In contrast to most other sensory modalities, the neuroanatomical substrates in the brain for pain sensation in general and visceral pain in particular, have only recently begun to be elucidated. Major advances in this field have come through functional anatomical and physiological studies in nonhuman primates and rats, which have identified substrates that underlie findings from functional imaging and microelectrode studies in humans.

In addition to the afferent pathways that process nociceptive signals at different levels of the neuraxis, pain processing involves a number of modulatory controls that exist throughout the nervous system and function to enhance or dampen the intensity of the original signal or to modify its quality. At the level of the spinal cord input from non-nociceptive and nociceptive afferent pathways can interact to modulate transmission of nociceptive information to higher brain centers. In addition, the brain contains modulatory systems that affect the conscious perception of sensory stimuli. Spinal nociceptive transmission is subject to descending modulatory influences from supraspinal structures e.g., periaqueductal gray, nucleus raphe magnus, locus coeruleus, nuclei reticularis gigantocellularis, and the ventrobasal complex of the thalamus (see Besson and Chaouch 1987; Hodge et al. 1986; Light 1992; Peng et al. 1996b; Willis 1982). Descending modulation can be inhibitory, facilitatory or both depending on the context of the stimulus or the intensity of the descending signal (Saab et al. 2004; Zhuo and Gebhart 2002). The descending influence from the ventromedial medulla is mediated mainly by pathways traveling in the dorsolateral spinal cord (Zhuo and Gebhart 2002) and can be inhibitory or facilitatory based on stimulus intensity. In contrast, descending control from the thalamus is context-specific in that it may facilitate or inhibit spinal nociceptive processing depending upon the presence or absence of central sensitization (Saab et al. 2004). For instance, serotonergic (Peng et al. 1995), noradrenergic (Peng et al. 1996a; Proudfit 1992), and to a lesser extent dopaminergic projections are major components of descending modulatory pathways (Dahlström and Fuxe 1964, 1965), in addition to a major role played by opiates and enkephalins (Duggan and North 1984; Duggan et al. 1977).

The activity of nociceptors can be affected by adequate stimuli, such as strong mechanical, thermal, or chemical stimuli (see Willis 1985; Willis and Coggeshall 2004), and also by chemical actions on surface membrane receptors of their axons. A battery of chemical mediators, including biogenic amines (such as glutamate, [gamma]-aminobutyric acid (GABA), histamine, serotonin, norepinephrine) (Dray et al. 1994; McRoberts et al. 2001), opiates (Joshi et al. 2000; Su et al. 1997), purines, prostanoids, proteases, cytokines, and other peptides (such as bradykinin, substance P, and CGRP) act in a promiscuous manner on a range of receptors expressed upon any one sensory ending (Kirkup et al. 2001).

Three distinct processes are involved in the actions of these substances on afferent nerves. First, by direct activation of receptors coupled to the opening of ion channels present on nerve terminals, the terminals are depolarized and firing of impulses is initiated. Second, by sensitization that develops in the absence of direct stimulation and results in hyperexcitability to both chemical and mechanical modalities, e.g., opiate receptors are ineffective in modulating the normal activity of joint nociceptors, but they were shown to become effective after the development of inflammation (Stein 1994). Sensitization may also involve postreceptor signal transduction that includes G-protein coupled alterations in second-messenger systems which in turn lead to phosphorylation of membrane receptors and ion channels that control excitability of the afferent endings. Third, by genetic changes in the phenotype of mediators, channels, and receptors expressed by the afferent nerve, for example after peripheral nerve injury, many afferent fibers express newly formed adrenoreceptors (Bossut and Perl 1995; Campbell et al. 1992; Sato and Perl 1991; Xie et al. 1995). A change in the ligand-binding characteristics or coupling efficiency of these newly expressed receptors could alter the sensitivity of the afferent terminals. Neurotrophins, in particular nerve growth factor and glial-derived neurotropic factor, influence different populations of visceral afferents and play an important role in adaptive responses to nerve injury and inflammation (McMahon 2004; Bielefeldt et al. 2006).

