The role of the endogenous neurotransmitters associated with neuropathic pain and in the opioid crisis: The innate pain-relieving system

Highlights

• Role of endogenous transmitters and receptors in the innate pain-relieving system.

• Demand for pain-relieving medicines has significantly increased.

• The number of analgesic drugs available for chronic pain is limited.

• Major public health concern because of opioid crisis in the USA and Canada.

Abstract

Neuropathic pain is a chronic pain caused by central and peripheral nerve injury, long-term diabetes or treatment with chemotherapy drugs, and it is dissimilar to other chronic pain conditions. Chronic pain usually seriously affects the quality of life, and its drug treatment may result in increased costs of social and medical care. As in the USA and Canada, in Europe, the demand for pain-relieving medicines used in chronic pain has also significantly increased, but most European countries are not experiencing an opioid crisis.

In this review, the role of various endogenous transmitters (noradrenaline, dopamine, serotonin, met- and leu-enkephalins, β-endorphin, dynorphins, cannabinoids, ATP) and various receptors (α₂, μ, etc.) in the innate pain-relieving system will be discussed. Furthermore, the modulation of pain processing pathways by transmitters, focusing on neuropathic pain and the role of the sympathetic nervous system in the side effects of excessive opioid treatment, will be explained.

Introduction

Pain is defined as an unpleasant sensory experience, and it is classified mainly based on pain duration, i.e., acute or chronic pain, and as physiological (nociceptive) or pathological pain. This classification indicates that pain is always subjective and has an emotional component.

Neuropathic pain is a chronic pain caused by central and peripheral nerve injury, long-term diabetes or treatment with chemotherapy drugs, and it is dissimilar to other chronic pain conditions. The International Association for the Study of Pain (IASP) recently identified neuropathic pain as “pain caused by a lesion or disease of the somatosensory system” (Jensen et al., 2011). Neuropathic pain of peripheral origin involves small unmyelinated C fibers and myelinated A fibers, namely, Aβ and Aδ fibers (Finnerup et al., 2016).

Somatosensory information is transmitted from the periphery to the spinal cord via the dorsal roots to the dorsal horn, the thalamus and finally to the primary sensory area of the cerebral cortex, resulting in pain sensation. Impairments of the somatosensory peripheral nervous system (e.g., due to diabetes or herpes) or central nervous system (CNS) (e.g., due to stroke) result in altered neurochemical transmission of sensory signals in the direction of the spinal cord and the brain and produce long-lasting pain.

Chronic pain usually seriously affects the quality of life, and its drug treatment may result in increased costs of social and medical care. In addition, in the USA, there is an enormous annual economic burden of medical treatment for acute and chronic pain and lost productivity (635 billion US$; Committee on Advancing Pain Research, 2011) (Nahin, 2015). Among the drugs used for the treatment of various types of pain (opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), selective COX2 inhibitors, antiepileptics, antidepressants, anticonvulsants and local anesthetics) (Rang et al., 2012), there is another social and clinical problem: the opioid crisis produced by the treatment of chronic pain with an overdose of opioids (Skolnick, 2018a,b). The main problem with opioid treatment is the tolerance and physical dependence that may occur in response to prolonged administration (Stein, 2016). Since 1999, the number of deaths from prescription opioids in the USA has increased by 400 % (www.cdc.gov/drugoverdose/epidemic February 1, 2017). Canada is also experiencing an opioid crisis. As in the USA and Canada, in Europe, the demand for pain-relieving medicines has also significantly increased, but most European countries are not experiencing an opioid epidemic. This difference might be because American doctors write five and half times more opioid prescriptions than their European colleagues (DeWeerdt, 2019). According to statistical surveys conducted by the IASP, approximately 20 % of Europeans suffer from chronic pain, and there is a similar prevalence in the USA.

Despite the progress made in preclinical studies and in the understanding of the mechanisms of nociception, the number of analgesic drugs available for chronic conditions, such as neuropathic pain, remains limited (Woolf, 2010).

There are several excellent reviews regarding the pharmacological management of chronic pain (Wozniak et al., 2012; Finnerup and Attal, 2016; Finnerup et al., 2016; Martikainen et al., 2018). In this article, however, we review the role of various endogenous transmitters in the modulation of pain processing pathways, focusing on chronic pain, such as neuropathic pain, and their role in the side effects of excessive opioid treatment.