•The sciatic nerve cuff model of neuropathic pain exhibits pain recovery.•Thermal hyperalgesia and dynamic weight bearing display similar pain recovery profiles, whereas mechanical allodynia ...persists.•Dynamic weight bearing is a non-reflexive, pain assessment of ongoing pain during nerve entrapment.
Chronic constriction injuries (CCI) of the sciatic nerve are widely used nerve entrapment animal models of neuropathic pain. Two common pain behaviors observed following CCI are thermal hyperalgesia and mechanical allodynia, measured by the Hargreaves and von Frey tests, respectively. While thermal hyperalgesia tends to recover by 30 days, mechanical allodynia can persist for many more months thereafter. Consequently, mechanical allodynia has been used extensively as a measure of ‘chronic pain’ focusing on the circuitry changes that occur within the spinal cord. Here, using the sciatic nerve cuff variant of CCI in mice, we propose that in contrast to these evoked measures of nociceptive hypersensitivity, dynamic weight bearing provides a more clinically relevant behavioral measure for ongoing pain during nerve injury. We found that the effect of sciatic nerve cuff on the ratio of weight bearing by the injured relative to uninjured hindlimbs more closely resembled that of thermal hyperalgesia, following a trend toward recovery by 30 days. We also found an increase in the percent of body weight bearing by the contralateral paw that is not seen in the previously tested behaviors. These results demonstrate that dynamic weight bearing is a reliable measure of non-evoked neuropathic pain and suggest that thermal hyperalgesia, rather than mechanical allodynia, provides a proxy measure for nerve entrapment-induced ongoing pain.
Under physiological conditions, momentary pain serves vital protective functions. Ongoing pain in chronic pain states, on the other hand, is a pathological condition that causes widespread suffering ...and whose treatment remains unsatisfactory. The brain mechanisms of ongoing pain are largely unknown. In this study, we applied tonic painful heat stimuli of varying degree to healthy human subjects, obtained continuous pain ratings, and recorded electroencephalograms to relate ongoing pain to brain activity. Our results reveal that the subjective perception of tonic pain is selectively encoded by gamma oscillations in the medial prefrontal cortex. We further observed that the encoding of subjective pain intensity experienced by the participants differs fundamentally from that of objective stimulus intensity and from that of brief pain stimuli. These observations point to a role for gamma oscillations in the medial prefrontal cortex in ongoing, tonic pain and thereby extend current concepts of the brain mechanisms of pain to the clinically relevant state of ongoing pain. Furthermore, our approach might help to identify a brain marker of ongoing pain, which may prove useful for the diagnosis and therapy of chronic pain.
Ongoing activity in nociceptors, a driver of spontaneous pain, can be generated in dorsal root ganglion neurons in the absence of sensory generator potentials if one or more of three ...neurophysiological alterations occur – prolonged depolarization of resting membrane potential (RMP), hyperpolarization of action potential (AP) threshold, and/or increased amplitude of depolarizing spontaneous fluctuations of membrane potential (DSFs) to bridge the gap between RMP and AP threshold. Previous work showed that acute, sustained exposure to serotonin (5-HT) hyperpolarized AP threshold and potentiated DSFs, leading to ongoing activity if a separate source of maintained depolarization was present. Cellular signaling pathways that increase DSF amplitude and promote ongoing activity acutely in nociceptors are not known for any neuromodulator. Here, isolated DRG neurons from male rats were used to define the pathway by which low concentrations of 5-HT enhance DSFs, hyperpolarize AP threshold, and promote ongoing activity. A selective 5-HT4 receptor antagonist blocked these 5-HT-induced hyperexcitable effects, while a selective 5-HT4 agonist mimicked the effects of 5-HT. Inhibition of cAMP effectors, protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), attenuated 5-HT's hyperexcitable effects, but a blocker of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels had no significant effect. 5-HT4-dependent PKA activation was specific to DRG neurons that bind isolectin B4 (a nonpeptidergic nociceptor marker). 5-HT's effects on AP threshold, DSFs, and ongoing activity were mimicked by a cAMP analog. Sustained exposure to 5-HT promotes ongoing activity in nonpeptidergic nociceptors through the Gs-coupled 5-HT4 receptor and downstream cAMP signaling involving both PKA and EPAC.
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•Sustained exposure to 5-HT induces nociceptor hyperexcitability via 5-HT4 receptors.•The hyperexcitable effects promote ongoing activity during modest depolarization.•A major effect is enhancement of irregular, depolarizing spontaneous fluctuations.•cAMP, PKA, and EPAC mediate hyperexcitable effects that promote ongoing activity.
