Non-Opioid Analgesic Studies Presented at the Society for Neuroscience Annual Meeting

Opioid analgesics, despite being effective on a number of pain modalities, are associated with serious adverse effects that include respiratory depression and addiction. The rise of the “opioid epidemic” has prompted the search for non-opiate analgesics with similar effectiveness, but increased safety.

At this year’s Society for Neuroscience annual meeting in San Diego, California, several studies presented such alternatives. Here are some of the most notable.

Placebo Analgesia for Neuropathic Pain

A study led by researchers from the Riken Center for Life Science Technologies in Kobe, Japan, investigated the mechanisms underlying placebo analgesia, and in particular, whether this phenomenon could be modulated in animals using Pavlovian conditioning.¹

Although an extensive body of work has established the neuroanatomical basis of placebo hypoalgesia and analgesia, consisting of a hierarchical recurrent system, little is known regarding the molecular mechanisms of these phenomena.²

In the study presented at the conference, neuropathic pain was induced in mice through the ligation of lumbar spinal nerves 5 and 6. The animals were then conditioned, using the analgesic gabapentin as the unconditioned stimulus.

Animal training consisted of pairing the gabapentin injection with a conditioned stimulus. Upon repeating such pairing, saline injections also resulted in placebo analgesia. This effect was abolished by administration of the µ-opioid receptor antagonist naloxone (5 mg/kg IP).

Small animal neuroimaging revealed that the medial prefrontal and anterior insular cortices of animals experiencing placebo analgesia were activated, when compared to animals that had also undergone conditioning and had been administered naloxone, whereas activity in the primary somatosensory and motor cortices was inhibited in the former.

Researchers concluded from these results, that Pavlovian conditioning could trigger placebo analgesia.

Curcumin for Burn Pain

Thermal injury leads to activation of inflammatory signaling pathways, resulting, among other events, in the phosphorylation of p38 Mitogen-Activated Protein Kinase (MAPK) and Nuclear Factor κB (NF-κB).

A group of scientists at the US Army Institute for Surgical Research in San Antonio, Texas, sought to investigate whether curcumin, an ingredient of Curcuma longa or turmeric, had analgesic properties, as assessed by inhibition of inflammatory pathways in a cell line derived from human keratinocytes, HaCaT.

Cultured HaCaT cells subjected to heat shock (20 min at 45 or 55⁰C) were treated with curcumin (100 µM for 24 h). This treatment inhibited basal NF-κB phosphorylation as well as heat shock-induced p38 MAPK phosphorylation.

In addition, daily subcutaneous injection of curcumin over a 5 day period (100 µg/100ul vehicle) reduced both thermal hyperalgesia and mechanical allodynia after 2 and 4 days, in rats subjected to full thickness thermal injury in their hindpaw, as a way to model burn pain. These analgesic effects of curcumin were observed in the ipsi- but not contra-lateral hindpaw, suggesting a local vs central action of the compound.

An in vitro assay was developed using tissue from dental pulp biopsies as a way to “evaluate the responsiveness of isolated human nociceptors, by measuring basal and stimulated release of neuropeptides.”⁴ In this system, capsaicin treatment—used to induce allodynia—led to the release of calcitonin gene-related peptide (CGRP) from the peripheral tissue.

Pre-treating the tissue with curcumin (100 µg/100ul vehicle) inhibited capsaicin-induced release of CGRP, suggesting that the compound may be effective to alleviate burn-associated pain.

Light Therapy for Acute and Chronic Pain

Rats subjected to noxious thermal stimuli–as a way to model neuropathic pain–were found to have increased latency of paw withdrawal when exposed to green light emitting diode ([LED], 525 nm, 8 h/day for 5 days), when compared to animals not exposed to LED, according to a study presented by researchers from the department of Anesthesiology at the University of Arizona in Tucson.⁵

This antinociceptive effect of LED was still observed for 4 days following the 5 day-long exposure to the LED, and was found to be mediated by stress-independent central pathways acting through the µ-opioid receptors.

Inactivating the ventromedial medulla to block pain pathways, or blocking rats from the LED light with opaque contacts, both inhibited LED-mediated antinociception. In addition, neither rats wearing green contacts and exposed to room light, nor rats with pigmentation, displayed behavior indicative of antinociception, leading the authors to implicate the visual system in this effect.

Dorsal root ganglia (DRG) host the cell bodies of neurons mediating pain information; proteomic profiling of DRG neurons revealed that rats exposed to LED had reduced expression of N-type calcium channels, inhibition of which leads to alleviation of chronic and neuropathic pain.⁶

Green LED was also effective in reversing both thermal and mechanical hyperalgesia in rat models of neuropathic pain, obtained through ligation of spinal nerves or injection of the HIV-1 envelope glycoprotein 120.

The researchers concluded that green LED therapy may offer an effective, non-pharmacologic option for the management of chronic pain.

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References

1. Cui YL, Zeng Y, Zeng Q, Hu D, Yang W, Hayashinaka E, Wada Y, Watanabe Y. Small-animal neuroimaging analysis of placebo analgesia.Presented at: Society for Neuroscience 2016. November 12-16, 2016; San Diego, CA. Abstract 617.01.
2. Büchel C, Geuter S, Sprenger C, Eippert F. Placebo analgesia: a predictive coding perspective. Neuron. 2014;81(6):1223-1239.
3. Clifford JL, Cheppudira BP, Trevino A, Greer A, Salas MM. Curcumin is an effective analgesic for burn pain: evidence from animal and human tissue based experiments. Presented at: Society for Neuroscience 2016. November 12-16, 2016; San Diego, CA. Abstract 617.05.
4. Fehrenbacher JC, Sun XX, Locke EE, Henry MA, Hargreaves KM. Capsaicin-evoked iCGRP release from human dental pulp: a model system for the study of peripheral neuropeptide secretion in normal healthy tissue. Pain. 2009;144(3):253-261.
5. Ibrahim MM, Gilbraith KB, Moutal A, Yang X, Chew L, Milnes-Largent T, Porreca F,  Malan TP,  Vanderah TW,  Patwardhan A,  Khanna R. Antinociceptive effects of light therapy on acute and chronic pain models. Presented at: Society for Neuroscience 2016. November 12-16, 2016; San Diego, CA. Abstract 617.09.
6. Snutch TP. Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx. 2005;2(4):662-670.