disparity are physical activity and sedentary behavior, given that AAs are less physically active, and physical activity is associated with antinociception (whereas sedentary behavior is linked to pronociception). However, impact of these factors on pain processing has largely been unexplored in AAs, especially before chronic pain onset. Objective: This study examined relationships between physical activity, sedentary behavior (sitting time), and laboratory measures of pain and pain modulation in adult AAs. These included heat pain threshold and tolerance, temporal summation of pain (TSP, a marker of central sensitization), and conditioned pain modulation (CPM, a marker of descending pain inhibition). Methods: Multiple regressions were conducted to examine the effects of physical activity and sitting time on heat threshold and tolerance. Multilevel models were conducted to assess the relationship between physical activity, sitting time, and temporal summation of pain. Additional multilevel models were conducted to assess the relationship between physical activity, sitting time, and conditioned pain modulation. Results: Higher level of physical activity, but not sitting time, was associated with reduced TSP slopes. Neither physical activity nor sitting time was associated with CPM slopes. No significant relationships between physical activity or sitting time and heat pain threshold or tolerance were detected. Conclusions: These findings suggest that physical activity is associated with reduced TSP, an effect which may be driven by reduced spinal hyperexcitability in more active individuals. Thus, structural and individual interventions designed to increase physical activity in healthy, young AAs may be able to promote antinociceptive processes (ie, reduced TSP/reduced pain facilitation) potentially protective against chronic pain.

Adversity type and timing predict temporal summation of pain in African-American adults.

African Americans are disproportionately exposed to adversity across the lifespan, which includes both stressful and traumatic events. Adversity, in turn, is associated with alterations in pain responsiveness. Racial differences in pain responsiveness among healthy adults are well established. However, the extent to which adversity type and timing are associated with alterations in pain responsiveness among healthy African-American adults is not well understood. The present study included 160 healthy African-American adults (98 women), ages 18 to 45. Outcome measures included pain tolerance and temporal summation of pain to evoked thermal pain. Composite scores were created for early-life adversity (childhood trauma, family adversity) and recent adversity (perceived stress, chronic stress burden). A measure of lifetime racial discrimination was also included. Higher levels of recent adversity were associated with higher temporal summation of pain, controlling for gender, age, and education. Neither early-life adversity nor lifetime racial discrimination were associated with temporal summation of pain. The present findings suggest that heightened temporal summation of pain among healthy African-American adults is associated with exposure to recent adversity events. Improved understanding of how recent adversity contributes to heightened temporal summation of pain in African Americans could help to mitigate racial disparities in pain experiences by identifying at-risk individuals who could benefit from early interventions.

Racial, Gender, and Neighborhood-Level Disparities in Pediatric Trauma Care.

BACKGROUND: Disparities in trauma outcomes and care are well established for adults, but the extent to which similar disparities are observed in pediatric trauma patients requires further investigation. The objective of this study was to evaluate the unique contributions of social determinants (race, gender, insurance status, community distress, rurality/urbanicity) on trauma outcomes after controlling for specific injury-related risk factors. STUDY DESIGN: All pediatric (age < 18) trauma patients admitted to a single level 1 trauma center with a statewide, largely rural, catchment area from January 2010 to December 2020 were retrospectively reviewed (n = 14,398). Primary outcomes were receipt of opioids in the emergency department, post-discharge rehabilitation referrals, and mortality. Multivariate logistic regressions evaluated demographic, socioeconomic, and injury characteristics. Multilevel logistic regressions evaluated area-level indicators, which were derived from abstracted home addresses. RESULTS: Analyses adjusting for demographic and injury characteristics revealed that Black children (n = 6255) had significantly lower odds (OR = 0.87) of being prescribed opioid medications in the emergency department compared to White children (n = 5883). Children living in more distressed and rural communities had greater odds of receiving opioid medications. Girls had significantly lower odds (OR = 0.61) of being referred for rehabilitation services than boys. Post hoc analyses revealed that Black girls had the lowest odds of receiving rehabilitation referrals compared to Black boys and White children. CONCLUSION: Results highlight the need to examine both main and interactive effects of social determinants on trauma care and outcomes. Findings reinforce and expand into the pediatric population the growing notion that traumatic injury care is not immune to disparities.

Cognitive-Affective-Behavioral Pathways Linking Adversity and Discrimination to Daily Pain in African-American Adults.

