Musculo-skeletal pain is a complex sensation where sensory, affective and cognitive dimensions of pain alongwith parallel neural networks in brain are associated with constellation of factors. Though pain occurs to show protective gesture, but when it surpasses threshold, exerts debilitating effect upon health and triggers concomitant physiological and psychological concerns of perilous ramifications. Right from the activation of primary afferent nociceptors upto the cortical processing of the pain in the higher regions of the brain, pain trajectory can be dissected into transduction, conduction, synaptic transmission and modulation. Besides, environmental, behavioral and psychological risks involved, all these stages of pain sensitivity, severity and analgesic responses are mediated by different set of genes and genetic variants.
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Transduction of noxious stimuli is regulated by transient receptor potential cation channel subfamily M, member 8 (TRPM8) and transient receptor potential cation channel subfamily A, member 1 (TRPA1) encoded by TRPM8 and TRPA1 genes, which plays an important role in the inhibition of background potassium channels. SCN10A encoded, voltage gated sodium channel Nav1.8 is essential for signal generation in response to cold stimuli. The nociception, due to heat stimulus and red hot chili pepper activates the ion channel TRPV1 and capsaicin receptors. However, TRPV1 also regulates the inflammatory pain thresholds, TRPV4, in conjunction with TRPV1 and TRPV2, transduces both thermo and mechano-sensations. The pain related transgenic knockout studies offered significant information on the genes that influence pain transduction. (Lacroix-Fralish ML. etal, 2007). Three genes SCN9A, SCN10A and SCN11A which encode sodium channels are observed to be expressed in sensing neurons. . SCN9A carriers, who have defective Nav1.7 remains pain free, which makes it a novel target for sodium selective analgesic drugs. SCN10A (Nav1.8) is also a significant contributors to the transduction signaling of pain pathway. Though, encoded channel Nav1.8 does not induces action potential but plays a significant role in setting the pain thresholds. SCN11A gets activated, close to the resting membrane potential and mutations in this gene have been associated to the loss of pain perception. Voltage gated sodium channel nociceptors specific genes SCN1A, SCN3A, SCN8A, SCN9A, SCN10A, SCN11A along with potassium channel encoding KCNQ genes play a significant role in nociceptive conduction. Synaptic transmission is regulated by several genes such as GR1N1, GR1N2, GR1A1-4, GR1C1-5, NK1R. Some voltage gated calcium channels encoding genes, such as CACNA1A-S, CACNA2D1 mediates the neurotransmitter release in the pre-synaptic membrane.Several genes and genetic variants have also been implicated in the central, peripheral and microglial pain modulation. (Foulks and Wood. 2008). How damage sensing neurons submit input signals regarding the extent and severity of pain to central nervous sytem (CNS) is highly complex. Very many brain areas are involved in sensory discrimination and affective evaluation which determine the nature of pain perception. Genetic variation of COMT gene that encodes catechol-o-methyltransferase regulates the inactivation of catecholamines neurotransmitters and reduced COMT enzymatic activity which leads to increased pain sensitivity and temporal summation of pain (diatchenko L et al. 2005) Decreased adrenalin metabolism due to reduced COMT activity increases pain through the stimulation of β2/ 3-adrenergic receptor antagonist.
A few genome wide association studies (GWAS) on musculo-skeletal phenotypes have been carried out which revealed some strongly associated SNPs within CCT5 and FAM173B genes that influence chronic widespread pain in lumbar spine region. Over the past decade, an intriguing development in cellular genomics has aroused curiosity of the possibility of miRNA in pain research. MicroRNAs (miRNAs) are family of small, noncoding RNAs that regulate gene expression in sequence specific manner. Their non-perfect pairing of 6-8 nucleotides with target mRNA subsequently forming miRNA Induced Silencing Complex (miRISC) generally results in translational repression, destabilization of mRNAs and gene silencing. Some miRNAs have been implicated in pain mechanism including neuronal plasticity, neurogenesis, nociceptor excitability, chronic pain conditions and pain threshold. They engrossed the attention when observed that these miRNAs play an evident role in the conditional deletion in nociceptors of the miRNA producing enzyme, Dicer and blocks inflammatory pain hypersensitivity. The pioneer studies on the role and relevance of miRNAs in pain demonstrated that miR-134 is modulated in the trigeminal ganglion in response to inflammatory pain. BDNF triggered miR-132 is upregulatedin cortical neurons which is identified as modulation of nociception signaling. miRNA Let-7 that target µ-opiod receptors plays considerable influence on the opioid tolerance in mice. Activity regulated miR-188 is a significant player of synaptic plasticity tuning. Dysregulation of miR-29a/b is associated with structural plasticity in psycho-stimulant exposure. In the traumatized spinal injury miR-219 is downregulated 7 days after contusion whereby sciatic nerve ligation induces an up-regulation of this miRNA. In chronic pain miR-124 down regulates in dorsal root ganglion neurons in inflammatory muscle as well as in sciatic nerve crush.
Researchers are instrumental in understanding the epigenetic mechanisms in relation to pain causation and alleviation. Epigenetic modifications play significant role in cytokine metabolism, neurotransmitter release and response, analgesic sensitivity and central sensitization. Changes in chromatin structure may lead to acute to chronic pin transition. Prior priming (sensitization) of spinal microglia with initial inflammatory challenge, subsequent challenges create enhanced pain intensity and duration. Effects of neonatal pain experience relates to adult pain sensitivity where they exhibit spinal neuronal circuits with increased input and segmental changes in nociceptive primary afferent axons and enhanced or altered pain stimulation. Histone modifications, a significant epigenetic mechanism which may alter the gene expression of pain is highly associated with glutamate decarboxylase (Gad2), Shal related subfamily member 3 (Kcnd3), melting CpG binding protein 2 (Mecp2), potassium voltage gated channels, oprin 1, Scn9a Genes. Histone acetylation and DNA methylation have also been implicated in chronic pain conditions. Though an epigenetic alteration in relation to the risk of pain is in infancy but in near future, such knowledgeable musings will unravel several novel targets for analgesic drugs and preventive modalities.
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Brain does more than understanding and responding to pain irrespective of sensory inputs and even in the absence of external inputs. Why even cordectomy or anesthetic blocks of sympathetic ganglia do not stop phantom limb pain? Pain genetics have the capacity to enrich us of several such intricate and unforeseen consequences involved with pain etiology, risk factors and variable analgesia. In future, investigation of relevant genomic sequences has many revelations in store for us, by which we will be able to regulate or control pain by switching on or off various genes that causes it.