Pain Perception after Isometric Exercise in Women with Fibromyalgia

Objective: The purpose of this study was to identify exercise protocols incorporating isometric contractions that provide pain relief in women with fibromyalgia. Design: A before-after trial. Setting: A physical therapy department in an academic setting. Participants: Fifteen women (mean ± SD, 52 ± 11y) with fibromyalgia. Interventions: Subjects completed 4 sessions: 1 familiarization and 3 experimental. The following randomized experimental sessions involved the performance of isometric contractions with the elbow flexor muscles that varied in intensity and duration: (1) 3 maximal voluntary contractions (MVCs), (2) 25% MVC held to task failure, and (3) 25% MVC held for 2 minutes. Main Outcome Measures: Experimental pain (pain threshold and pain rating), Fibromyalgia Impact Questionnaire, and fibromyalgia pain intensity (visual analog scale). Results: After all 3 isometric contractions, there was considerable variability between subjects in the pain response. Based on the changes in experimental pain, subjects were divided into 3 groups (increase, decrease, no change in pain). Multiple regression analysis revealed that age, baseline experimental pain, and change in fibromyalgia pain intensity were significant predictors of the experimental pain response after the isometric contractions. Conclusions: We identified subgroups of women with fibromyalgia based on how they perceived pain after isometric contractions. The greatest pain relief for women with fibromyalgia occurred at a younger age and in women with the greatest experimental pain before exercise. Additionally, we established a link between experimental and clinical pain relief after the performance of isometric contractions

CaMKII Controls Whether Touch Is Painful

The sensation of touch is initiated when fast conducting low-threshold mechanoreceptors (Aβ-LTMRs) generate impulses at their terminals in the skin. Plasticity in this system is evident in the process of adaption, in which a period of diminished sensitivity follows prior stimulation. CaMKII is an ideal candidate for mediating activity-dependent plasticity in touch because it shifts into an enhanced activation state after neuronal depolarizations and can thereby reflect past firing history. Here we show that sensory neuron CaMKII autophosphorylation encodes the level of Aβ-LTMR activity in rat models of sensory deprivation (whisker clipping, tail suspension, casting). Blockade of CaMKII signaling limits normal adaptation of action potential generation in Aβ-LTMRs in excised skin. CaMKII activity is also required for natural filtering of impulse trains as they travel through the sensory neuron T-junction in the DRG. Blockade of CaMKII selectively in presynaptic Aβ-LTMRs removes dorsal horn inhibition that otherwise prevents Aβ-LTMR input from activating nociceptive lamina I neurons. Together, these consequences of reduced CaMKII function in Aβ-LTMRs cause low-intensity mechanical stimulation to produce pain behavior. We conclude that, without normal sensory activity to maintain adequate levels of CaMKII function, the touch pathway shifts into a pain system. In the clinical setting, sensory disuse may be a critical factor that enhances and prolongs chronic pain initiated by other conditions. SIGNIFICANCE STATEMENT: The sensation of touch is served by specialized sensory neurons termed low-threshold mechanoreceptors (LTMRs). We examined the role of CaMKII in regulating the function of these neurons. Loss of CaMKII function, such as occurred in rats during sensory deprivation, elevated the generation and propagation of impulses by LTMRs, and altered the spinal cord circuitry in such a way that low-threshold mechanical stimuli produced pain behavior. Because limbs are protected from use during a painful condition, this sensitization of LTMRs may perpetuate pain and prevent functional rehabilitation

Involvement of Noradrenergic Neurotransmission in the Stress- but not Cocaine-Induced Reinstatement of Extinguished Cocaine-Induced Conditioned Place Preference in Mice: Role for β-2 Adrenergic Receptors

The responsiveness of central noradrenergic systems to stressors and cocaine poses norepinephrine as a potential common mechanism through which drug re-exposure and stressful stimuli promote relapse. This study investigated the role of noradrenergic systems in the reinstatement of extinguished cocaine-induced conditioned place preference by cocaine and stress in male C57BL/6 mice. Cocaine- (15 mg/kg, i.p.) induced conditioned place preference was extinguished by repeated exposure to the apparatus in the absence of drug and reestablished by a cocaine challenge (15 mg/kg), exposure to a stressor (6-min forced swim (FS); 20–25°C water), or administration of the α-2 adrenergic receptor (AR) antagonists yohimbine (2 mg/kg, i.p.) or BRL44408 (5, 10 mg/kg, i.p.). To investigate the role of ARs, mice were administered the nonselective β-AR antagonist, propranolol (5, 10 mg/kg, i.p.), the α-1 AR antagonist, prazosin (1, 2 mg/kg, i.p.), or the α-2 AR agonist, clonidine (0.03, 0.3 mg/kg, i.p.) before reinstatement testing. Clonidine, prazosin, and propranolol failed to block cocaine-induced reinstatement. The low (0.03 mg/kg) but not high (0.3 mg/kg) clonidine dose fully blocked FS-induced reinstatement but not reinstatement by yohimbine. Propranolol, but not prazosin, blocked reinstatement by both yohimbine and FS, suggesting the involvement of β-ARs. The β-2 AR antagonist ICI-118551 (1 mg/kg, i.p.), but not the β-1 AR antagonist betaxolol (10 mg/kg, i.p.), also blocked FS-induced reinstatement. These findings suggest that stress-induced reinstatement requires noradrenergic signaling through β-2 ARs and that cocaine-induced reinstatement does not require AR activation, even though stimulation of central noradrenergic neurotransmission is sufficient to reinstate