The tendency to ruminate, magnify, and experience helplessness in the face of pain - known as pain catastrophizing - is a strong predictor of pain outcomes and is associated with adversity. The ability to maintain functioning despite adversity - referred to as resilience - also influences pain outcomes. Understanding the extent to which pain catastrophizing and resilience influence relations between adversity and daily pain in healthy African-American adults could improve pain risk assessment and mitigate racial disparities in the transition from acute to chronic pain. This study included 160 African-American adults (98 women). Outcome measures included daily pain intensity (sensory, affective) and pain impact on daily function (pain interference). Adversity measures included childhood trauma exposure, family adversity, chronic burden from recent stressors, and ongoing perceived stress. A measure of lifetime racial discrimination was also included. Composite scores were created to capture early-life adversity (childhood trauma, family adversity) versus recent-life adversity (perceived stress, chronic burden). Increased pain catastrophizing was correlated with increased adversity (early and recent), racial discrimination, pain intensity, and pain interference. Decreased pain resilience was correlated with increased recent-life adversity (not early-life adversity or racial discrimination) and correlated with increased pain intensity (not pain-related interference). Bootstrapped multiple mediation models revealed that relationships between all adversity/discrimination and pain outcomes were mediated by pain catastrophizing. Pain resilience, however, was not a significant mediator in these models. These findings highlight opportunities for early interventions to reduce cognitive-affective-behavioral risk factors for persisting daily pain among African-American adults with greater adversity exposure by targeting pain catastrophizing.

Social determinants of trauma care: Associations of race, insurance status, and place on opioid prescriptions, postdischarge referrals, and mortality.

BACKGROUND: Racial disparities in trauma care have been reported for a range of outcomes, but the extent to which these remain after accounting for socioeconomic and environmental factors remains unclear. The objective of this study was to evaluate the unique contributions of race, health insurance, community distress, and rurality/urbanicity on trauma outcomes after carefully controlling for specific injury-related risk factors. METHODS: All adult (age, ≥18 years) trauma patients admitted to a single Level I trauma center with a statewide, largely rural, catchment area from January 2010 to December 2020 were retrospectively reviewed. Primary outcomes were mortality, rehabilitation referral, and receipt of opioids in the emergency department. Demographic, socioeconomic, and injury characteristics as well as indicators of community distress and rurality based on home address were abstracted from a trauma registry database. RESULTS: Analyses revealed that Black patients (n = 13,073) were younger, more likely to be male, more likely to suffer penetrating injuries, and more likely to suffer assault-based injuries compared with White patients (n = 10,946; all p < 0.001). In adjusted analysis, insured patients had a 28% lower risk of mortality (odds ratio, 0.72; p = 0.005) and were 92% more likely to be referred for postdischarge rehabilitation than uninsured patients (odds ratio, 1.92; p = 0.005). Neither race- nor place-based factors were associated with mortality. However, post hoc analyses revealed a significant race by age interaction, with Black patients exhibiting more pronounced increases in mortality risk with increasing age. CONCLUSION: The present findings help disentangle the social determinants of trauma disparities by adjusting for place and person characteristics. Uninsured patients were more likely to die and those who survived were less likely to receive referrals for rehabilitation services. The expected racial disparity in mortality risk favoring White patients emerged in middle age and was more pronounced for older patients. LEVEL OF EVIDENCE: Prognostic and epidemiological, Level III.

Predicting pain among female survivors of recent interpersonal violence: A proof-of-concept machine-learning approach.

Interpersonal violence (IPV) is highly prevalent in the United States and is a major public health problem. The emergence and/or worsening of chronic pain are known sequelae of IPV; however, not all those who experience IPV develop chronic pain. To mitigate its development, it is critical to identify the factors that are associated with increased risk of pain after IPV. This proof-of-concept study used machine-learning strategies to predict pain severity and interference in 47 young women, ages 18 to 30, who experienced an incident of IPV (i.e., physical and/or sexual assault) within three months of their baseline assessment. Young women are more likely than men to experience IPV and to subsequently develop posttraumatic stress disorder (PTSD) and chronic pain. Women completed a comprehensive assessment of theory-driven cognitive and neurobiological predictors of pain severity and pain-related interference (e.g., pain, coping, disability, psychiatric diagnosis/symptoms, PTSD/trauma, executive function, neuroendocrine, and physiological stress response). Gradient boosting machine models were used to predict symptoms of pain severity and pain-related interference across time (Baseline, 1-,3-,6- follow-up assessments). Models showed excellent predictive performance for pain severity and adequate predictive performance for pain-related interference. This proof-of-concept study suggests that machine-learning approaches are a useful tool for identifying predictors of pain development in survivors of recent IPV. Baseline measures of pain, family life impairment, neuropsychological function, and trauma history were of greatest importance in predicting pain and pain-related interference across a 6-month follow-up period. Present findings support the use of machine-learning techniques in larger studies of post-IPV pain development and highlight theory-driven predictors that could inform the development of targeted early intervention programs. However, these results should be replicated in a larger dataset with lower levels of missing data.