Ion channels on nociceptors act as molecular transducers that depolarize these neurons, thereby setting off nociceptive impulses along the pain pathways (Price 2000; Costigan and Woolf 2000). Among these ion channels are the members of the transient receptor potential (TRP) family, activated by changes in temperature and extracellular pH and the presence of vanilloid ligands, such as capsaicin and mustard oil (Woolf and Ma 2007). The thermosensitive TRP family constitutes an interface with the environment and includes a number of diverse channels, each with a distinct thermal threshold and a different set of chemical activators. To date, the most studied member of the TRP family is the TRPV1 receptor (Di Marzo et al. 2002; Cortright and Szallasi 2004). Activation of primary afferents can also be brought about by other types of ion channels, including the degenerin epithelial sodium channel (ENaC) family (Kellenberger and Schild 2002; Price et al. 2001) and the acid-sensing ion channel (ASIC) family, of which ASIC3 has been implicated in the perception of noxious mechanical stimulation in mammals (Mogil et al. 2005). Tissue damage also results in the release of high concentrations of ATP, which can act on ligand-gated purinergic P2X channels and P2Y receptors to activate nociceptors (Khakh and North 2006).

Voltage-gated sodium channels (VGSCs) are also critical for the initiation of action potentials in the peripheral terminals of nociceptors and conduction along axons in peripheral nerves to the spinal cord. VGSCs allow sodium ion influx in response to local membrane depolarization, such as the potential generated in the peripheral terminals of nociceptors (Cummins et al. 2007). Different roles have been attributed to each sodium channel in influencing neuronal excitability, often associated with expression in specific subclasses of DRG neurons.

In the CNS, the central axon terminals of primary afferent neurons release neurotransmitters in the dorsal horn of the spinal cord. Like most neurons in the CNS, Aδ and C fiber nociceptors use glutamate as their fast neurotransmitter. Glutamate binds to ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptors, as well as to metabotropic glutamate receptors expressed in the dorsal horn. AMPA receptors produce fast excitatory postsynaptic potentials that signal the onset, intensity, duration, and location of peripheral noxious stimulation. More-intense or sustained activation of C fiber nociceptors also results in the release of neuropeptide neuromodulators, such as substance P and the calcitonin-gene-related peptide (CGRP), which produce slow synaptic potentials via the neurokinin 1 receptor (NK1R) and the CGRP-1 and CGRP-2 receptors, respectively. The presence of these peptides enables considerable use-dependent functional plasticity in the control of pain transmission, since their release typically follows high-intensity stimulation (Schaible 2004; for a review, see Bingham et al. 2009).

Presynaptic voltage-gated calcium channels, such as CaV2.2, contribute substantially to controlling neurotransmitter release from synaptic vesicles in the dorsal horn. Neurotransmitter release is also regulated by presynaptic inhibition produced by the neurotransmitter γ-aminobutyric acid (GABA) acting on GABA_A ion channels and GABA_B receptors. Other presynaptic inhibitory receptors include the cannabinoid receptor 1 (CB1) and the three opioid receptors μ, δ, and κ. GABA also induces postsynaptic inhibition in dorsal horn neurons comparable to that caused by the neurotransmitter glycine (Woolf and Salter 2000). Each of the elements involved in the regulation of spinal neurotransmitter release constitutes potential targets for pain pharmacotherapy.

Multiple molecular mechanisms have been associated with producing the sensation of pain many of which have been largely developed through the use of genetic manipulations. These signaling pathways involve many molecular components that could potentially be targets for pharmacotherapeutic intervention, but the complexity of these systems might also mean that multiple sites must be affected simultaneously to disrupt propagation of pain signals or restore homeostatic conditions. This makes the idea of a “silver bullet” for the treatment of pain all the more challenging.

Gender differences are a hallmark of pain perception, particularly visceral pain; however, little is known about the biological causes of these differences (Fillingim 2000; Keogh 2009, see also Keogh 2011). Recent studies have shown that estrogen receptors located on nociceptive neurons in the spinal cord play an important role in the sexually differentiated responses of these neurons to nociceptive visceral stimuli (Al-Chaer, unpublished observations). Similarly gender differences have been reported in the cortical representation of pain. Activation in the sensory–motor and parieto-occipital areas is common in both males and females following rectal distension; however, greater activation in the anterior cingulate/prefrontal cortices has been found in women (Kern et al. 2001). These actual gender differences in the processing of sensory input substantiate reports that perceptual responses are exaggerated in female patients with chronic pain.

Translational research in the immediate and extended future can be expected to maintain ongoing progress in each of the following areas:

However, given the immediate need for pain relief in severe conditions refractory to conventional treatment and the reported success, albeit anecdotal, of many alternative and complementary therapies, focused research on the mechanisms of these therapies is likely to yield beneficial results in the immediate future.