Nociceptive TRP Channels and Sex Steroids

*Óscar Enciso-Pablo, Karina Angélica Méndez-Reséndiz, Tamara Rosenbaum and Sara Luz Morales-Lázaro*

### **Abstract**

Proteins belonging to Transient Receptor Potential (TRP) family are nonselective cation channels that play an essential role in mammalian physiology, functioning as transducers of several environmental signals including those of chemical, thermal and mechanical natures. A subgroup of these receptors is expressed in sensory neurons where they are activated by noxious stimuli and are key players of pain responses in the organism. Some TRP channels are molecular targets for the classical and non-classical effects of sex steroids. This chapter will describe the close relationship between nociceptive TRP channels and sex steroids as well as their impact on nociception and pain-related responses.

**Keywords:** TRP channels, nociception, steroids, pain, sensory neurons

#### **1. Introduction**

The somatosensory system is a complex network of neurons and peripheral receptors that encodes specific information about the state of organisms and their environment, providing them with the ability to detect harmful stimuli [1–3].

According to the International Association for the Study of Pain (IASP), the neuronal process encoding noxious stimuli is known as nociception. A subpopulation of high-threshold sensory neurons known as nociceptors mediates this process by detecting harmful signals from chemical and physical nature **Figure 1** [1, 4]. Nociceptors are neurons with a peripheral axonal branch that innervates cutaneous, articular and visceral afferents, and a central axonal branch that innervates the dorsal horn of the spinal cord. The cell bodies of mammalian nociceptors are located in the dorsal root ganglia (DRG) and in the trigeminal ganglia (TG) and they are classified as medium and small diameter neurons. The axons of these nociceptors are classified as Aδ- and C-fibers depending on their diameter, degree of myelinization, conduction speed and the type of sensory stimuli that they transmit [1, 4, 5].

The Aδ-fibers are characterized by 2–6 μm diameters, are myelinated and present a relatively fast conduction speed between 5 and 30 m/s. The central branch of these fibers reaches the superficial laminae of the dorsal horn. These nociceptor fibers allow the conduction of cold, pressure and heat signals [5].

Remarkably, C-fibers are the ones to mainly establish nociceptive innervation. These are unmyelinated axons with a diameter of 0.4 to 1.2 μm and a conduction speed between 0.5 and 2 m/s. C-fibers innervate laminae I and II of the dorsal horn

#### **Figure 1.**

*Nociception. Harmful stimuli are transduced along the terminal axon of specialized pseudounipolar neurons (nociceptors), which are classified as unmyelinated C fibers (red) and thinly myelinated A*δ *fibers (orange); myelinated A*β *fibers (blue) transduce innocuous stimuli. The cell bodies of these peripheral sensory neurons are located in the dorsal root ganglia and trigeminal ganglia. Nociceptors innervate the epidermis and viscera, transducing noxious stimuli through the activation of several ion channels such as members of the TRP family. Finally, the information is transmitted to second order neurons located in the dorsal horn: C fibers and A*δ *fibers mainly establish contact with neurons from layers I and II, while tactile A*β *fibers end mainly in layers III and V.*

of the spinal cord and are activated in a polymodal fashion by mechanical, thermal (noxious cold or heat) and chemical stimuli [4, 5].

Diverse injurious stimuli detected by nociceptors are transformed into electrical activity, a process known as transduction where thermal, mechanical, or chemical signals are converted into ion flux through the activation of specialized ion channels [1]. In this way, noxious signals trigger fluctuations in the electrochemical gradient of nociceptors leading to membrane depolarization and subsequent action potentials, as a direct consequence of changes in the activation of ion channels expressed in the nociceptors [6]. Action potentials reach second-order neurons housed in the superficial laminae of the dorsal horn that project towards the spinothalamic and/or spinoparabrachial tracts contributing to the perception of noxious stimuli [2, 3, 7].

The study of the impact of sex steroids on the processing of noxious stimuli has been relevant to our understanding of the underlying differences between females and males. In the last decades, growing evidence related to sexual dimorphism in the perception of harmful signals and the development of pain conditions has been highlighted [8]. Several studies in humans using mechanical, chemical, electrical, or thermal stimuli have suggested that women have more sensitivity to some noxious stimuli than men [8–11]. However, other contrasting reports have concluded that there is no difference in nociception between genders [12, 13]. Even though these differences are still not clear, the most reasonable explanation pinpoints sex steroids as the most relevant effectors. For example, some conditions such as headache, back and temporomandibular pain increase with pubertal development in girls, where the gonadal steroids produce crucial changes in women physiology [14]. Remarkably, differences in the perception of thermal stimuli between different sexes have also been reported, suggesting that women have greater sensitivity to heat than men [15]. In relation to this, an epidemiological study indicated that low testosterone concentrations in women are associated with an increase in the sensation of cold [16], clearly suggesting that steroids influence nociception.
