The journal of pain : official journal of the American Pain Society
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Endomorphin 2 (EM2) is the predominant endogenous mu-opioid receptor (MOR) ligand in the spinal cord. Given its endogenous presence, antinociceptive responsiveness to the intrathecal application of EM2 most likely reflects its ability to modulate nociception when released in situ. In order to explore the physiological pliability of sex-dependent differences in spinal MOR-mediated antinociception, we investigated the antinociception produced by intrathecal EM2 in male, proestrus female, and diestrus female rats. Antinociception was reflected by changes in tail flick latency to radiant heat. In females, the spinal EM2 antinociceptive system oscillated between analgesically active and inactive states. During diestrus, when circulating estrogens are low, spinal EM2 antinociceptive responsiveness was minimal. In contrast, during proestrus, when circulating estrogens are high, spinal EM2 antinociception was robust and comparable in magnitude to that manifest by males. Furthermore, in proestrus females, spinal EM2 antinociception required spinal dynorphin and kappa-opioid receptor activation, concomitant with MOR activation. This is required for neither spinal EM2 antinociception in males nor the antinociception elicited in proestrus females by spinal sufentanil or [d-Ala(2),N-methyl-Phe(4),Gly-ol(5)]-enkephalin, which are prototypic MOR-selective nonpeptide and peptide agonists, respectively. These results reveal that spinal EM2 antinociception and the signaling mechanisms used to produce it fundamentally differ in males and females. ⋯ The inability to mount spinal EM2 antinociception during defined stages of the estrus (and presumably menstrual) cycle and impaired transition from spinal EM2 analgesically nonresponsive to responsive physiological states could be causally associated with the well-documented greater severity and frequency of chronic intractable pain syndromes in women vs men.
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Randomized Controlled Trial
Timing and gender determine if acute pain impairs working memory performance.
The effects of pain on memory are complex, and little is known about the vulnerability of working memory (WM) performance when individuals complete a WM test while concurrently experiencing pain. Here, we subjected 78 healthy nonsmoking participants to either acute pain or a control condition while we administered a WM test. In this context, we also tested WM 20 minutes after pain in order to determine if timing of pain affected WM performance, and assessed objective and subjective measures of pain. We hypothesized that pain would impair WM performance during pain. Further, women's WM performance would be impaired more than men. Importantly, there was an interaction between gender and condition, with women exposed to pain experiencing impairments during but not after the cold pressor task. Our data imply that timing and gender are critically important in whether acute pain is costly to WM performance. Our findings have interesting clinical, professional, and educational implications, and understanding the influence of pain could help to improve the interpretation of WM tests in these diverse settings. ⋯ Results of this study support the growing body of work that attests to the detrimental effect of pain on WM performance. Further, this study provides new evidence that concurrently experiencing cold pressor pain impairs WM in regularly menstruating women and women taking a contraceptive.
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Despite the high prevalence of neck pain among women, menstrual effects on regional pain outcomes have not been investigated in this clinical population. This study evaluated menstrual effects on mechanical pain sensitivity (pressure pain threshold [PPT]), neck pain intensity (numeric pain rating scale [NPRS]), and neck-related disability (Neck Disability Index [NDI]) in 22 normally menstruating (NM) and 17 hormonal contraceptive users with chronic neck pain. Sex hormones, PPT, and NDI were measured during the early follicular (F1), late follicular (F2), and luteal (L) menstrual phases. Daily NPRS scores were recorded in an online symptom diary and averaged within each phase. Estradiol and progesterone increased only for NM women in F2 and L, respectively. Phase effects on PPT (η(2) = .003), NDI (η(2) = .003), and NPRS (η(2) = .016) for NM women were small and did not differ from those for the hormonal contraceptive users (P ≥ .386). Averaged across the menstrual cycle, PPT scores explained 29% of the variance in NPRS scores for NM women but were not associated with NDI scores in either group. Results indicate that the magnitude of menstrual effects on mechanical pain sensitivity and the severity of neck pain and disability do not exceed thresholds of clinically detectable change in women with chronic neck pain. ⋯ Fluctuations in evoked and clinical pain outcomes across the menstrual cycle do not appear to be of sufficient magnitude to impact clinical decision making for women with chronic neck pain.
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Somatic symptoms experienced by women with a menstrually related mood disorder (MRMD) during their premenstrual luteal phase contribute to functional impairment. Yet, investigations on pathophysiological mechanisms contributing to heightened pain sensitivity in MRMD are sparse. During the luteal phase, 61 women with an MRMD and 61 non-MRMD controls were evaluated for β-adrenergic receptor (β-AR) responsivity using the isoproterenol sensitivity test. A subset (43 MRMD and 50 non-MRMD) then entered a double-blind, placebo-controlled, crossover protocol to examine the effect of β-AR blockade with intravenous propranolol on sensitivity to experimental (cold pressor and ischemic) and clinical (McGill Pain Questionnaire score) pain. Women with an MRMD exhibited greater β1- and β2-AR responsivity, ischemic pain intensity, and affective clinical pain ratings than controls. Propranolol increased cold pressor pain tolerance in both groups, but it decreased cold pain intensity and ischemic pain unpleasantness ratings only in non-MRMD women. In contrast, propranolol decreased affective ratings of clinical pain in women with MRMD. Exploratory analyses indicated that only in MRMD women did greater β-AR responsivity predict greater sensitivity to cold pressor and ischemic pain. This study provides the first evidence for a role of β-AR mechanisms in the hyperalgesia and clinical pain experienced by women with MRMDs. ⋯ This article describes the effects of β-adrenergic receptor stimulation and blockade on experimental and clinical pain sensitivity in women with an MRMD. The results of this study may have implications for the management of the substantial somatic premenstrual symptomatology experienced by women with an MRMD.