**4. Primary afferent nociceptors as target in modulation of nociception**

Visceral nociceptive signal transduction depends on type of pain (type of sensory fiber), severity, duration and effects of other endogenous nociceptive-mediated molecules. Extrinsic primary afferent fibers can be directly modulated by activation of different chemosensitive or mechanosensitive receptors in target organs. There are 31 pairs of polymodal nerves carrying sensory motor and autonomic signal transduction in human spinal cord. This information is further transferred to the CNS by the spinothalamic ascending pathways to the primary sensory motor cortex for integration and analysis. In DRG neurons, afferent and efferent processes function as a single axon-proximal and distal part connected to somata as an offshoot. DRG first synapses with a dorsal horn neuron through the contralateral spinothalamic tract. These primary sensory neurons have been studied intensively in pain sensory physiology. Smallto-medium size DRG neurons express a variety of receptors involved in pain perception such as ATP-sensitive P2X3, capsaicin-sensitive TRPV1 or acid-sensitive ASIC channels. Since DRG neurons are responsive to estrogen [10] through ERα type [11] and show sensitization, it makes them a suitable model to study gender differences in nociception. Interestingly, TRPV1 and P2X3 transduction is significantly altered during inflammatory response. DRG is also an important site for primary afferent fiber convergence and visceral organ cross-sensitization. Even the role of DRG in neuromodulation of nociception is a novel topic in visceral and chronic pain, we hope to convince the scientific community that the DRG is an active structure rather than passive. The future studies may reveal more neuroplastic changes at the level of first-order sensory neurons. New hypotheses will drive translational research that should improve the outcomes of clinical interventions to relive patients from suffering.

Pelvic pain is very subjective and thus difficult to standardize for any scientific modeling since its etiology affects different systems. In addition to nervous, urinary, gastrointestinal, reproductive and psychological systems are involved. Nociceptive behavior is highly complex: the affective experience leads to avoidance and often protective escape. New data will hopefully lead to the development of effective gender-specific therapies. Involvement of peripheral nervous system in mediating and/or regulating chronic visceral pain associated with nociception through structural and physiological changes at the level of DRG is confirmed. The new principle of neuroplasticity at the level of peripheral nervous system is important to understand the etiology of many chronic diseases associated with visceral pain (**Figure 1**). Peripheral sensitization at the level of primary afferent neurons (pain generator) leads to neuroplastic changes with major structural alterations. The observation that 17β-estradiol increased survival of DRG neurons [13] put this sex steroid hormone as potential neuroplastic modulator of sensory afferent neurons. Estradiol may act as transmitter molecule by changing excitability of DRG [14]. DRG neuroplasticity also contributes to hyperalgesia [15]. Noteworthy, treating pain can restore normal nervous system function. As with all new stories, the unusual concept gets most attention of medical and clinical communities. We convey the message by driving translational science into the new horizon and propose a multicomponent conceptual model of neuroplasticity associated with functional disorders.

**Figure 1.** Conceptual model of regulatory mechanisms mediating neuroplasticity of visceral nociception at the level of

Neuroplasticity of Primary Sensory Neurons in Visceral Nociception

http://dx.doi.org/10.5772/intechopen.73699

5

This work is supported by National Institute of Health grant: SC1 NS 063939 (PI—Victor

1 Department of Internal Medicine, Charles R. Drew University of Medicine and Science,

**Acknowledgements**

primary afferent sensory neurons.

Chaban).

USA

**Author details**

Victor V. Chaban1,2\*

\*Address all correspondence to: victorchaban@cdrewu.edu

2 Department of Medicine, University of California, Los Angeles, USA

### **5. Discussion**

Pain is a complex and personal experience. Chronic visceral pain affects mood, and social and professional life. A delicate balance between biochemical and physiological changes and cognitive approaches is the most appropriate strategy to study clinical aspects of nociception. Pain in women can originate due to inflammation of a pelvic organ (gut, uterus and bladder) that can heighten the sensitivity of noninflamed organ that are innervated by the same afferent neuronal pathway [12]. Commonly, the overlapping of pelvic pain occurs between the lower gut, uterus and urinary bladder. Common convergence of different visceral primary afferents onto one spinal secondary neuron transmitting signals to the supraspinal nuclei can either synthesize or attenuate intrinsic cellular functions via activation of P2X<sup>3</sup> receptors by ATP and TRPV1 receptors by capsaicin within the L1 -S3 DRG neurons. Furthermore, in addition to ATP, prostaglandin E2 (PGE2) is synthesized and realized during distention and contributes to hyperalgesia. We showed that PGE2 enhanced calcium responses induced by pronociceptive molecules such as ATP and capsaicin [2]. Together, our studies opened up a new paradigm of neuroplasticity: modulation of primary sensory neurons by sex steroids that may lead to structural changes within DRG. Estrogen can gate primary afferent nociceptors to enhance or decrease nociception.

