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Serotonin (5-hydroxytryptamine, 5-HT) released by platelets, mast cells, and immunocytes is a potent inflammatory mediator which modulates pain and itch sensing in the peripheral nervous system. The serotonergic receptors expressed by primary afferent neurons involved in these sensory functions are not fully identified and appear to be to a large extent species dependent. Moreover, the mechanisms through which 5-HT receptor activation is coupled to changes in neuronal excitability have not been completely revealed. Using a combination of in vitro (calcium and voltage imaging and patch-clamp) and in vivo behavioral methods, we used both male and female Wistar rats to provide evidence for the involvement of two 5-HT receptor subtypes, 5-HT1A and 5-HT3, in mediating the sustained and transient effects, respectively, of 5-HT on rat primary afferent neurons involved in pain and itch processing. In addition, our results are consistent with a model in which sustained serotonergic responses triggered via the 5-HT1A receptor are due to closure of background potassium channels, followed by membrane depolarization and action potentials, during which the activation of voltage-gated calcium channels leads to calcium entry. Our results may provide a better understanding of mammalian serotonergic itch signaling.
Transcranial direct current stimulation was suggested to provide beneficial effects in chronic migraine, a condition often associated with medication overuse for which no long-term therapy is available.
Although support provision by a partner is an important resource for individuals with chronic pain (ICPs), it poses a challenge for partners because it competes with other important personal goals of partners. The current study examined the impact of experimentally induced goal conflict in partners on their motives for helping, quality of provided help, and on partners' and ICPs' affect. Sixty-eight couples, with at least one person having chronic pain, performed two series of household activities, with partners either asked to be simply available for help (i.e., control condition) or to additionally work on a puzzle task (i.e., goal conflict condition). Couples reported on interpersonal (e.g., helping motives) and intrapersonal (e.g., affect) outcomes. In addition, quality of partners' helping behavior and ICPs' pain behavior were videotaped and coded afterwards. In the goal conflict condition, ICPs were less satisfied with the received help and they experienced more pain. Also, the quality of the provided help was lower and partners experienced less positive and more negative affect. Addressing partners' goal conflict in clinical practice may help to avoid its negative impact on both ICPs and partners. Perspective: This article provides a compelling argument to include partners in chronic pain treatment by demonstrating the detrimental effects of partners' experienced conflicts in goals upon the quality of help they provide, partners' affective functioning and ICPs' pain-related outcomes.
Endothelin-1 (EDN1) can evoke histamine-independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL-25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model.
At least one third of HIV-1-afflicted individuals experience peripheral neuropathy. Although the underlying mechanisms are not known, they may involve neurotoxic HIV-1 proteins. We assessed the influence of the neurotoxic HIV-1 regulatory protein, Tat, on inflammatory and neuropathic nociceptive behaviors using transgenic male and female transgenic mice that conditionally expressed (or did not express) HIV-1 Tat in glial fibrillary acidic protein-expressing glia in the central and peripheral nervous systems. Tat induction significantly attenuated the time spent paw-licking following formalin injection (2.5%, i.pl.) in both male and female mice. However, significant sex differences were observed in the onset and magnitude of inflammation and sensory sensitivity following complete Freund's adjuvant (CFA) injection (10%, i.pl.) after Tat activation. Unlike female mice, males showed a significant attenuation of paw swelling and an absence of mechanical/thermal hypersensitivity in response to CFA after Tat induction. Male Tat(+) mice also showed accelerated recovery from chronic constrictive nerve injury (CCI)-induced neuropathic mechanical and thermal hypersensitivity compared to female Tat(+) mice. Morphine (3.2 mg/kg) fully reversed CCI-induced mechanical hypersensitivity in female Tat(-) mice, but not in Tat(+) females. The ability of Tat to decrease edema, paw swelling, and limit allodynia suggest a sequela of events in which Tat-induced functional deficits precede the onset of mechanical hypersensitivity. Moreover, HIV-1 Tat attenuated responses to inflammatory and neuropathic insults in a sex-dependent manner. HIV-1 Tat appears to directly contribute to HIV sensory neuropathy and reveals sex differences in HIV responsiveness and/or the underlying peripheral neuroinflammatory and nociceptive mechanisms.
