Pain
-
Randomized Controlled Trial
The Relationship between Fear of Social and Physical Threat and their Effects on Social Distress and Physical Pain Perception.
Past research has found that measuring individuals' fear of pain predicts their physical pain perceptions: those reporting higher levels of fear of pain report higher levels of pain. We investigated links between fear of social threat and fear of physical pain, testing whether these fears predict responses to social distress and physical pain. In 3 studies, we found that fear of social and physical threat were related yet distinct psychological constructs (study 1), that fear of social (but not physical) threat predicted the perception of social distress (study 2), and that fear of physical (but not social) pain predicted the perception of physical pain (study 3). ⋯ However, we also found that these effects were specific, such that each type of fear uniquely predicted the experience of the same type of distress. We argue that timely identification of high levels of social threat-related fear is critical for identifying individuals who will benefit most from preventative interventions aimed to limit negative cycles of high avoidance and increased social threat perception. Furthermore, our work sets a boundary condition to pain overlap theory by showing that high levels of fear of one type of pain (e.g., social) are specifically linked to increased perception of that particular type of pain (e.g., social) but not the other (e.g., physical).
-
The pathophysiology of the complex regional pain syndrome involves enhanced neurogenic inflammation mediated by neuropeptides. Neutral endopeptidase (neprilysin, NEP) is a key enzyme in neuropeptide catabolism. Our previous work revealed that NEP knock out (ko) mice develop more severe hypersensitivity to thermal and mechanical stimuli after chronic constriction injury (CCI) of the sciatic nerve than wild-type (wt) mice. ⋯ Gene expression of the ET-1 receptors ETAR and ETBR was not different between genotypes and was not altered after CCI, but was increased after additional MP treatment. The ETBR agonist IRL-1620 was analgesic in NEP ko mice after CCI, and the ETBR antagonist BQ-788 showed a trend to reduce the analgesic effect of MP. The results provide evidence that MP reduces CCI-induced hyperalgesia in NEP ko mice, and that this may be related to ET-1 via analgesic actions of ETBR.
-
α2-Adrenoceptors are widely distributed throughout the central nervous system (CNS) and the systemic administration of α2-agonists such as dexmedetomidine produces clinically useful, centrally mediated sedation and analgesia; however, these same actions also limit the utility of these agents (ie, unwanted sedative actions). Despite a wealth of data on cellular and synaptic actions of α2-agonists in vitro, it is not known which neuronal circuits are modulated in vivo to produce the analgesic effect. To address this issue, we made in vivo recordings of membrane currents and synaptic activities in superficial spinal dorsal horn neurons and examined their responses to systemic dexmedetomidine. ⋯ In the brainstem, low doses of systemic dexmedetomidine produced an excitation of locus coeruleus neurons. These results suggest that systemic α2-adrenoceptor stimulation may facilitate inhibitory synaptic responses in the superficial dorsal horn to produce analgesia mediated by activation of the pontospinal noradrenergic inhibitory system. This novel mechanism may provide new targets for intervention, perhaps allowing analgesic actions to be dissociated from excessive sedation.
-
Prostacyclin is an important mediator of peripheral pain sensation. Here, we investigated its potential participation in mediating neuropathic pain and found that prostacyclin receptor (IP) knockout mice exhibited markedly decreased pain behavior. Application of an IP antagonist to the injury site or selective IP deficiency in myeloid cells mimicked the antinociceptive effect observed in IP knockout mice. ⋯ Fittingly, the IL1-receptor antagonist anakinra (IL-1ra) decreased neuropathic pain behavior in wild-type mice but not in IP knockout mice. Finally, continuous, but not single administration, of the cyclooxygenase inhibitor meloxicam early after nerve injury decreased pain behavior and the number of resident macrophages. Thus, early synthesis of prostacyclin at the site of injury causes accumulation of IL1β-expressing macrophages as a key step in neuropathic pain after traumatic injury.
-
The formalin test still surprises with its biphasic pain-related behavior resulting from a quiescent interphase that does not occur with other algogenic compounds and remains unexplained. The first phase has been attributed to TRPA1-mediated excitation of nociceptors, the second phase to their inflammatory and/or spinal sensitization. We show that the second and interphase require higher formaldehyde concentrations to emerge, and that from 12 mM on calcium influx is induced in TRPA1-deficient sensory neurons as well as in native HEK293T cells. ⋯ The parameters gained were entered into a computational model to predict the activation pattern of primary afferents. The model supports a peripherally generated biphasic response, the time course matching the behavioral results. In conclusion, the interphase is a result of hyperpolarization and transient inactivation by formaldehyde of the surviving neurons; their recovery and the centrifugal spread of formalin in the skin induce a second phase of nociceptive activity before the formalin concentration falls below threshold.