Intervention with Spinal NMDA, Adenosine, and NO Systems for Pain Modulation

Abstract

Understanding of the complex pharmacology of the spinal cord may lead to rational advances in pain treatment. It appears that a number of specific neurochemical mechanisms exist, by which spinally administered receptor selective agents may modify nociceptive transmission. Spinal administration of pure competitive N-methyl-D-aspartate (NMDA) antagonists affects only hyperpathic pain components, i.e. with signs of central sensitization, and most probably has a very limited role in postoperative pain treatment. On the other hand, it is well established that the non-competitive NMDA-antagonist ketamine gives good postoperative analgesia, probably by cerebral mechanisms also affecting other sensory modalities. Pure adenosine A1-receptor agonism at the spinal level mainly affects sensory allodynia to vibration, and is probably no alternative for postoperative pain treatment. In contrast, i.v. infusions of the non-selective A1/A2-receptor agonist adenosine given during a surgical procedure seem to decrease postoperative pain and requirements for postoperative analgesia. This apparent contradiction must be analysed further. Several drugs commonly used to treat postoperative pain, such as opioids, NSAIDs, ketamine and paracetamol, are linked to nitric oxide (NO) in their mechanism of action. The biosynthesis of NO in the central nervous system (CNS) is tonically involved in the nociceptive processing.

Comparative trial of botulinum toxin type A and methylprednisolone for the treatment of tension-type headache

“…It is postulated that BTX-A acts directly on affected pericranial muscles, causing relaxation and, thus, reduction in pain. In addition, BTX-A may also act on afferent pathways, affecting pain perception and, thereby indirectly relieving pain [36,37].…”

The Role of Adenosine Signaling in Headache: A Review

“…Adenosine A 1 receptors have been found to play a vital role in the adenosine-induced antinociceptive effects of acupuncture in mice where adenosine A 1 knock-out mice did not experience the anti-nociceptive effects of acupuncture in an inflammatory or neuropathic pain model [71]. Intrathecal injection of an adenosine A 1 agonist in humans decreased postoperative pain [72]. Interestingly, intrathecal injection of adenosine (i.e., non-subtype specific action) prevents post-operative pain but causes headache, suggesting that other adenosine receptor subtypes may play an opposing role in headache when compared to other forms of pain [73,74].…”

A1adenosine receptor agonists and their potential therapeutic applications

“…Evidence suggests that agonism at the A 1 -AdoRs may provide benefit for the following disease states: paroxysmal supraventricular tachycardia (PSVT) -break the atrial arrhythmia to return to sinus rhythm [7][8][9][10] ; atrial fibrillation (AF) -provide ventricular rate control [11][12] ; type 2 diabetes (T2D) -lower NEFA, TGs and enhancing insulin sensitivity [13][14][15][16] ; dental and neuropathic pain [17][18][19] ; and angina [20][21][22] . The A 1 -AdoR is found in the atrio-ventricular (AV) and sino-atrial (SA) nodes, where stimulation by an A 1 -AdoR agonist results in negative dromotropic and chronotropic effects, respectively [9,23] .…”