PKMζ is essential for spinal plasticity underlying the maintenance of persistent pain

Oncostatin M (OSM) is a member of the interleukin-6 cytokine family and regulates eg. gene activation, cell survival, proliferation and differentiation. OSM binds to a receptor complex consisting of the ubiquitously expressed signal transducer gp130 and the ligand binding OSM receptor subunit, which is expressed on a specific subset of primary afferent neurons. In the present study, the effect of OSM on heat nociception was investigated in nociceptor-specific gp130 knock-out (SNS-gp130 ^-/- ) and gp130 floxed (gp130 ^fl/fl ) mice. Subcutaneous injection of pathophysiologically relevant concentrations of OSM into the hind-paw of C57BL6J wild type mice significantly reduced paw withdrawal latencies to heat stimulation. In contrast to gp130 ^fl/fl mice, OSM did not induce heat hypersensitivity in vivo in SNS-gp130 ^-/- mice. OSM applied at the receptive fields of sensory neurons in in vitro skin-nerve preparations showed that OSM significantly increased the discharge rate during a standard ramp-shaped heat stimulus. The capsaicin- and heat-sensitive ion channel TRPV1, expressed on a subpopulation of nociceptive neurons, has been shown to play an important role in inflammation-induced heat hypersensitivity. Stimulation of cultured dorsal root ganglion neurons with OSM resulted in potentiation of capsaicin induced ionic currents. In line with these recordings, mice with a null mutation of the TRPV1 gene did not show any signs of OSM-induced heat hypersensitivity in vivo. The present data suggest that OSM induces thermal hypersensitivity by directly sensitizing nociceptors via OSMR-gp130 receptor mediated potentiation of TRPV1.     

Do genetic predictors of pain sensitivity associate with persistent widespread pain?

Genetic risk factors for pain sensitivity may also play a role in susceptibility to chronic pain disorders, in which subjects have low pain thresholds. The aim of this study was to determine if proposed functional single nucleotide polymorphisms (SNPs) in the GTP cyclohydrolase (GCH1) and μ opioid receptor (OPRM1) genes previously associated with pain sensitivity affect susceptibility to chronic widespread pain (CWP). Pain data was collected using body manikins via questionnaire at three time-points over a four year period from subjects aged 25-65 in the North-West of England as part of a population based cohort study, EPIFUND. CWP was defined at each time point using standard criteria. Three SNPs forming a proposed "pain-protective" haplotype in GCH1 (rs10483639, rs3783641 and rs8007267) and two SNPs in OPRM1 (rs1777971 (A118G) and rs563649) were genotyped in cases with persistent CWP (CWP present at ≥2 time-points) and controls who were pain-free at all time-points. The expectation-maximisation algorithm was used to estimate haplotype frequencies. The frequency of the "pain-protective" (CAT - C allele of rs10483639, A allele of rs3783641 and T allele of rs8007267) haplotype was compared to the frequency of the other haplotypes between cases and controls using the χ² test. Allele frequencies and carriage of the minor allele was compared between cases and controls using χ² tests for the OPRM1 SNPs. The frequency of the proposed GCH1 "pain-protective" haplotype (CAT) did not significantly differ between cases and controls and no significant associations were observed between the OPRM1 SNPs and CWP. In conclusion, there was no evidence of association between proposed functional SNPs, previously reported to influence pain sensitivity, in GCH1 and OPRM1 with CWP. Further evidence of null association in large independent cohorts is required to truly exclude these SNPs as genetic risk factors for CWP.     

A straightjacket for pain?

Perception of pain involves both the peripheral and central nervous systems. Starting with a whole-genome RNA interference screen in Drosophila, Neely et?al. (2010) identify a mammalian gene that is required not only for efficient transfer of pain signals between brain centers, but also for the suppression of inappropriate signaling between other sensory systems.     

Do doctors undertreat pain?

Routinely, physicians discount patients' pain reports and provide too little analgesia too late. Critics call them callous, sadistic, and Puritanical, but the causes of these clinical practices are different — namely, a psychological need to distance themselves from the pain they encounter and inflict, and more subtly, a peculiar concept of pain acquired in medical training.
Physicians learn to think of pain as a symptom to observe and explore in diagnosing and monitoring disease — not as a complaint to relieve quickly or fully. Moreover, pain-relief is regarded as subordinate to, and competing with efforts to cure or maintain the life of a patient. This training, I suggest, gives physicians a new, clinical concept of pain at odds with their prior, lay concept of pain whose manifestations standardly call for sympathetic efforts at relief.
The conceptual nature of this difference is obscured by thinking of pain as a solely private sensation, rather than as a sensation with public and social aspects (a la Wittgenstein). Although suppressed in certain clinical circumstances, these standard public and social aspects are shown in the very tests used in clinical pain research.
This clinical pain concept is rooted in Medicine conceived as preeminently curative and life-prolonging. Physicians are, however, themselves undermining this professional self-definition (by treating AIDS and Alzheimer's patients; by no longer pressing their patients to 'fight to the end'; by collaborating with non-medical healers). Accordingly, pain-relief may gain greater therapeutic status, and, so too, the ordinary concept of pain that medical training has suppressed.     

Do glial cells control pain?

Management of chronic pain is a real challenge, and current treatments that focus on blocking neurotransmission in the pain pathway have resulted in limited success. Activation of glial cells has been widely implicated in neuroinflammation in the CNS, leading to neurodegeneration in conditions such as Alzheimer's disease and multiple sclerosis. The inflammatory mediators released by activated glial cells, such as tumor necrosis factor-a and interleukin-1b not only cause neurodegeneration in these disease conditions, but also cause abnormal pain by acting on spinal cord dorsal horn neurons in injury conditions. Pain can also be potentiated by growth factors such as brain-derived growth factor and basic fibroblast growth factor, which are produced by glia to protect neurons. Thus, glial cells can powerfully control pain when they are activated to produce various pain mediators. We review accumulating evidence that supports an important role for microglial cells in the spinal cord for pain control under injury conditions (e.g. nerve injury). We also discuss possible signaling mechanisms, in particular mitogen-activated protein kinase pathways that are crucial for glial-mediated control of pain.Investigating signaling mechanisms in microglia might lead to more effective management of devastating chronic pain.