**Figure 1.** Conceptual model of regulatory mechanisms mediating neuroplasticity of visceral nociception at the level of primary afferent sensory neurons.

Pelvic pain is very subjective and thus difficult to standardize for any scientific modeling since its etiology affects different systems. In addition to nervous, urinary, gastrointestinal, reproductive and psychological systems are involved. Nociceptive behavior is highly complex: the affective experience leads to avoidance and often protective escape. New data will hopefully lead to the development of effective gender-specific therapies. Involvement of peripheral nervous system in mediating and/or regulating chronic visceral pain associated with nociception through structural and physiological changes at the level of DRG is confirmed. The new principle of neuroplasticity at the level of peripheral nervous system is important to understand the etiology of many chronic diseases associated with visceral pain (**Figure 1**). Peripheral sensitization at the level of primary afferent neurons (pain generator) leads to neuroplastic changes with major structural alterations. The observation that 17β-estradiol increased survival of DRG neurons [13] put this sex steroid hormone as potential neuroplastic modulator of sensory afferent neurons. Estradiol may act as transmitter molecule by changing excitability of DRG [14]. DRG neuroplasticity also contributes to hyperalgesia [15]. Noteworthy, treating pain can restore normal nervous system function. As with all new stories, the unusual concept gets most attention of medical and clinical communities. We convey the message by driving translational science into the new horizon and propose a multicomponent conceptual model of neuroplasticity associated with functional disorders.

## **Acknowledgements**

**4. Primary afferent nociceptors as target in modulation of** 

of clinical interventions to relive patients from suffering.

by ATP and TRPV1 receptors by capsaicin within the L1

enhance or decrease nociception.

Visceral nociceptive signal transduction depends on type of pain (type of sensory fiber), severity, duration and effects of other endogenous nociceptive-mediated molecules. Extrinsic primary afferent fibers can be directly modulated by activation of different chemosensitive or mechanosensitive receptors in target organs. There are 31 pairs of polymodal nerves carrying sensory motor and autonomic signal transduction in human spinal cord. This information is further transferred to the CNS by the spinothalamic ascending pathways to the primary sensory motor cortex for integration and analysis. In DRG neurons, afferent and efferent processes function as a single axon-proximal and distal part connected to somata as an offshoot. DRG first synapses with a dorsal horn neuron through the contralateral spinothalamic tract. These primary sensory neurons have been studied intensively in pain sensory physiology. Smallto-medium size DRG neurons express a variety of receptors involved in pain perception such as ATP-sensitive P2X3, capsaicin-sensitive TRPV1 or acid-sensitive ASIC channels. Since DRG neurons are responsive to estrogen [10] through ERα type [11] and show sensitization, it makes them a suitable model to study gender differences in nociception. Interestingly, TRPV1 and P2X3 transduction is significantly altered during inflammatory response. DRG is also an important site for primary afferent fiber convergence and visceral organ cross-sensitization. Even the role of DRG in neuromodulation of nociception is a novel topic in visceral and chronic pain, we hope to convince the scientific community that the DRG is an active structure rather than passive. The future studies may reveal more neuroplastic changes at the level of first-order sensory neurons. New hypotheses will drive translational research that should improve the outcomes

Pain is a complex and personal experience. Chronic visceral pain affects mood, and social and professional life. A delicate balance between biochemical and physiological changes and cognitive approaches is the most appropriate strategy to study clinical aspects of nociception. Pain in women can originate due to inflammation of a pelvic organ (gut, uterus and bladder) that can heighten the sensitivity of noninflamed organ that are innervated by the same afferent neuronal pathway [12]. Commonly, the overlapping of pelvic pain occurs between the lower gut, uterus and urinary bladder. Common convergence of different visceral primary afferents onto one spinal secondary neuron transmitting signals to the supraspinal nuclei

addition to ATP, prostaglandin E2 (PGE2) is synthesized and realized during distention and contributes to hyperalgesia. We showed that PGE2 enhanced calcium responses induced by pronociceptive molecules such as ATP and capsaicin [2]. Together, our studies opened up a new paradigm of neuroplasticity: modulation of primary sensory neurons by sex steroids that may lead to structural changes within DRG. Estrogen can gate primary afferent nociceptors to


can either synthesize or attenuate intrinsic cellular functions via activation of P2X<sup>3</sup>

**nociception**

4 Neuroplasticity - Insights of Neural Reorganization

**5. Discussion**

This work is supported by National Institute of Health grant: SC1 NS 063939 (PI—Victor Chaban).