Exercise is the most common treatment recommended by healthcare providers for the treatment of musculoskeletal pain. We examined whether voluntary running wheel exercise improves pain and bone ...remodeling in rats with monosodium iodoacetate-induced unilateral knee joint pain. During acquisition of wheel running before osteoarthritis (OA) treatment, rats separated into 2 groups characterized by either high or low levels of voluntary wheel running as indicated by distance and peak speed. After the induction of knee joint OA, all rats showed diminished voluntary wheel running throughout the study. Voluntary wheel running failed to alter evoked nociceptive responses evaluated as weight asymmetry or hind paw tactile thresholds at any timepoint of the study. By contrast, relief of ongoing pain was demonstrated by conditioned place preference produced by lidocaine injection into the monosodium iodoacetate-treated knee in high but not low-running rats. Both high and low voluntary runners showed diminished trabecular bone loss compared with sedentary controls. These observations indicate that both high-intensity and low-intensity exercise is beneficial in protecting against bone remodeling in advanced OA. The data suggest that similar to clinical observation, bone remodeling does not correlate with pain. In addition, these results suggest that higher intensity exercise may relieve persistent ongoing OA pain while maintaining movement-evoked nociception. The relief of ongoing pain can potentially offer significant improvement in quality of life, whereas preservation of responses to movement-evoked pain may be especially important in protecting the joint from damage because of overuse.
Temporomandibular joint osteoarthritis (TMJOA) is a prevalent source of temporomandibular joint disorder (TMD). Women are more commonly diagnosed with TMD and are more likely to seek care at tertiary ...orofacial pain clinics. Limited knowledge regarding mechanisms underlying temporomandibular joint (TMJ) pain impairs development of improved pain management strategies. In a rat model of unilateral TMJOA, monosodium iodoacetate (MIA) produces joint pathology in a concentration-dependent manner. Unilateral MIA produces alterations in meal patterns in males and females without altering overnight time spent eating or weight across 2 weeks. Monosodium iodoacetate (80 mg/mL)-treated males develop ongoing pain within 2 weeks after MIA injection. Females develop ongoing pain at a 5-fold lower MIA concentration (16.6 mg/m). Monosodium iodoacetate (80 mg/mL)-treated males show spread of tactile hypersensitivity across the face during the first week after injection and then to the fore paws and hind paws during the second week after injection, indicating development of central sensitization. At the lower dose, female rats demonstrate a similar spread of tactile hypersensitivity, whereas male rats do not develop ongoing pain or spread of tactile hypersensitivity outside the area of the ipsilateral temporomandibular joint. These observations indicate that females have a higher susceptibility to development of ongoing pain and central sensitization compared with male rats that is not due to differences in MIA-induced joint pathology. This model of TMJOA pain can be used to explore sex differences in pain processes implicated in development of neuropathic pain, ongoing pain, and central sensitization, allowing for development of individualized strategies for prevention and treatment of TMD joint pain.
Pyramidal neurons in the anterior cingulate cortex (ACC), a prefrontal region involved in processing the affective components of pain, display hyperexcitability in chronic neuropathic pain ...conditions, and their silencing abolishes hyperalgesia. We show that dopamine, through D1 receptor (D1R) signaling, inhibits pyramidal neurons of mouse ACC by modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Activation of G
-coupled D1R by dopamine induces the opening of HCN channels at physiological membrane potentials, driving a significant decrease in input resistance and excitability. Systemic L-DOPA in chronic neuropathic mice rescues HCN channel activity, normalizes pyramidal excitability in ACC, and blocks mechanical and thermal allodynia. Moreover, microinjection of a selective D1R agonist in the ACC relieves the aversiveness of ongoing neuropathic pain, while an ACC D1R antagonist blocks gabapentin- and lidocaine-evoked antinociception. We conclude that dopaminergic inhibition via D1R in ACC plays an analgesic role in physiological conditions and is decreased in chronic pain.
Spontaneous pain is often discussed in the context of both chronic inflammatory and neuropathic pain conditions, and it has been suggested that spontaneous pain, rather than stimulus-evoked pain, may ...be the more significant clinical problem. The following issues are discussed here. First, it is suggested that the concept of spontaneous pain makes no sense when the pain is the result of an ongoing inflammatory reaction. Evidence is reviewed that indicates that spontaneous pain is present in patients with neuropathic pain, but perhaps only in a subset of such patients. Second, it is suggested that in the presence of allodynia and hyperalgesia, stimulation from the activities of daily life occurs very many times a day and that these stimulus-evoked pains may summate to give a fluctuating level of daily pain that both patients and investigators mistake for spontaneous pain.
