Differential Modulation of Nociceptive versus Non-Nociceptive Synapses by Endocannabinoids

Abstract

BackgroundAlthough a number of clinical and preclinical studies have demonstrated analgesic effects of cannabinoid treatments, there are also instances when cannabinoids have had no effect or even exacerbated pain. The observed pro-nociceptive effects appear to be due to cannabinoid-induced disinhibition of afferent synaptic input to nociceptive circuits. To better understand how cannabinoid-mediated plasticity can have both pro- and anti-nociceptive effects, we examined the possibility that cannabinoids differentially modulate nociceptive vs. non-nociceptive synapses onto a shared postsynaptic target. These experiments were carried out in the central nervous system (CNS) of the medicinal leech, in which it is possible to intracellularly record from presynaptic nociceptive (N-cell) or pressure-sensitive (P-cell) neurons and their shared postsynaptic targets.ResultsThe endocannabinoid 2-arachidonoyl glycerol (2AG) elicited significant long-lasting depression in nociceptive (N-cell) synapses. However, non-nociceptive (P-cell) synapses were potentiated following 2AG treatment. 2AG-induced potentiation of non-nociceptive synapses was blocked by the TRPV antagonist SB366791, suggesting involvement of the same TRPV-like receptor that has already been shown to mediate endocannabinoid-dependent depression in nociceptive inputs. Treatment with the GABA receptor antagonist bicuculline also blocked 2AG-induced potentiation, consistent with the idea that increased synaptic signaling was the result of endocannabinoid-mediated disinhibition. Interestingly, while bicuculline by itself increased non-nociceptive synaptic transmission, nociceptive synapses were depressed by this GABA receptor antagonist indicating that nociceptive synapses were actually excited by GABAergic input. Consistent with these observations, GABA application depolarized the nociceptive afferent and hyperpolarized the non-nociceptive afferent.ConclusionsThese findings show that endocannabinoids can differentially modulate nociceptive vs. non-nociceptive synapses and that GABAergic regulation of these synapses plays an important role in determining whether endocannabinoids have a potentiating or depressing effect.

Differential effects of GABA in modulating nociceptive vs. non-nociceptive synapses

“…2A, B; t = 9.28, P < 0.001; N = 5 for treatment and control groups; N cell responses: Fig. 2C, D; t = 9.96 P < 0.001; N = 6 for treatment and control groups), again consistent with previous findings (Higgins et al, 2013). In two out of the five P cell recordings, a delayed (>500 ms) depolarization was also observed following the initial GABA-elicited hyperpolarization.…”

“…In agreement with our previous study (Higgins et al, 2013) and earlier findings by others (Sargent et al, 1977), GABA focally applied to the soma via a ''puffer'' patch electrode hyperpolarized the P cell, (Fig. 2A), but depolarized the N cell (Fig.…”

“…Both N and P cells are readily identifiable afferent neurons that have glutamatergic synaptic input onto a number of shared targets, including the longitudinal (L) motor neurons that innervate the longitudinal muscles and contribute to the defensive withdrawal reflex, whole-body shortening (Nicholls and Purves, 1970;Shaw and Kristan, 1995). Previous studies have shown that while the P cell is hyperpolarized by GABA, GABA depolarizes the N cell (Sargent et al, 1977;Higgins et al, 2013). Furthermore, inhibition of GABA-A receptors with bicuculline (BIC) has opposing effects on synaptic transmission; enhancing P cell synapses (presumably due to disinhibition), but depressing N cell synapses (see Fig.…”

“…Furthermore, inhibition of GABA-A receptors with bicuculline (BIC) has opposing effects on synaptic transmission; enhancing P cell synapses (presumably due to disinhibition), but depressing N cell synapses (see Fig. 1) (Higgins et al, 2013). Because it is possible to make intracellular recordings of the individual neurons in the N-to-L and P-to-L synaptic pathways, this provides a unique opportunity to directly examine the cellular basis for the differential effects of GABA on a synaptic circuit.…”

Pain in aquatic animals

“…These nociceptors have similar properties to mammalian nociceptors including responding to multiple types of noxious, damaging stimuli, classifying them as polymodal (Pastor et al, 1996). Further studies have demonstrated that analgesic compounds and stimulation of adjacent touch receptors can reduce nociceptor activity (Higgins et al, 2013;Yuan and Burrell, 2013), the latter being comparable with gate control in mammals whereby touch modulates pain transmission (Melzack and Wall, 1965). Therefore, the physiological and molecular mechanisms may be highly conserved between aquatic invertebrates, vertebrates and terrestrial vertebrate groups (Sneddon et al, 2014).…”