Based on reports from the International Association for the Study of Pain (IASP), pain is defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage’’ and varies with the subject’s emotional status (Raja et al., 2020). Pain can be characterized by its duration as either acute or chronic. In contrast to chronic pain, acute pain is considered a potent protective mechanism of the body to avoid potential damage and protect wounded tissue (Matsuda et al., 2019). Acute pain may also be differentiated from chronic pain by its rapid onset and short duration. Chronic pain lasts or reoccurs for more than a three-month period (Bonezzi et al., 2020). Pain can also be classified as neuropathic, nociceptive, or inflammatory, depending on its etiology. Neuropathic pain is pain resulting from a somatosensory nervous system lesion, while nociceptive pain is the response to the stimulation of nociceptors by noxious stimuli and its transmission to the central nervous system (CNS) (Finnerup et al., 2021). On the other hand, inflammatory pain results from increased sensitivity due to the stimulation of sensory neurons by inflammatory mediators (Prescott et al., 2017).

NO has numerous roles in pain modulation on both the central and peripheral level. NO is a signaling molecule synthesized from L-arginine, which then produces L-citrulline and NO through nitric oxide synthase (NOS) activity (Cury et al., 2011). NOS has three isoforms: neuronal NOS (nNOS), inducible NOS (iNOS) and endothelial NOS (eNOS) (K. Chen et al., 2010). It is known that nNOS and eNOS are found in the brain and dependent on Ca2+-calmodulin. In contrast, iNOS is always active and involved in inflammation (Freire et al., 2009). Activation of N-methyl-D-aspartic acid (NMDA) receptors by glutamate in spinal cord dorsal horns leads to synthesis of NO. NO acts as a neurotransmitter on nerve endings and activates guanylyl cyclase (GC) to increase cyclic guanosine 3’, 5’- monophosphate (cGMP) (Cury et al., 2011).

The interaction between hormones and pain is a complex and unsettled process, despite multiple studies investigating this topic (refer to Table 1 for animal models exploring the role of NO in this relationship). Pain generation and modulation can be explained through the effects of multiple hormones, including adrenocorticotropin (ACTH), the growth hormone (GH), calcitonin (CT), sex hormones, melatonin, vasopressin, and hormones involved in the renin-angiotensin-aldosterone system (RAAS) (X. Chen et al., 2016). Pain can be identified both as the stressor and consequence of stress. In both scenarios, the hypothalamus is stimulated and results in the secretion of corticotropin releasing hormone (CRH) and vasopressin, which further promotes the secretion of ACTH from the pituitary (G. Blackburn-Monro et al., 2003). Numerous studies have demonstrated that the resulting cortisol release can have a protective or injurious role, depending on whether the stressor is present in the short term or whether maladaptive responses occur (Hannibal et al., 2014). All the mentioned hormones indirectly affect supraspinal regions of pain pathways, such as the somatosensory cortex, amygdala, hypothalamus, periaqueductal gray matter (PAG) and nucleus accumbens (NAc) (Yang et al., 2019).

Pain mechanisms can be explained on a molecular, hormonal, central, and/or peripheral level, as they are intricate components of a multifaceted sensory system. This article aims to describe the relationship between nitric oxide and hormone signaling included in pain generation and modulation.