Development of TRPM8 Antagonists to Treat Chronic Pain and Migraine

A review. Development of pharmaceutical antagonists of transient receptor potential melastatin 8 (TRPM8) have been pursued for the treatment of chronic pain and migraine. This review focuses on the current state of this progress

Evidence for Transient Receptor Potential (TRP) Channel Contribution to Arthritis Pain and Pathogenesis

Based on clinical and preclinical evidence, Transient Receptor Potential (TRP) channels have emerged as potential drug targets for the treatment of osteoarthritis, rheumatoid arthritis, and gout. This review summarizes the relevant data supporting a role for various TRP channels in arthritis pain and pathogenesis, as well as the current state of pharmacological efforts to ameliorate arthritis symptoms in patient populations

Mechanosensory and ATP Release Deficits following Keratin14-Cre-Mediated TRPA1 Deletion Despite Absence of TRPA1 in Murine Keratinocytes.

Keratinocytes are the first cells that come into direct contact with external tactile stimuli; however, their role in touch transduction in vivo is not clear. The ion channel Transient Receptor Potential Ankyrin 1 (TRPA1) is essential for some mechanically-gated currents in sensory neurons, amplifies mechanical responses after inflammation, and has been reported to be expressed in human and mouse skin. Other reports have not detected Trpa1 mRNA transcripts in human or mouse epidermis. Therefore, we set out to determine whether selective deletion of Trpa1 from keratinocytes would impact mechanosensation. We generated K14Cre-Trpa1fl/fl mice lacking TRPA1 in K14-expressing cells, including keratinocytes. Surprisingly, Trpa1 transcripts were very poorly detected in epidermis of these mice or in controls, and detection was minimal enough to preclude observation of Trpa1 mRNA knockdown in the K14Cre-Trpa1fl/fl mice. Unexpectedly, these K14Cre-Trpa1fl/fl mice nonetheless exhibited a pronounced deficit in mechanosensitivity at the behavioral and primary afferent levels, and decreased mechanically-evoked ATP release from skin. Overall, while these data suggest that the intended targeted deletion of Trpa1 from keratin 14-expressing cells of the epidermis induces functional deficits in mechanotransduction and ATP release, these deficits are in fact likely due to factors other than reduction of Trpa1 expression in adult mouse keratinocytes because they express very little, if any, Trpa1

<i>Trpa1</i> mRNA is poorly detected in mouse epidermal keratinocytes.

<p>(<b>A</b>) Following Cre-mediated recombination of genomic <i>Trpa1</i> DNA, an excision product is amplified in the epidermis of <i>K14Cre</i>-<i>Trpa1</i>^fl/fl mice (left), but not in the control (<i>K14Cre-Trpa1</i>^<i>+/+</i>) mice. Mutant mice (<i>K14Cre-Trpa1</i>^<i>fl/fl</i>) mice were either from an independently maintained colony (mutant-colony), or generated as littermates from heterozygous breeders (mutant—littermate). No excision product was observed in the DRGs of either control or mutant mice. Positive control band was obtained from DRG tissue from an <i>AdvillinCre-Trpa1</i>^<i>fl/fl</i> mouse (right). For panels B-F, mRNA was isolated from DRG and epidermis from control mice. (<b>B</b>) Amplification plot showing <i>Gapdh</i> and <i>Trpa1</i> mRNA transcript amplification. <i>Gapdh</i> was consistently detected and quantified in both DRG and epidermal samples (top). <i>Trpa1</i> mRNA was strongly detected in DRG samples; however, the same PCR protocol did not detect measurable <i>Trpa1</i> in epidermal samples (bottom). (<b>C</b>) Two different primer sets to detect <i>Trpa1</i> were effective in measuring <i>Trpa1</i> from DRG samples using SYBR Green qPCR, but did not amplify <i>Trpa1</i> from epidermal samples or cultured epidermal keratinocytes. Primer set 1 targets exons 22–23 within the deleted pore region of <i>Trpa1</i>; primer set 2 targets exons 17–19, upstream of the deleted pore region. (<b>D</b>) Three sets of Taqman primer-probes were similarly unable to detect <i>Trpa1</i> transcripts in control epidermis. Primer set 3 targets exons 13–14, set 4 targets exons 22–23, and set 5 targets exons 23–24 of <i>Trpa1</i>. (<b>E</b>) Neither qPCR for exons 22–23 (set 1) nor exons 22–23 (set 4) were capable of detecting <i>Trpa1</i> in neonatal mouse epidermis. (<b>F</b>) Two days after hindpaw injection of CFA, <i>Trpa1</i> remained undetected in epidermis. <i>N</i>.<i>d</i>. denotes transcript not detected.</p