Pain
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Several studies implicated cyclic adenosine monophosphate (cAMP) as an important second messenger for regulating nociceptor sensitization, but downstream targets of this signaling pathway which contribute to neuronal plasticity are not well understood. We used a Cre/loxP-based strategy to disable the function of either HCN2 or PKA selectively in a subset of peripheral nociceptive neurons and analyzed the nociceptive responses in both transgenic lines. ⋯ Facilitation of Ih via cAMP, a hallmark of the Ih current, was abolished in neurons without PKA activity. Collectively, these results show a significant contribution of both genes to inflammatory pain and suggest that PKA-dependent activation of HCN2 underlies cAMP-triggered neuronal sensitization.
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Pain is known to interrupt attentional performance. Such interference effects seem to occur preferentially for tasks that are complex and/or difficult. However, few studies have directly manipulated memory load in the context of pain interference to test this view. ⋯ These results suggest that while cognitive load may influence the interruptive effect of pain on attention, this effect may be selective. Because pain affected the high-load version of the n-back task but did not interrupt performance on attentional switching or dual-task paradigms, this means that our findings did not completely support our hypotheses. Future research should explore further the parameters and conditions under which pain-related interference occurs.
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The magnitude of antinociception elicited by intrathecal endomorphin 2 (EM2), an endogenous mu-opioid receptor (MOR) ligand, varies across the rat estrous cycle. We now report that phasic changes in analgesic responsiveness to spinal EM2 result from plastic interactions within a novel membrane-bound oligomer containing estrogen receptors (mERs), aromatase (aka estrogen synthase), metabotropic glutamate receptor 1 (mGluR1), and MOR. During diestrus, spinal mERs, activated by locally synthesized estrogens, act with mGluR1 to suppress spinal EM2/MOR antinociception. ⋯ Finally, spinal neurons were observed not only to coexpress MOR, mERα, aromatase, and mGluR1 but also be apposed by EM2 varicosities. This suggests that modulation of spinal analgesic responsiveness to exogenous EM2 likely reflects changes in its endogenous analgesic activity. Analogous suppression of spinal EM2 antinociception in women (eg, around menses, comparable with diestrus in rats) as well as the (pathological) inability to transition out of that suppressed state at other menstrual cycle stages could underlie, at least in part, the much greater prevalence and severity of chronic pain in women than men.
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Migraine is currently conceptualized as a chronic disease with episodic manifestations. In some patients, migraine attack frequency increases, leading to chronic migraine. Daily preventive therapy is initiated to decrease attack frequency. ⋯ Furthermore, propranolol prevents (1) the elevated touch-evoked Fos expression within the trigeminocervical complex, (2) enhanced both spontaneous activity, and evoked responses of second-order trigeminovascular neurons, (3) elevated touch-evoked rostral ventromedial medulla and locus coeruleus Fos expression and (4) diffuse noxious inhibitory controls impairment, induced by repeated IS injections. Our results suggest that propranolol exerts its prophylactic action, at least in part, by blocking the chronic sensitization of descending controls of pain, arising from the rostral ventromedial medulla and locus coeruleus, and in turn preventing the maintenance of a state of facilitated trigeminovascular transmission within the trigeminocervical complex. Assessing changes in these brain areas has the potential to elucidate the mechanisms for migraine transformation and to reveal novel biological and molecular targets for specific migraine-preventive therapies.