Establishing a Cohort and a Biorepository to Identify Biomarkers for Early Detection of Lung Cancer: The Nashville Lung Cancer Screening Trial Cohort.

Rationale: A prospective longitudinal cohort of individuals at high risk of developing lung cancer was established to build a biorepository of carefully annotated biological specimens and low-dose computed tomography (LDCT) chest images for derivation and validation of candidate biomarkers for early detection of lung cancer.Objectives: The goal of this study is to characterize individuals with high risk for lung cancer, accumulating valuable biospecimens and LDCT chest scans longitudinally over 5 years.Methods: Participants 55-80 years of age with a 5-year estimated risk of developing lung cancer >1.5% were recruited and enrolled from clinics at the Vanderbilt University Medical Center, Veteran Affairs Medical Center, and Meharry Medical Center. Individual demographic characteristics were assessed via questionnaire at baseline. Participants underwent an LDCT scan, spirometry, sputum cytology, and research bronchoscopy at the time of enrollment. Participants will be followed yearly for 5 years. Positive LDCT scans are followed-up according to standard of care. The clinical, imaging, and biospecimen data are collected prospectively and stored in a biorepository. Participants are offered smoking cessation counseling at each study visit.Results: A total of 480 participants were enrolled at study baseline and consented to sharing their data and biospecimens for research. Participants are followed with yearly clinic visits to collect imaging data and biospecimens. To date, a total of 19 cancers (13 adenocarcinomas, four squamous cell carcinomas, one large cell neuroendocrine, and one small-cell lung cancer) have been identified.Conclusions: We established a unique prospective cohort of individuals at high risk for lung cancer, enrolled at three institutions, for whom full clinical data, well-annotated LDCT scans, and biospecimens are being collected longitudinally. This repository will allow for the derivation and independent validation of clinical, imaging, and molecular biomarkers of risk for diagnosis of lung cancer.Clinical trial registered with ClinicalTrials.gov (NCT01475500).

Activation of Membrane Estrogen Receptors Attenuates NOP-Mediated Tactile Antihypersensitivity in a Rodent Model of Neuropathic Pain.

Women manifest a higher prevalence of several chronic pain disorders compared to men. We demonstrated earlier that estrogen rapidly attenuates nociceptin/orphanin FQ (N/OFQ) peptide receptor (NOP)-mediated thermal antinociception through the activation of membrane estrogen receptors (mERs). However, the effect of mER activation on NOP-mediated attenuation of tactile hypersensitivity in a neuropathic model of pain and the underlying mechanisms remain unknown. Following spared nerve injury (SNI), male and ovariectomized (OVX) female rats were intrathecally (i.t.) injected with a selective mER agonist and nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for NOP, and their effects on paw withdrawal thresholds (PWTs) were tested. In addition, spinal cord tissue was used to measure changes in phosphorylated extracellular signal regulated kinase (ERK), protein kinase A (PKA), protein kinase C (PKC), and protein kinase B (Akt) levels. SNI significantly reduced PWTs in males and OVX females, indicating tactile hypersensitivity. N/OFQ restored PWTs, indicating an antihypersensitive effect. Selective mER activation attenuated the effect of N/OFQ in an antagonist-reversible manner. SNI led to a robust increase in the phosphorylation of ERK, PKA, PKC, and Akt. However, mER activation did not further affect it. Thus, we conclude that activation of mERs rapidly abolishes NOP-mediated tactile antihypersensitivity following SNI via an ERK-, PKA-, PKC-, and Akt-independent mechanism.

Negative modulation of spinal κ-opioid receptor-mediated antinociception by the µ-opioid receptor at selective doses of (-)-pentazocine.