Which is more important-stimulus-evoked pain or spontaneous pain? This review suggests that to answer the question we will need to distinguish neuropathic spontaneous pain from inflammatory ongoing pain and to differentiate both from summated allodynic and hyperalgesic pains caused by the stimuli of daily life.
Unresolved inflammation is a significant predictor for developing chronic pain, and targeting the mechanisms underlying inflammation offers opportunities for therapeutic intervention. During ...inflammation, matrix metalloproteinase (MMP) activity contributes to tissue remodeling and inflammatory signaling, and is regulated by tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 and -2 have known roles in pain, but only in the context of MMP inhibition. However, TIMP-1 also has receptor-mediated cell signaling functions that are not well understood. Here, we examined how TIMP-1-dependent cell signaling impacts inflammatory hypersensitivity and ongoing pain. We found that hindpaw injection of complete Freund's adjuvant (CFA) increased cutaneous TIMP-1 expression that peaked prior to development of mechanical hypersensitivity, suggesting that TIMP-1 inhibits the development of inflammatory hypersensitivity. To examine this possibility, we injected TIMP-1 knockout (T1KO) mice with CFA and found that T1KO mice exhibited rapid onset thermal and mechanical hypersensitivity at the site of inflammation that was absent or attenuated in WT controls. We also found that T1KO mice exhibited hypersensitivity in adjacent tissues innervated by different sets of afferents, as well as skin contralateral to the site of inflammation. Replacement of recombinant murine (rm)TIMP-1 alleviated hypersensitivity when administered at the site and time of inflammation. Administration of either the MMP inhibiting N-terminal or the cell signaling C-terminal domains recapitulated the antinociceptive effect of full-length rmTIMP-1, suggesting that rmTIMP-1inhibits hypersensitivity through MMP inhibition and receptor-mediated cell signaling. We also found that hypersensitivity was not due to genotype-specific differences in MMP-9 activity or expression, nor to differences in cytokine expression. Administration of rmTIMP-1 prevented mechanical hypersensitivity and ongoing pain in WT mice, collectively suggesting a novel role for TIMP-1 in the attenuation of inflammatory pain.
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•Kinesins (KIF’s) are ATP driven nanomotors involved in the trafficking of nociceptors.•Tozasertib attenuates evoked and spontaneous ongoing-pain in nerve-injured rats.•Aurora kinase ...inhibition interferes with KIF17-NR2B mediated inflammatory signaling.•Tozasertib treatment does not produce CNS side effects unlike morphine.•Inhibition of KIF17-NMDA crosstalk may be a potential target for neuropathic pain.
Kinesins (KIF’s) are the motor proteins which are recently reported to be involved in the trafficking of nociceptors leading to chronic pain. Aurora kinases are known to be involved in the regulation of KIF proteins which are associated with the activation of N-methyl-D-aspartate (NMDA) receptors. Here, we investigated the effect of tozasertib, a pan-Aurora kinase inhibitor, on nerve injury-induced evoked and chronic ongoing pain in rats and the involvement of kinesin family member 17 (KIF17) and NMDA receptor subtype 2B (NR2B) crosstalk in the same. Rats with chronic constriction injury showed a significantly decreased pain threshold in a battery of pain behavioural assays. We found that tozasertib 10, 20, and 40 mg/kg intraperitoneally (i.p.) treatment showed a significant and dose-dependent inhibition of both evoked and chronic ongoing pain in rats with nerve injury. Tozasertib (40 mg/kg i.p.) and gabapentin (30 mg/kg i.p.) treatment significantly inhibits spontaneous ongoing pain in nerve injured rats but did not produce any place preference behaviour in healthy naïve rats pointing towards their non-addictive analgesic potential. Moreover, tozasertib (10, 20, and 40 mg/kg i.p.) and gabapentin (30 mg/kg i.p.) treatment did not altered the normal pain threshold in healthy naïve rats and didn’t produce central nervous system associated side effects as well. Western blotting and reverse transcription polymerase chain reaction studies suggested enhanced expressions of NR2B and KIF-17 along with increased nuclear factor kappa β (NFkβ), tumour necrosis factor-α (TNF-α), interleukin 1β (IL-1β), and interleukin 6 (IL-6) levels in dorsal root ganglion (DRG) and spinal cord of nerve injured rats which was significantly attenuated on treatment with different does of Tozasertib. Findings from the current study suggests that inhibition of pan-Aurora kinase decreased KIF-17 mediated NR2B activation which further leads to significant inhibition of evoked and chronic ongoing pain in nerve-injured rats.
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