The present series of studies examine the impact of systemically administered therapeutics on peripheral nerve injury (males; unilateral sciatic chronic constriction injury [CCI])-induced suppression of voluntary wheel running, across weeks after dosing cessation. Following CCI, active phase running distance and speed are suppressed throughout the 7-week observation period. A brief course of morphine, however, increased active phase running distance and speed throughout this same period, an effect apparent only in sham rats. For CCI rats, systemic co-administration of morphine with antagonists of either P2X7 (A438079) or TLR4 ((+)-naloxone) (receptors critical to the activation of NLRP3 inflammasomes and consequent inflammatory cascades) returned running behavior of CCI rats to that of shams through 5+ weeks after dosing ceased. This is a striking difference in effect compared to our prior CCI allodynia results using systemic morphine plus intrathecal delivery of these same antagonists, wherein a sustained albeit partial suppression of neuropathic pain was observed. This may point to actions of the systemic drugs at multiple sites along the neuraxis, modulating injury-induced, inflammasome-mediated effects at the injured sciatic nerve and/or dorsal root ganglia, spinal cord, and potentially higher levels. Given that our data to date point to morphine amplifying neuroinflammatory processes put into motion by nerve injury, it is intriguing to speculate that co-administration of TLR4 and/or P2X7 antagonists can intervene in these inflammatory processes in a beneficial way. That is, that systemic administration of such compounds may suppress inflammatory damage at multiple sites, rapidly and persistently returning neuropathic animals to sham levels of response.
Neuropathic pain (NP) remains a major debilitating condition affecting more than 26% of breast cancer survivors worldwide. NP is diagnosed using a validated 10-items Douleur Neuropathique – 4 screening questionnaire which is administered 3 months after surgery and requires patient-doctor interaction. To develop an effective prognosis model admissible soon after surgery, without the need for patient-doctor interaction, we sought to [1] identify specific pain characteristics that can help determine which patients may be susceptible to NP after BC surgery, and 2) assess the utility of machine learning models developed in objective [1] as a knowledge discovery tool for downstream analysis.
Pain catastrophizing (PC) has been recognized as an important and consistent psychosocial predictor of nearly every key pain-related outcome. The purpose of this study was to develop a new measure of PC using modern psychometric methodology. People with chronic pain (N=795) responded to thirty items. Data were analyzed using Item Response Theory (IRT), including assessment of differential item functioning (DIF) and reliability. Sensitivity to change and validity were examined using data collected from patients undergoing spinal fusion surgery (n=184) and participating in an ongoing longitudinal aging with a disability survey study (n=1388). The final 24-item bank had no items with significant local dependence, misfit, or DIF. Results provided strong evidence of reliability and validity. Six- and 2-item short forms were developed for use when computer adaptive testing (CAT) is not feasible or desirable. The item bank was named the University of Washington Concerns About Pain (CAP) scale because the term "catastrophizing" was considered stigmatizing by people with chronic pain. Guidance for score interpretation was developed with extensive feedback from individuals with chronic pain. The CAP item bank, short forms, and user manuals are free and publicly available to all users and can be accessed online at https://uwcorr.washington.edu/measures/. PERSPECTIVE: This article presents the development of the University of Washington Concerns About Pain scale, the first IRT-based item bank of pain catastrophizing. The measure is intended for clinicians interested in improving outcomes of patients with chronic pain and for researchers who study impact of and treatment interventions aimed at reducing pain catastrophizing.
Pain is an unfortunate consequence of many medical procedures, which in some patients becomes chronic and debilitating. Among the factors affecting medical pain, clinician-patient (C-P) similarity and nonverbal communication are particularly important for pain diagnosis and treatment. Participants (N=66) were randomly assigned to the clinician and patient roles and were grouped into C-P dyads. Clinicians administered painful stimuli to patients as an analogue of a painful medical procedure. We manipulated the perceived C-P similarity of each dyad using groups ostensibly based on shared beliefs and values, and each patient was tested twice: Once with a same group clinician (concordant, CC) and once with a clinician from the other group (discordant, DC). Movement synchrony was calculated as a marker of nonverbal communication. We tested whether movement synchrony mediated the effects of group concordance on patients' pain and trust in the clinician. Movement synchrony was higher in CC than DC dyads. Higher movement synchrony predicted reduced pain and increased trust in the clinician. Movement synchrony also formally mediated the group concordance effects on pain and trust. These findings increase our understanding of the role of nonverbal C-P communication on pain and related outcomes and suggest that interpersonal synchrony may be associated with better patient outcomes, independent of the specific treatment provided. Perspective This article demonstrates that movement synchrony in clinician-patient interactions is an unobtrusive measure related to their relationship quality, trust towards the clinician, and pain. These findings suggest that interpersonal synchrony may be associated with better patient outcomes, independent of the specific treatment provided.