The mixed-action κ-opioid receptor (KOR) agonist, pentazocine, binds to both KOR and the µ-opioid receptor (MOR). Racemic (±)-pentazocine and (-)-pentazocine, each administered systemically, have been shown to produce antinociception in various animal models. In contrast, racemic (±)-pentazocine failed to produce antinociception when administered intrathecally (i.t.). However, whether spinal activation of KOR and MOR by (-)-pentazocine produces antinociception and the relative contribution of KOR and MOR in mediating antinociception remain unknown. Hence, we investigated whether i.t. (-)-pentazocine produces dose-dependent modulation of acute thermal nociception. Drugs were administered intrathecally in Sprague-Dawley rats and tail flick latency was recorded. Pentazocine produced a significant antinociceptive effect that was mediated by KOR and/or MOR at differential doses. MOR blockade restored the antinociceptive effect of an ineffective dose and prolonged the duration of an effective dose of pentazocine. Hence, spinal KOR and MOR mediated the effect of pentazocine. This study provides evidence that spinal MOR negatively modulates the KOR-mediated antinociceptive effect of i.t. pentazocine.

Activation of the trigeminal α2-adrenoceptor produces sex-specific, estrogen dependent thermal antinociception and antihyperalgesia using an operant pain assay in the rat.

Higher prevalence of several pain disorders in women and sexual dimorphism in G-protein coupled receptor-induced analgesia has been reported. We have previously shown that α2-adrenoceptor-induced antinociception is sex-specific and attenuated by estrogen in the female rat. However, this evidence was obtained using reflexive withdrawal-based nociceptive assays conducted on restrained animals that may not involve cerebral processing. Hence, we evaluated whether activation of the trigeminal α2-adrenoceptor produces sex-specific antinociceptive and antihyperalgesic effects in the orofacial region of the rat using a reward conflict-based operant paradigm in which animals must tolerate nociceptive thermal stimulation to be rewarded. Male and ovariectomized (OVX) Sprague-Dawley rats were implanted intracisternally with a PE10 cannula for drug injections. A group of OVX rats (OVX+E) was administered subcutaneously with estradiol 48h before the test. Effect of clonidine, an α2-adrenoceptor agonist, was determined on the operant pain assay using a fully automated Orofacial Pain Assessment Device. Number of spout licks, thermode contacts, and amount of reward intake were automatically recorded by the ANY-maze software. Using acute pain modeling, clonidine produced a dose-dependent increase in all three parameters in male and OVX groups, however, it was ineffective in the OVX+E group. Similarly, using inflammatory pain modeling, clonidine significantly increased these parameters in carrageenan-treated male and OVX groups but not in the OVX+E group. Thus, α2-adrenoceptor activation produces sex-specific antinociception and antihyperalgesia and estrogen attenuates these effects in female rats using an operant pain assay. These findings may help the discovery of effective analgesics for each sex.

Estrogen facilitates and the kappa and mu opioid receptors mediate antinociception produced by intrathecal (-)-pentazocine in female rats.

Pentazocine, a mixed-action kappa opioid receptor (KOR) agonist, has high affinity for both KOR and the mu opioid receptor (MOR), and has been shown clinically to alleviate pain with a pronounced effect in women. However, whether local application of pentazocine in the spinal cord produces antinociception and the contribution of spinal KOR and MOR in mediating the effect of pentazocine in female rats remain unknown. Also, it is not known whether pentazocine-induced antinociception in females is estrogen-dependent. Hence, we investigated whether intrathecal (i.t.) (-)-pentazocine produces thermal antinociception and whether estrogen modulates the drug effect in female rats. Only the highest dose of pentazocine (500 nmol) was effective in producing antinociception in ovariectomized (OVX) rats. In contrast, pentazocine produced antinociception in estradiol-treated ovariectomized females (OVX+E) rats with the lowest effective dose being 250nmol. KOR or MOR mediated the effect of the lowest effective dose in OVX+E rats; however, MOR blockade extended the KOR-mediated effect of 500nmol pentazocine in both groups. In normally cycling females, the 250nmol dose was effective in producing antinociception at the proestrous, but not at the diestrous stage of the estrous cycle. Thus, estrogen facilitates and KOR or MOR mediates. the antinociceptive effect of i.t. (-)-pentazocine in female rats. Selective doses of (-)-pentazocine, with or without MOR blockade, may have a therapeutic benefit.

Sex-specificity and estrogen-dependence of kappa opioid receptor-mediated antinociception and antihyperalgesia.

