The search for novel analgesics: targets and mechanisms

Abstract

The management of the pain state is of great therapeutic relevance to virtually every medical specialty. Failure to manage its expression has deleterious consequence to the well-being of the organism. An understanding of the complex biology of the mechanisms underlying the processing of nociceptive information provides an important pathway towards development of novel and robust therapeutics. Importantly, preclinical models have been of considerable use in determining the linkage between mechanism and the associated behaviorally defined pain state. This review seeks to provide an overview of current thinking targeting pain biology, the use of preclinical models and the development of novel pain therapeutics. Issues pertinent to the strengths and weaknesses of current development strategies for analgesics are considered.

Figure 1.. Summary of peripheral targets in nociceptive processing

Stimuli, such as tissue injury, inflammation, or infection, lead to the release of pro-inflammatory mediators from local/resident cells (mast cells, Schwann cells), migrating cells (macrophages, neutrophils), damaged cells, and blood vessels, at the peripheral terminal. These mediators act on receptors expressed on dorsal root ganglion cells and, when activated, evoke excitation and activation of intracellular kinases. This results in the phosphorylation of receptors inducing activation at lower thresholds, increased afferent traffic, and terminal sensitization. DRG, dorsal root ganglion; DNA, deoxyribonucleic acid; RNA, ribonucleic acid; FP, formyl peptide; 5-HT, 5-hydroxytryptamine (serotonin); CGRP, calcitonin gene related peptide; ATP, adenosine triphosphate; NGF, nerve growth factor; BDNF, brain-derived neurotrophic factor; CCL, chemokine (C-C motif) ligand; CX3CL1, chemokine (C-X3-C motif) ligand; TNF, tumor necrosis factor; IL, interleukin; sP, substance P; H+, hydrogen ions; TRK, tyrosine receptor kinase; NK-1, neurokinin 1; ASIC, acid-sensing ion channel; TRPV1, transient receptor potential cation channel subfamily V, member 1; TRPA1, transient receptor potential cation channel, subfamily A, member 1; Na_v1.7, voltage-gated sodium channel type 1.7; Ca_v2.2, voltage gated calcium channel type 2.2; PKC, protein kinase C; PKA, protein kinase A; CaMK, calcium/calmodulin-dependent protein kinase; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; MAPK, mitogen-activated protein kinase; GPCR, G protein-coupled receptor; TLR, Toll-like receptor.

Figure 2.. Summary of central targets in nociceptive processing

Stimuli, such as tissue injury, inflammation, or nerve injury activates the primary afferents and induces CaV and SNARE-dependent release of neurotransmitters, growth factors and neuropeptides from the spinal primary afferents. Release of these substances activates the resident glial cells and migrating cells (T cells, macrophages and neutrophils) in the spinal cord along with the second order neurons. These cells release a constellation of pro-inflammatory and anti-inflammatory molecules which further act on the second order neurons activating several protein kinases responsible for the phosphorylation of several membrane bound receptors leading to the activation of second order neurons, thus initiating and maintaining the hyperexcitable state of these neurons, and further sending the nociceptive signals to higher brain centers. The second order neurons also project onto raphe-spinal serotonergic neurons which, through the bulbospinal pathway, terminate in dorsal horn neurons and serve to facilitate the excitability of dorsal horn projection neurons. 5-HT3, 5 hydroxytryptamine 3 receptor; AMPA-CP, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-calcium permeable; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor; CaMK, calmodulin-dependent protein kinase; CaV, voltage-gated calcium channels; CCL, chemokine (C-C motif) ligand; CGRP, calcitonin gene related peptide; CX3CL1, chemokine (C-X3-C motif) ligand; GABA-A, gamma aminobutyric acid; IFNγ, interferon gamma; IL, interleukin; MAPK, mitogen-activated protein kinase; mGluR, metabotropic glutamate receptor; NK-1, neurokinin-1; NMDA, N-methyl D-aspartate; PKA, protein kinase A; PKC, protein kinase C; SNARE soluble N-ethylmaleimide-sensitive factor activating protein receptor; sP, substance P; TNF, tumor necrosis factor.