Intrathecal Clonidine Reduces Hypersensitivity After Nerve Injury by a Mechanism Involving Spinal m4 Muscarinic Receptors

Abstract

Neuraxial clonidine is an effective adjunct in the treatment of neuropathic pain and increases acetylcholine concentrations in cerebrospinal fluid in humans. These data in animals suggest that spinal m4 type muscarinic receptors are important to the effect of clonidine in treating hypersensitivity to touch after nerve injury.

Neuronal nitric oxide synthase is upregulated in a subset of primary sensory afferents after nerve injury which are necessary for analgesia from α2-adrenoceptor stimulation

“…Other studies support a role for M4 muscarinic receptors in analgesia from cholinergic agonists [7], and M4 receptor blockade antagonizes clonidine efficacy after peripheral nerve injury [12]. The current study adds to radioligand binding [11] and Western blot [12] studies by demonstrating a lack of change in location, as well as expression level, of M4 receptors in spinal cord after nerve injury. We conclude, therefore, that the novel dependency of α2-AR analgesia on cholinergic mechanisms after nerve injury does not reflect a change in location or expression of M4 receptors.…”

“…M2-IR increases in uninjured (L4 level) and injured (L5 and L6 level) primary afferent neuronal cell bodies after spinal nerve ligation, as does the ability of the muscarinic agonist, bethanechol, to inhibit excitation of these cells [10]. Other studies support a role for M4 muscarinic receptors in analgesia from cholinergic agonists [7], and M4 receptor blockade antagonizes clonidine efficacy after peripheral nerve injury [12]. The current study adds to radioligand binding [11] and Western blot [12] studies by demonstrating a lack of change in location, as well as expression level, of M4 receptors in spinal cord after nerve injury.…”

“…Spinally released acetylcholine produces analgesia primarily by actions on M2 and M4 receptors [7]. We previously showed that analgesia from intrathecal injection of the α2-AR agonist, clonidine after nerve injury was partially blocked by a highly selective toxin to M4 receptors [12]. A final purpose of the current study was to determine whether nerve injury altered the expression of M4 receptors in the spinal cord and whether blockade of α2-AR agonist analgesia by destruction of p75 NTR expressing cells altered M4 receptor expression.…”

Alleviation of chronic pain following rat spinal cord compression injury with multimodal actions of huperzine A

“…infusion; in future studies atropine's impact also should be measured earlier, at the peak effect time of HUP-A treatment. Our result suggests that HUP-A has a cholinergic inhibitory action on DH pain transmission, possibly through the activation of M2 and M4 mAChRs on GABAergic inhibitory interneurons that mitigate the release of primary afferent-derived glutamate in the DH (15,16). The decrease in nociceptive neurotransmission likely was mediated also by the observed immunoreactivity decrease in substance P from primary afferents onto second-order DH neurons (Fig.…”

“…1D) (13), might be an exceptional prospect for multimodal treatment of SCI-induced neuropathic pain. We tested whether HUP-Aderived NMDA blockade and the overall HUP-A-derived augmentation of cholinergic neurotransmission arising from AChE inhibition might be harnessed specifically to stage a multifocal intervention in post-SCI pain pathways because (i) antagonism of NMDA receptor prevents the post-SCI hyperexcitability of neurons in the dorsal horn (DH) of the spinal cord that feature a wide, dynamic range of pain transmission (7); (ii) activation of presynaptic α3β2 nicotinic ACh receptors (nAChR) minimizes release of glutamate from C-fiber terminals in the DH that are involved in nociceptive neurotransmission (14); (iii) activation of GABAergic interneurons via stimulation of their M2 and M4 muscarinic ACh receptors (mAChR), in turn, inhibits presynaptic release of glutamate from primary afferent axons (15,16); (iv) activation of the α4β2 nAChR on GABAergic inhibitory interneurons mitigates the firing of secondary spinothalamic pain transmission neurons (17); and (v) stimulation of the α7 nAChR on microglial cells blocks their activation, ameliorating neuroinflammation (18,19). The primary goal of our study is to develop a class of therapeutics for the management of chronic neuropathic Significance Neuropathic pain, one of the most debilitating sequelae of neurotrauma, is an unmet clinical need for at least 40% of patients with spinal cord injury (SCI).…”