Inhibitory pain modulation

Siqueira-Lima, P. S., Araujo, A. A. S., Lucchese, A. M., Quintans, J. S. S., Menezes, P. R, Barreto, P. A., deLuccaJunior, W., Santos, M. R. V., Bonjardim, L. R., and Quintans-Junior, L. J. (2014). P-cyclodextrin complex containing Lippia grata leaf essential oil reduces orofacial nociception in mice-evidence of possible involvement of descending inhibitory pain modulation pathway. Basic and Clinical Pharmacology and Toxicology, 114(2), 188-196. 

GABAergic and glycinergic interneurons are involved in tonic inhibition of nociceptive input and loss of these neurons is implicated in the development of chronic and neuropathic pain [5]. Endogenous opioids and noradrenergic pathways are also involved in inhibitory pain modulation. 

Langoth et al. [86] studied the properties of matrix-based tablets containing the novel pentapeptide leu-enkephalin (Tyr-Gly-Gly-Phe-Leu) that has been shown to have pain-modulating properties. The matrix-based tablets were made with the thiolated polymer PCP. The covalent attachment of cysteine to the anionic polymer PCP leads to an improvement of the stability of matrix tablets, enhances the mucoadhesive properties, and increases the inhibitory potency of PCP towards buccal enzymes. All these factors lead to stability of the peptide and a controlled drug release for the peptide was obtained for more than 24 h. Also, the tablets based on thiolated PCP remained attached on freshly excised porcine mucosa 1.8 times longer than the corresponding unmodified polymer. 

Glycine, the smallest amino acid, is known to be an inhibitory neurotransmitter, but only a few studies investigated its role in pain modulation (Webb and Lynch,... 

Another intriguing observation is that the female sex-hormone 17/i-estradiol (28) could dramatically potentiate capsaicin responses, whereas the male hormone testosterone had marginal inhibitory activity. Sex differences in pain responses have long been known, with women being more sensitive to capsaicin-induced pain than men [94]. The differential modulation of capsaicin responses by female and male hormones might provide a rationale to explain this observation. 

The diagram below shows the pathway of pain transmission from the peripheral nerves to the cerebral cortex. There are three levels of neuronal involvement and the signals may be modulated at two points during their course to the cerebral cortex. Descending inhibitory pathways arise in the midbrain and pass to the dorsal horn as shown. Multiple different neurotransmitters are involved in the pathway and include gamma-aminobutyric acid (GABA), N-methyl-D-aspartate (NMDA), noradrenaline and opioids. 

Opioid systems are intimately involved in the whole pleasure-pain modality (Bolles Fanselow, 1982) and affect conscious and unconscious behaviour. Though acutely painful stimuli may press urgently into consciousness, inhibitory modulators serve to remove pain from the conscious level allowing appropriate adaptive behaviour. Thus a soldier wounded in battle may feel no pain until removed from the front and potentially painful stimuli may pass unnoticed during the excitement of sporting activities (Melzack Wall, 1988). 

Immune-modulating agents that prevent activation of immune cells and/or the inhibitory agents of inflammatory cytokines could prevent the neuropathic pain caused by vincristine. These agents could increase the tolerability of vincristine when used for the treatment of leukemia and lymphoma. 

Dickenson, A. H., Chapman, V., and Green, G. M. (1997). The pharmacology of excitatory and inhibitory amino add-mediated events in the transmission and modulation of pain in the spinal... 

Initially, Gly was described to be restricted to the mammalian spinal cord, but subsequently it has been detected supraspinally as well (Legendre, 2001). Gly receptors (GlyRs) belong to the superfamily of receptor channels, which are generally composed of five subunits (al-4, P) (Webb and Lynch, 2007). The different a-and P-subunits are differently localized. The GlyR is a pentameric chloride channel, and it is classically known for mediating inhibitory synaptic transmission between interneurons and motor neurons in reflex circuits of the spinal cord, but they are also found presynaptically, where they modulate neurotransmitter release (Lynch, 2009 Webb and Lynch, 2007). The picture is complicated by the fact that Gly also binds to and activates NMDA receptors, therefore, it can influence the pain threshold by this action as well (see above. Section 2.3.1) (Zeilhofer, 2005). 

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