This investigation determined whether the activation of the kappa opioid receptor (KOR) in the spinal cord produces estrogen-dependent, sex-specific modulation of acute and inflammation-induced persistent nociception. We demonstrate for the first time that KOR antinociception and gene expression are enhanced by exogenous or endogenous estrogen in the female. The lack of KOR antinociception and KOR gene expression are not altered by the hormonal status (testosterone or estrogen) in males. Cannulae were implanted intrathecally in male, gonadectomized male (GDX), intact and ovariectomized female (OVX) Sprague-Dawley rats. Estradiol was injected subcutaneously, 48h before testing (GDX+E and OVX+E). Intrathecal injection of U50,488H, a selective KOR agonist, dose dependently increased heat-evoked tail flick latencies (TFLs) in proestrous and OVX+E groups, but not in male, GDX, GDX+E, OVX, and diestrous groups. Further, estrogen dose-dependently enhanced the effect of U50,488H in OVX rats. KOR selective antagonist, nor-binaltorphimine (Nor-BNI), blocked the antinociceptive effect of U50,488H. U50,488H reversed the carrageenan-induced thermal hyperalgesia in OVX+E rats, but not in male or OVX rats. However, U50,488H treatment did not alter mechanical thresholds in any group, with or without inflammation. KOR gene expression was enhanced in proestrous and OVX+E groups as compared to any other group. We conclude that selective activation of KOR in the spinal cord produces sex-specific, stimulus- and estrogen-dependent attenuation of acute and inflammatory pain in the rat via estrogen-induced upregulation of the KOR gene expression in the spinal cord. These findings may further implicate estrogen dependence of KOR effects in learning, epilepsy, stress response, addiction etc.

Testosterone is essential for alpha(2)-adrenoceptor-induced antinociception in the trigeminal region of the male rat.

Activation of the alpha(2)-adrenoceptor has been shown to produce antinociception. We have previously shown that the antinociceptive effect of clonidine, an alpha(2)-adrenoceptor agonist, is sex-specific and is abolished by exogenous estrogen in ovariectomized rats or high level of endogenous estrogen in proestrous females. Here, we investigated whether testosterone mediates the antinociceptive effect of clonidine in the trigeminal region of the male rat. Clonidine (7 microg/5 microl) was injected intracisternally through a PE-10 cannula implanted dorsal to the trigeminal region in orchidectomized (GDX) male Sprague-Dawley rats. In separate groups, testosterone propionate (250 microg/100 microl; GDX+T) or beta-estradiol benzoate (100 microg/100 microl; GDX+E) were injected subcutaneously 24 and 48 h respectively prior to the N-methyl-D-aspartic acid (NMDA)--or heat-evoked nociceptive test. NMDA-induced number of scratches or duration of scratching behavior did not change significantly in control groups with or without hormonal replacement. Clonidine significantly reduced both measures only in the GDX+T group but not in GDX or GDX+E group. Clonidine also significantly increased head withdrawal latency (HWL) in the GDX+T group, but not in GDX or GDX+E group. The antinociceptive effect of clonidine was reversed by yohimbine, an alpha(2)-adrenoceptor antagonist, in GDX+T group. We conclude that testosterone is required for the expression of antinociception produced by selective activation of the alpha(2)-adrenoceptor in the trigeminal region of the male rat. These findings further our understanding of sex-related differences in the modulation of nociception and may provide insight into development and administration of analgesic agents in young vs. aging men.

Estrogen-dependent, sex-specific modulation of mustard oil-induced secondary thermal hyperalgesia by orphanin FQ in the rat.

Activation of opioid receptor-like 1 receptor (ORL(1)) by intrathecal administration of orphanin FQ (OFQ), an endogenous ligand for the ORL(1) receptor, has been shown to produce antinociception. In addition, we have recently shown gonadal hormone-dependent, sex-specific modulation of acute spinal nociception such that estrogen attenuated OFQ-induced antinociception in the female whereas testosterone was required for the expression of antinociception in the male. However, sex-related differences in the role of OFQ under hyperalgesic conditions are unknown. Hence, we investigated whether OFQ produces sex-specific modulation of mustard oil-induced secondary thermal hyperalgesia in the rat. Mustard oil application to the hind limb significantly reduced the tail-flick latencies (TFL) in male, and ovariectomized (OVX), estradiol treated ovariectomized (OVX+E), proestrous (ProE) and diestrous (DiE) females. Intrathecal administration of OFQ not only attenuated mustard oil-induced decrease in TFLs, i.e. reversed hyperalgesia, but also led to a significant increase in TFLs above the baseline, i.e. produced antinociception in male, OVX, and diestrous rats. However, OFQ failed to alter TFLs in proestrous or OVX+E females, thus these two groups with elevated estrogen levels remained hyperalgesic following mustard oil treatment. These findings demonstrate that OFQ modulates mustard oil-induced secondary hyperalgesia in an estrogen-dependent, sex-specific manner.

Knockout of spinophilin, an endogenous antagonist of arrestin-dependent alpha2-adrenoceptor functions, enhances receptor-mediated antinociception yet does not eliminate sex-related differences.

We have previously shown gonadal steroid-dependent, gender specific modulation of nociception by alpha(2)-adrenoceptors. Agonist activation of the receptor enhances its association with spinophilin that antagonizes arrestin functions both by diminishing receptor phosphorylation by G-protein-coupled receptor kinase 2 (GRK2) and by competing for receptor interactions with arrestin. Since spinophilin is highly enriched in dendritic spines, we investigated whether alpha(2)-adrenoceptor-induced antinociception as well as sex-related differences are modified in spinophilin knockout mice. We evaluated alpha(2)-adrenoceptor antinociception in a heat-evoked tail flick test in spinophilin wild type (Sp(+/+)) and knockout (Sp(-/-)) mice. Baseline tail flick latencies (TFLs) did not change between any groups. Interestingly, the alpha(2)-adrenoceptor agonist, clonidine, increased TFL in male and diestrous (low estrogen) Sp(-/-) as well as Sp(+/+) mice; in fact, this increase in TFL was significantly higher in Sp(-/-) male and diestrous groups than in their Sp(+/+) counterparts. This unexpected finding is consistent with enhanced alpha(2)-adrenoceptor-mediated sedation observed previously in Sp(-/-) mice, presumably due to accelerated endocytosis of desensitized receptors and recycling of refreshed receptors when arrestin is not competed for by spinophilin in Sp(-/-) mice. Despite modulation of alpha(2)-adrenoceptor effects in Sp(-/-) mice, sex-related differences were retained; thus, clonidine was ineffective in proestrous females (highest estrogen levels), in both Sp(-/-) and Sp(+/+) mice, reaffirming that estrogen suppresses alpha(2)-adrenoceptor-evoked antinociception. These findings show that elimination of spinophilin enhances alpha(2)-adrenoceptor-evoked antinociception in estrogen-deprived physiological settings, suggesting a role for spinophilin to suppress these effects, and yet this enhanced response cannot overcome the absence of antinociception with elevated estrogen levels.

Activation of opioid receptor like-1 receptor in the spinal cord produces sex-specific antinociception in the rat: estrogen attenuates antinociception in the female, whereas testosterone is required for the expression of antinociception in the male.

Sex-related differences in the perception and modulation of pain have been reported. The present study is the first to investigate systematically whether activation of opioid receptor-like 1 receptor (ORL1) by orphanin FQ (OFQ) produces sex-specific modulation of spinal nociception and whether estrogen or testosterone contributes to these differences using the rat as an experimental animal. Two behavioral models, the NMDA and heat-induced nociceptive tests, were used to examine sex-specific modulation of spinal nociception. Intrathecal microinjection of OFQ in male, ovariectomized (OVX), and diestrous rats produced a significant antinociceptive effect on both tests. However, OFQ failed to produce antinociception in proestrous rats, the phase of the estrous cycle with the highest levels of circulating estradiol, and produced a dose-dependent effect in OVX females treated with 1 ng to 100 microg of estradiol. The antinociceptive effects of OFQ were dose dependent in male and OVX animals and were reversibly antagonized by UFP-101 ([Nphe1,Arg14,Lys15]N/OFQ(1-13)-NH2), an ORL1 receptor-selective antagonist. Interestingly, OFQ was ineffective in gonadectomized (GDX) males, whereas testosterone replacement restored the antinociceptive effect of OFQ in GDX males. We conclude that OFQ produces sex-specific modulation of spinal nociception; estrogen attenuates antinociception in the female in parallel with normal cycling of estrogen levels, and testosterone is required for the expression of antinociception in the male; thus, the sensitivity of the male to the antinociceptive effects of OFQ is not simply attributable to the intrinsically low estrogen levels in these animals.